Lung cancer - PDF

     Textbook of

Second Edition

          Edited by
Heine Hansen
       Published in association with
the European Society for Medical Oncology
Textbook of Lung Cancer
Textbook of Lung Cancer
        Second Edition
                Edited by

      Heine Hansen MD FRCP
              Finsen Center
        National University Hospital
© 2008 Informa UK Ltd

First published in the United Kingdom in 2000

Second edition published in the United Kingdom in 2008 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ.
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     List of Contributors                                                              vii
     Preface                                                                           xi
     Color plate                                                                      xiii
 1. Etiology of lung cancer                                                             1
    Aage Haugen, Steen Mollerup
 2. Epidemiology of lung cancer: a century of great success and ignominious failure    10
    Peter Boyle, Sara Gandini, Nigel Gray
 3. Molecular biology of lung cancer                                                   20
    Thomas Tuxen Poulsen, Hans Skovgaard Poulsen, Helle Pappot
 4. Tobacco policy                                                                     35
    Nigel Gray
 5. Smoking cessation programs                                                         41
    Philip Tønnesen
 6. Current status of lung cancer screening                                            53
    James L Mulshine
 7. Histopathology of lung tumors                                                      61
    Elisabeth Brambilla, Sylvie Lantuejoul
 8. Clinical diagnosis and basic evaluation                                            75
    John J Mullon, Eric J Olson
 9. Staging, classification, and prognosis                                             97
    Michael Dusmet, Peter Goldstraw
10. Treatment of non-small cell lung cancer
     10.1 Treatment of NSCLC: surgery                                                 123
          Robert J Korst
     10.2 Treatment of NSCLC: radiotherapy                                            136
          Merideth MM Wendland, William T Sause
vi Contents

        10.3 Treatment of NSCLC: chemotherapy                                      147
             Athanasios G Pallis, Sophia Agelaki, Vassilis Georgoulias
  11. Treatment of small cell lung cancer
        11.1 Treatment of SCLC: surgery                                            170
             Hisao Asamura, Riken Kawachi
        11.2 Treatment of SCLC: radiotherapy                                       177
             Christopher M Lee, William T Sause
        11.3 Treatment of SCLC: chemotherapy                                       184
             Heine H Hansen, Morten Sørensen
  12.   Malignant mesothelioma                                                     190
        Bruce Robinson, Anna Nowak, Cleo Robinson, Jenette Creaney
  13. Summary of treatment                                                         207
      Heine H Hansen
  14. Therapeutic bronchoscopy for palliation of lung tumors                       210
      Paul WA Kunst, Pieter E Postmus, Thomas G Sutedja
  15. Complications of lung cancer                                                 218
      Vincenzo Minotti, Michele Montedoro, Maurizio Tonato
  16. Quality of life and supportive care                                          236
      Jean-Paul Sculier, Anne–Pascal Meert, Marianne Paesmans, Thierry Berghmans
  17. The cost and cost-effectiveness of lung cancer management                    247
      William K Evans, Christopher J Longo
  18.   The future                                                                 264
        Giovanni Selvaggi, Giorgio Vittorio Scagliotti

        Appendix: Chemotherapy                                                     275
        List of drugs                                                              331
        Index                                                                      333

Sophia Agelaki MD                             Jenette Creaney MD
Department of Medical Oncology                School of Medicine and Parmacology
University Hospital of Heraklion              Sir Charles Gairdner Hospital
Heraklion                                     Perth, WA
Greece                                        Australia

                                              Michael Dusmet MD FMH
Hisao Asamura MD
                                              Department of Thoracic Surgery
Division of Thoracic Surgery                  Royal Brompton Hospital
National Cancer Center Hospital               London
Tokyo                                         UK
                                              Williams K Evans MD FRCPC
Thierry Berghmans MD                          Department of Oncology
Department of Critical Care and               McMaster University
Thoracic Oncology                             Hamilton, Ontario
Institut Jules Bordet                         Canada
Belgium                                       Sara Gandini MD
                                              Division of Epidemiology and Biostatics
                                              European Institute of Oncology
Peter Boyle MD
International Agency for Research on Cancer
France                                        Vassilis Georgoulias MD PhD
                                              Department of Medical Oncology
Elisabeth Brambilla MD PhD                    University Hospital of Heraklion
Deptartment of Pathology                      Heraklion
Michallon Hospital                            Greece
CHRU Grenoble
National Institute for Health and             Peter Goldstraw MD
Medical Research                              Department of Thoracic Surgery
University Fourier Grenoble                   Royal Brompton Hospital
Grenoble                                      London
France                                        UK
viii List of Contributors

Nigel Gray AO MBBS FRACP FRACMA                      Christopher J Longo PhD MSc BA
Tobacco Unit                                         DeGroote School of Business
International Agency for Research on Cancer          McMaster University
Lyon                                                 Hamilton, Ontario
France                                               Canada

Heine H Hansen MD                                    Anne–Pascal Meert MD
The Finsen Center                                    Department of Critical Care and
National University Hospital                         Thoracic Oncology
Copenhagen                                           Institut Jules Bordet
Denmark                                              Brussels
Aage Haugen PhD
Department of Chemical and Biological                Vincenzo Minotti MD
Working Environment                                  Department of Medical Oncology
National Institute of Occupational Health            Santa Maria Della Misericordia Hospital
Oslo                                                 Perugia
Norway                                               Italy
                                                     Steen Mollerup PhD
Riken Kawachi MD
                                                     Department of Chemical and Biological
Division of Thoracic Surgery
                                                     Working Environment
National Cancer Center Hospital
                                                     National Institute of Occupational Health
Robert J korst MD                                    Michele Montedoro MD
Daniel and Gloria Blumenthal Cancer Center           Department of Medical Oncology
Valley Health System                                 Santa Maria Della Misericordia Hospital
Valley Hospital                                      Perugia
Paramus, NJ                                          Italy
                                                     John J Mullon MD
Peter WA Kunst MD PhD                                Division of Pulmonary and Critical Care Medicine
Department of Pulmonary Diseases                     Mayo Clinic College of Medicine
HAGA Hospital                                        Rochester, MN
The Hague                                            USA
The Netherlands
                                                     James L Mulshine MD
Sylvie Lantuejoul MD PhD                             Rush University Medical Center
Department of Pathology                              Chicago, IL
Michallon Hospital                                   USA
CHRU Grenoble
National Institute for Health and Medical Research   Anna Nowak MD
University J. Fourier Grenoble                       School of Medicine and Pharmacology
Grenoble                                             Sir Charles Gairdner Hospital
France                                               Perth, WA
Christopher M Lee MD
Department of Radiation Oncology                     Eric J Olson MD
University of Utah School of Medicine                Division of Pulmonary and Critical Care Medicine
Huntsman Cancer Hospital                             Mayo Clinic College of Medicine
Salt Lake City, UT                                   Rochester, MN
USA                                                  USA
                                                                                  List of Contributors ix

Marianne Paesmans MSc                          William T Sause MD
Data Center                                    LDS Hospital Radiation Center
Institut Jules Bordet                          Salt Lake City, UT
Brussels                                       USA
                                               Giorgio V Scagliotti MD
Athanasios G Pallis MD PhD                     Department of Clinical and Biological Sciences
Department of Medical Oncology                 University of Turin
University Hospital of Heraklion               Orbassano, Turin
Heraklion                                      Italy
                                               Jean-Paul Sculier MD PhD
Helle Pappot MD                                Department of Critical Care and Thoracic Oncology
Department of Oncology                         Institut Jules Bordet
Copenhagen University Hospital                 Brussels
Copenhagen                                     Belgium
                                               Giovanni Selvaggi MD
Pieter E Postmus MD PhD                        Department of Clinical and Biological Sciences
Department of Pulmonary Diseases               University of Turin
Vrije Universiteit University Medical Center   Orbassano, Turin
Amsterdam                                      Italy
The Netherlands                                Morten Sørensen MD
                                               The Finsen Center
Hans Skovgaard Poulsen MD DMSc
                                               National University Hospital
Department of Radiation Biology
Copenhagen University Hospital
Denmark                                        Tom G Sutedja MD PhD
                                               Department of Pulmonary Diseases
Thomas Tuxen Poulsen MSc                       Vrije Universiteit University Medical Center
Department of Radiation Biology                Amsterdam
Copenhagen University Hospital                 The Netherlands
Denmark                                        Maurizio Tonato MD
                                               Regional Cancer Center
Bruce WS Robinson MBBS MD FRACP                Poloclinico Hospital
FRCP DTM&H FCCP                                Perugia
National Research Centre for Asbestos          Italy
Related Diseases
School of Medicine and Pharmacology            Philip Tønnesen MD
Sir Charles Gairdner Hospital                  Department of Pulmonary Medicine
Perth, WA                                      Gentofte University Hospital
Australia                                      Hellerup
Cleo Robinson MD
National Research Centre for Asbestos          Merideth MM Wendland MD
Related Diseases                               Department of Radiation Oncology
School of Medicine and Pharmacology            Huntsman Cancer Hospital
Sir Charles Gairdner Hospital                  University of Utah
Perth, WA                                      Salt Lake City, UT
Australia                                      USA

Since the publication of the first issue of this textbook      Among the epidemiologic changes we also see a
in 2000, the epidemiologic features of smoking have         change in the histopathologic pattern, with a relative
undergone continuous changes and the worldwide              decrease in squamous cell carcinoma and a rise in ade-
intensification of the battle against tobacco consump-      nocarcinoma. Lately, important new information as
tion is changing the geographic pattern. In the USA,        regards the biology of lung cancer is emerging, includ-
some western European countries, and Australia, the         ing new treatment approaches. The result is a slow, but
incidence of lung cancer is decreasing among males,         steady improvement of the overall management of lung
while the disease continues to increase among females.      cancer based on an increasing use of combined modal-
In the southern and eastern parts of Europe, lung can-      ity therapy, consisting of surgery, chemotherapy, and
cer is on a rapid rise, and a similar pattern is seen in    radiotherapy applied concurrently or sequentially in
highly populated countries like China, Indonesia, and       early stage disease. Furthermore, new techniques are
Japan. Other regions of the world, such as the Middle       gaining ground, both within surgery and radiotherapy,
East, Africa, and South America, show the same dismal       and targeted medical therapy is being offered to more
picture.                                                    and more patients.
   Worldwide, the annual number of new cases of lung           The textbook brings up-to-date information about
cancer is estimated at more than one million and is         lung cancer, based on worldwide experience, for the
expected to increase to ten million in 2025. Fortunately,   use of the many physicians involved in this field.
the political efforts to reduce the use of tobacco are
getting increasing attention in many countries and the                                             Heine H Hansen
statistics are now showing the first positive results.
                Color Plates

                      (a)                                                         (c)


Figure 8.5
18F-FDG-PET scan with CT fusion demonstrating a primary adenocarcinoma in the left upper lobe (a), with contralateral hilar metastasis
(b). (c) Coronal 18F-FDG-PET without CT fusion, demonstrating no extrathoracic involvement. Transbronchial needle aspirate of the right
hilar lymph node confirmed metastatic adenocarcinoma with stage IIIB NSCLC assigned.
xiv Color Plates

                    (a)                                                         (c)


Figure 8.6
18F-FDG-PET scan with CT fusion demonstrating a primary adenocarcinoma involving the left upper lobe with ipsilateral mediastinal
lymph node metastasis (a), and left adrenal mestastasis (b). (c) Coronal 18F-FDG-PET without CT fusion demonstrating mediastinal and
extrathoracic (left adrenal) involvement. CT-guided biopsy of the left adrenal confirmed metastatic adenocarcinoma with stage IV NSCLC
                                                                                                                          Color Plates xv

Figure 9.13
The nodal chart established by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC)
in 1997.3

Figure 11.2.2
Anterior-posterior digitally reconstructed radiograph (DRR) illustrating a typical radiation portal which includes the primary tumor mass
and adjacent hilar/mediastinal lymph nodes.
xvi Color Plates

Figure 11.2.3
Conformal radiotherapy planning techniques allow escalated radiation doses to be delivered safely with simultaneous sparing of
surrounding critical structures. In this example, a combination of anterior-posterior and oblique fields (four fields in total) are utilized to
decrease radiation dose to the nearby spinal cord.

Figure 11.2.4
Right lateral digitally reconstructed radiograph (DRR) illustrating a typical portal used for prophylactic cranial irradiation.
    1         Etiology of lung cancer
              Aage Haugen, Steen Mollerup

              Contents Introduction • Carcinogens in tobacco smoke • Environmental tobacco smoke • Air pollution,
              radon, workplace exposure, and viruses • Genetic susceptibility and lung cancer etiology • Females and
              lung cancer susceptibilty

INTRODUCTION                                                    Available evidence indicates that carcinogenic PAH
                                                             compounds and the tobacco-specific carcinogen NNK
Lung cancer, which was rare at the beginning of the          (4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone)
20th century, is now a global problem. It is the most        are of major importance in lung cancer induction in
frequent cancer in the world.1 Presently, 1.2 million        smokers.8 Most studies on tobacco smoking genotoxic-
people die of lung cancer each year and the global inci-     ity in the lung have focused on these compounds. They
dence of lung cancer is increasing. A major contribu-        are strong carcinogens and tobacco contains relatively
tion to this trend comes from the former socialist           high amounts of PAHs and N-nitrosamines. However,
economies and developing countries where smoking             compounds such as aldehydes, butadiene, and ben-
rates are still high. Consequently, lung cancer will         zene, which appear to have lower carcinogenic poten-
remain a major cause of cancer death worldwide in the        tial, are found in much higher quantities in tobacco
21st century even though the prevalence of tobacco use       smoke.
has declined in many high-income countries.                     PAHs are formed by incomplete combustion of
   That carcinogens in tobacco smoke play a major            tobacco during smoking. PAHs, particularly benzo(a)
role in lung cancer is unquestionable. About 85–90%          pyrene, induce tumors of the lung in laboratory ani-
of lung cancer patients are smokers.2 However, lung          mals by various routes of administration. Furthermore,
cancer also occurs in people who have never smoked,          studies have demonstrated that human lung tissue can
and this implies that factors such as environmental          metabolize PAHs to reactive metabolites that can inter-
tobacco smoke (ETS), environmental and domestic              act with DNA, forming mutagenic DNA adducts.9 DNA
air pollution, work-related risk factors, radon exposure,    adduct formation is thought to be the primary initiating
and viruses may also have an impact on lung cancer           event in carcinogenesis and may be predictive of
incidence rates. In addition, since fewer than 20% of        lung cancer risk.10,11 PAH–DNA adducts have been
smokers will develop lung cancer in their lifetime, inher-   detected in human lung samples, and increased levels
ited predisposition may be an important component.           of PAH–DNA adducts in human lung tissue of smokers
                                                             and ex-smokers relative to non-smokers have been
CARCINOGENS IN TOBACCO SMOKE                                 reported in several studies.9 The major adduct formed
                                                             by activated benzo(a)pyrene, the (+)-anti-benzo(a)
Lung carcinogenesis is mediated through an interaction       pyrene-guanine adduct, is premutagenic, mispairing
between several putative carcinogens. A smoker inhales       with A and generating primarily G-to-T transversions.
gas-phase smoke (so-called ‘mainstream smoke’) as well       The role of PAHs in lung cancer is consistent with data
as particulates (tar). Cigarette smoke is a complex mix-     on mutational analysis of the TP53 gene with the dem-
ture of compounds and more than 4000 compounds               onstration of a large number of G-to-T transversions at
have been identified in tobacco mainstream smoke3–7          certain bases (hotspots) in this gene in smokers’ lung
(Table 1.1). Studies have led to the identification of       tumors.12 In vitro studies have shown a direct molecu-
60–70 carcinogens: polycyclic aromatic hydrocarbons          lar link between benzo(a)pyrene and the development
(PAHs), heterocyclic hydrocarbons, N-nitrosamines,           of lung cancer. Exposure of human epithelial cell cul-
aromatic amines, N-heterocyclic amines, aldehydes,           tures to the reactive diol epoxide metabolites of this
various organic compounds, inorganic compounds such          carcinogen resulted in the formation of adducts and
as hydrazine and some metals, and free radical species.      TP53 hotspot mutations, similar to that observed in
Table 1.2 lists likely causative agents for lung cancer.     lung tumors in smokers.13
2 Textbook of Lung Cancer

 Table 1.1 Carcinogens in cigarette smoke

 Agent                                  Amount in mainstream   IARC evaluation of
                                        cigarette smoke         carcinogenicity

                                                               In animals           In humans    IARC group

 Polynuclear aromatic hydrocarbons
 Benzo[a]anthracene             20–70 ng                       Sufficient                        2A
 Benzo[b]fluoranthene           4–22 ng                        Sufficient                        2B
 Benzo[j]fluoranthene           6–21 ng                        Sufficient                        2B
 Benzo[k]fluoranthene           6–12 ng                        Sufficient                        2B
 Benzo[a]pyrene                 8.5–11.6 nga                   Sufficient                        2A
 Dibenz[a,h]anthracene          4 ng                           Sufficient                        2A
 Dibenzo[a,i]pyrene             1.7–3.2 ng                     Sufficient                        2B
 Dibenzo[a,e]pyrene             Present                        Sufficient                        2B
 Indeno[1,2,3-cd]pyrene         4–20 ng                        Sufficient                        2B
 5-Methylchrysene               ND-0.6 ng                      Sufficient                        2B
 Heterocyclic hydrocarbons
 Furan                          20–40 µgb                      Sufficient                        2B
 Dibenz(a,h)acridine            ND–0.1 ng                      Sufficient                        2B
 Dibenz(a,j) acridine           ND–10 ng                       Sufficient                        2B
 Dibenzo(c,g)carbazole          ND–0.7 ng                      Sufficient                        2B
 Benzo(b)furan                  Present                        Sufficient                        2B
 N-Nitrosodimethylamine         0.1–180 ngb                    Sufficient                        2A
 N-Nitrosoethylmethylamine      ND–13 ng                       Sufficient                        2B
 N-Nitrosodiethylamine          ND–25 ngb                      Sufficient                        2A
 N-Nitrosopyrrolidine           1.5–110 ngb                    Sufficient                        2B
 N-Nitrosopiperidine            ND–9 ng                        Sufficient                        2B
 N-Nitrosodiethanolamine        ND–36 ngb                      Sufficient                        2B
 N′-Nitrosonornicotine          154–196 nga                    Sufficient                        2Bc
 4-(Methylnitrosamino)-         110–133 nga                    Sufficient                        2Bc
 Aromatic amines
 2-Toluidine                    30–200 ngb                     Sufficient           Limited      2A
 2,6-Dimethylaniline            4–50 ng                        Sufficient                        2B
 2-Naphthylamine                1–22 ngb                       Sufficient           Sufficient   1
 4-Aminobiphenyl                2–5 ngb                        Sufficient           Sufficient   1
 N-Heterocyclic amines
 A-α-C                          25–260 ng                      Sufficient                        2B
 MeA-α-C                        2–37 ng                        Sufficient                        2B
 IQ                             0.3 ng                         Sufficient                        2A
 Trp-P-1                        0.3–0.5 ng                     Sufficient                        2B
 Trp-P-2                        0.8–1.1 ng                     Sufficient                        2B
 Glu-P-1                        0.37–0.89 ng                   Sufficient                        2B
 Glu-P-2                        0.25–0.88 ng                   Sufficient                        2B
 PhIP                           11–23 ng                       Sufficient                        2B

                                                                                                                           Etiology of lung cancer 3

Table 1.1 Continued

Agent                                           Amount in mainstream               IARC evaluation of
                                                cigarette smoke                     carcinogenicity

                                                                                   In animals                 In humans          IARC group

Formaldehyde                  10.3–25 µga                                          Sufficient                 Limited            2A
Acetaldehyde                  770–864 µga                                          Sufficient                                    2B
Phenolic compounds
Catechol                      59–81 µga                                            Sufficient                                    2B
Caffeic acid                  <3 µg                                                Sufficient                                    2B
Volatile hydrocarbons
1,3-Butadiene                 20–40 µgb                                            Sufficient                 Limited            2A
Isoprene                      450–1000 µg                                          Sufficient                                    2B
Benzene                       12–50 µgb                                            Sufficient                 Sufficient         1
Nitromethane                  0.5–0.6 µg                                           Sufficient                                    2B
2-Nitropropane                0.7–1.2 ngc                                          Sufficient                                    2B
Nitrobenzene                  25 µg                                                Sufficient                                    2B
Miscellaneous organic compounds
Acetamide                     38–56 µg                                             Sufficient                                    2B
Acrylamide                    Present                                              Sufficient                                    2A
Acrylonitrile                 3–15 µg                                              Sufficient                                    2B
Vinyl chloride                11–15 ng                                             Sufficient                 Sufficient         1
1,1-Dimethylhydrazine         Present                                              Sufficient                                    2B
Ethylene oxide                7 µg                                                 Sufficient                 Limited            1
Propylene oxide               0–100 ng                                             Sufficient                                    2B
Hydrazine                     24–43 ng                                             Sufficient                                    2B
Urethane                      20–38 ngb                                            Sufficient                                    2B
Metals and metal compounds
Arsenic                       40–120 ngb                                           Sufficient                 Sufficient         1
Beryllium                     0.5 ng                                               Sufficient                 Sufficient         1
Nickel                        ND–600 ng                                            Sufficient                 Sufficient         1
Chromium (hexavalent)         4–70 ng                                              Sufficient                 Sufficient         1
Cadmium                       41–62 ngb                                            Sufficient                 Sufficient         1
Cobalt                        0.13–0.20 ng                                         Sufficient                                    2B
Lead (inorganic)              34–85 ng                                             Sufficient                 Limited            2A
Radio-isotope polonium-210    0.03–1.0 pCi                                         Sufficient                                    1
Modified from Hoffmann and Hoffmann,4 this table shows components of unfiltered mainstream cigarette smoke, with amounts given per cigarette.
Virtually all these compounds are known carcinogens in experimental animals. In combination with data on cancer in humans and – in some cases –
other relevant data, IARC Monograph classifications for these agents have been established as Group 2B (possibly carcinogenic to humans), Group 2A
(probably carcinogenic to humans), or Group 1 (carcinogenic to humans).
Abbreviations: ND, not detected; A-α-C, 2-amino-9H-pyrido[2,3-b]indole; IQ, 2-amino-3-methylimidazo-[4,5-b]quinoline;
Trp-P-1, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole; Trp-P-2, 3-amino-1-methyl-5H-pyrido[4,3-b]indole; Glu-P-1, 2-amino-
6-methyl[1,2-a:3′2″-d]imidazole; Glu P-2, 2-aminodipyridol[1,2-a:3′,2″-d]imidazole; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine;
pCi, picoCurie.
  Data from Swauger et al (2002) (for ‘full-flavor’ cigarettes).5
  Data from US Department of Health and Human Services (1989).6
 Corrected value (see Fowler and Bates, 2000).7
4 Textbook of Lung Cancer

 Table 1.2 Causative agents in cigarette smoke
                                                               of the carcinogenic process, but can also be potential
                                                               promoters during carcinogenesis. This is particular true
 Carcinogens                          Tumor promoters/         for tobacco smoke, where exposure to multiple agents
                                      co-carcinogens           occurs. Cigarette smoke contains a substantial amount
 Major risk factors                                            of chromium, cadmium, and nickel. It is known that
 PAHs                                 Catechol                 chromium accumulates in the lung and tobacco smok-
 Nitroso compounds                    Phenol                   ing is the main source of cadmium exposure in humans.
                                      Aldehydes                It has been reported that chromates are carcinogenic in
                                      Oxidative radicals       rats, inducing lung tumors after instillation.17 Cadmium
 Minor risk factors                                            chloride aerosols produce lung adenocarcinoma and
 Polonium-210                                                  squamous cell carcinoma in rats,18 and nickel subsul-
 Aldehydes                                                     fide yields lung cancer in rats upon inhalation.19 Because
 Butadiene                                                     of their relatively high levels in cigarette smoke, these
 Ni, Cd, Cr                                                    metals may play a role in lung carcinogenesis. They are
 Oxidative radicals                                            likely to contribute to lung cancer induction by multi-
                                                               ple mechanisms such as inducing DNA damage (single
                                                               strand breaks, cross-linking of DNA and proteins), and
                                                               they could potentiate the genotoxicity of other DNA-
   The concentration of nitrosamines found in tobacco          damaging agents and enhance mutagenesis. Many stud-
products is relatively high, and except for some occu-         ies have demonstrated that reactive oxygen species are
pational exposure situations, heavy smokers have the           implicated in metal carcinogenesis.
highest exposure to N-nitroso compounds. The so-                  Table 1.2 lists other constituents of tobacco-smoke
called tobacco-specific N-nitrosamines (TSNAs), prin-          that could be involved in lung cancer induction. How-
cipally the nicotine-derived NNK, are the strongest            ever, less importance has been attributed to these com-
respiratory carcinogens identified in tobacco products.        pounds in comparison with PAH and NNK. Inhalation
Adenocarcinoma of the lung is the main type of lung            studies of formaldehyde and acetaldehyde have dem-
cancer induced by NNK, and both benign and malig-              onstrated that they are respiratory carcinogens in the
nant tumors are formed in rats, mice, and hamsters.14          rat.20 These compounds are weak carcinogens, but the
Moreover, human lung tissue metabolically activates            levels are relatively high in cigarette smoke.
NNK, although less effectively than rodent lung tissue.           Polonium-210 (210Po) is a natural constituent of ciga-
This activation is mediated by P450 monooxygenases,            rette smoke and will deposit in the lungs of smokers,
cyclooxygenases, and lipooxygenases. Metabolites of            emitting alpha particles.21 The content of several car-
NNK have been reported in urine from smokers, and              cinogens in tobacco has been reduced due to changes
NNK and N′-nitrosonornicotine (NNN)-specific DNA               in tobacco processing methods and new cigarette fil-
adducts have been reported at increased levels in the          ters, but this is not the case with the 210Po concentra-
lungs of smokers.8,15 A high frequency of G-to-A transi-       tion, neither in tobacco nor in tobacco smoke. Radiation
tions in the TP53 gene is consistent with the mutational       exposure may induce lung cancer both alone and in
spectrum expected from NNK.12 NNK might also exert             interaction with other carcinogens in tobacco. Animal
its biologic activity through cell surface receptors such      studies have shown that 210Po is a strong pulmonary
as nicotine acetylcholine receptors (nAchRs) and               carcinogen in rats and Syrian golden hamsters.22
β-adrenergic receptors.16 Adenocarcinoma has now                  Cigarette smoke contains large amounts of free radi-
overtaken squamous cell carcinoma as the most com-             cals and is known to induce oxidative damage. Both gas
mon lung cancer type, consistent with the role of NNK          and particulate phases are highly oxidized, and damage
in lung carcinogenesis. NNK concentrations in main-            the lung. Alkenes (i.e. unsaturated aliphatic hydrocar-
stream smoke have increased while those of benzo(a)            bons), nitrosamines, aromatic and heterocyclic hydro-
pyrene have decreased since the 1960s.                         carbons, amines, and catechol and hydroquinone are
   There are relatively high levels of metals in cigarette     all well known sources of reactive oxygen species such
smoke (Figure 1.1). At least 30 metals have been               as hydroxyl radicals, superoxides, and peroxides.23 Dam-
identified.3,4 The contribution of these metals to increased   age can also result from the activation of phagocytic cells
lung cancer risk is poorly understood. Experimental evi-       that generate reactive oxygen species (ROS).24 Cigarette
dence indicates that many metals are effective initiators      smoke is a strong inflammatory stimulus that induces
                                                                                                                      Etiology of lung cancer 5

                                               Causative agents in cigarette smoke:
                                                    PAH, NNK, 210Po, Cr, Cd,
                                                Ni, aldehydes, oxidative radicals

                                                  Phase 1
                                                                     P 450
                                                                                     Phase 2
                         Susceptibility:                  DNA-damaging                                  Excretion
                          Variation in                     metabolites
                        metabolism and                                               Synergistic effect:
                          DNA repair                                                     Asbestos
                           Nutrition                                                Chloromethyl ethers
                         Immunologic                                                   Mustard gas
                                                         Chronic exposure
                            status                                                    Radioactive ore

                                                                          Preneoplastic                              Lung
                       Normal cells            Initiated cells                                     Progression
                                                                              cells                                 cancer
                                      DNA                        DNA                      DNA
                                      repair                     repair                   repair
                                Days                             10–30 years                           Months

                                                   Genetic changes:
                         TP53, KRAS, EGFR, inactivation of FHIT/RASSF1/SEMA3B (3p), INK4, RB
                                      Activation of CCDN1; MYC1 - amplification
                                             LOH (2q, 5q, 9q, 18q, 22q)

Figure 1.1
Lung carcinogenesis.

proinflammatory cytokines and recruits activated mac-                             Nicotine is the agent in tobacco capable of producing
rophages and neutrophils to lung tissue.25 Neutrophils                         addiction, or nicotine dependence, and exists at high
play an important role in the defense of the lung through                      concentrations in the blood of smokers. Direct involve-
a variety of activities and generate oxidative radicals                        ment of nicotine in the development of lung cancer has
when exposed to PAHs and aromatic amines. The oxi-                             not yet been shown, but nicotine does appear to play an
dative capacity of neutrophils is therefore important                          important role and may have multiple sites of action. It
as a potential cause of oxidative damage to the lung.                          is absorbed rapidly when smokers inhale. Specific,
Several epidemiologic studies have associated lung                             high-affinity nAChRs are found on human lung cancer
inflammatory diseases such as asthma, bronchitis, and                          cells of all histologic types as well as in normal lung
chronic obstructive pulmonary disease (COPD) with an                           tissue.27 Chronic exposure to nicotine can lead to the
increased risk of lung cancer development.                                     activation of growth-promoting pathways upon its
   DNA is an important target for ROS. In order for                            interaction with nAChRs, and may also affect apoptosis
ROS to induce DNA damage, a sufficient concentration                           and angiogenesis.28
must be available to overwhelm the antioxidant capac-
ity of the lung. Products that result from oxidative dam-
age to both lipids and DNA have been detected in                               ENVIRONMENTAL TOBACCO SMOKE
smokers at higher levels than in non-smokers. Although
the direct role of such products in carcinogenesis is                          Environmental tobacco smoke (ETS), or passive
unclear, 8-oxoguanine (8-oxo-G), a frequent product of                         smoking, is a mixture of exhaled mainstream smoke
oxidative damage, has miscoding properties associated                          and sidestream smoke diluted with ambient air. Ciga-
with the cancer induction process.26 Studies indicate                          rettes generate a large amount of ETS and affected indi-
that unrepaired 8-oxo-G gives rise to G-to-T transver-                         viduals are exposed to the same carcinogens as an active
sions. The most abundant genetic change induced as a                           smoker. However, the relative proportions of the par-
consequence of oxidative damage is GC-to-AT transi-                            ticular compounds may differ between mainstream and
tion. Apart from oxidative modification of DNA bases,                          sidestream smoke. For example, due to filters, concen-
free radicals are also able to induce single strand                            trations of PAHs such as benzo(a)pyrene and benzo(a)
breaks.                                                                        anthracene in the sidestream are approximately 10-fold
6 Textbook of Lung Cancer

higher than those in mainstream smoke. Benzene, form-       with numerous air pollutants that vary during the year
aldehyde, hydrazine, butadiene, N-nitrosamines, ani-        and over time. Since the lung has a large respiratory
line, 2-naphthylamine, and 4-aminobiphenyl may              volume (500–600 liters of air/h) with a large surface
also be present at higher concentrations in sidestream      area (75–85 m2), and a large blood perfusion, exposure
smoke.29                                                    to toxic compounds in the ambient air could lead to
   Many epidemiologic studies, which were evaluated         lung toxicity and lung cancer development even at low
by the IARC in 2004,3 have shown an increased lung          levels.
cancer risk in never-smokers exposed to ETS. This is           Radon, a naturally reactive but chemically inert gas
particularly true for spouses of active smokers, where      found ubiquitously in the environment, emanates as a
ETS-exposed never-smoking females and males have an         toxic gas from the soil and from building material of
excess risk of lung cancer in the order of 20 or 30%,       terrestrial origin, such as stone, bricks, and concrete.
respectively. Never-smokers exposed to ETS in the           High levels of radon exposure occur in occupational
workplace may also be at an increased risk (12–19%).        settings, particularly in uranium mines. People are also
Experimental studies have confirmed the carcinogenic        subjected to residential radon exposure, which may be
potential of ETS. Thus, concentrations of tobacco-          increasing due to the tendency to reduce ventilation
smoke-related compounds adducted to biologic macro-         rates in indoor air. The carcinogenicity of radon is
molecules such as proteins, and to a lesser extent DNA,     attributable mainly to its short-lived, radioactive, alpha-
have been found to be increased in individuals exposed      emitting daughters, polonium-214 and polonium-218.35
to ETS.3 Also, lung tumors from ETS-exposed non-            In miners, increasing risk of lung cancer is associated
smoking individuals show TP53 and KRAS mutations            with increasing cumulative exposure to radon.36 There
similar to those found in tumors from smokers, although     is also compelling evidence that indoor radon is an
at a lower frequency.30,31                                  important contributor to the risk of lung cancer.37 The
                                                            dose–response relation between residential radon expo-
                                                            sure and excess risk of lung cancer appears to be linear
AIR POLLUTION, RADON, WORKPLACE EXPOSURE,                   with no threshold. Overall estimates have been made
AND VIRUSES                                                 that radon may contribute to 9% of all lung cancers,
                                                            and the available data suggest that the risks of lung
The different incidence rates for lung cancer among         cancer from exposure to radon and smoking are at least
non-smokers in different countries suggest that envi-       additive.
ronmental agents can modify the risk. Air pollution is a       Workplace exposure plays an important role in the
complex mixture of different gaseous and particulate        causation of lung cancer. The evidence for lung cancer
components that may pose a moderate risk factor for         induction by occupational exposure to metals such as
lung cancer. Numerous air pollutants resulting from         beryllium, chromium, nickel and arsenic is convincing
heavy traffic, burning of fossil fuels, and industrial      and well documented.38 High exposure to PAH occurs
plants are potential contributors to the incidence of       in several occupations, such as those involved in alu-
lung cancer. These include PAH, formaldehyde, ben-          minium production, coke production, and coal gasifi-
zene, ethylene oxide, petroleum vapors, and metals. An      cation, iron and steel workers, bus drivers (because of
association between lung cancer and air pollution has       diesel engine exhaust), roofers, and asphalt workers.
been reported in studies from cities. Urban residents       The lung is the major target organ among PAH-exposed
with the highest exposure levels seem to have an            workers.39 Although occupational exposure to asbestos
increase in lung cancer in the range of 1.5 times that of   is no longer an issue in most developed countries, in
rural residents.32 In a large European prospective study,   several developing countries exposure is widespread
it was found that residence in proximity to heavy-traffic   and may be a significant etiologic factor for lung cancer.
roads or exposure to NO2 concentrations greater than        As in most other exposure scenarios, tobacco smoking
30 µg/m3 can increase the risk of lung cancer.33 In the     is the main cause of lung cancer in asbestos-exposed
case of NO2, the lung cancer risk ratio has shown an        workers, and the relative risk seems to be higher among
exposure–response relationship.34 In other studies, par-    non-smokers compared to smokers.40 Crystalline silica,
ticulate matter (fine particles), SO2, and black smoke      which may be inhaled in occupational settings, has been
have all been associated with a moderate increase in the    classified as a lung carcinogen, with an apparent linear
risk of lung cancer. However, analysis is complicated       dose–response relationship without any threshold.41
due to the fact that air pollution is a complex mixture,    It is important to note, however, when assessing the
                                                                                              Etiology of lung cancer 7

etiology of lung cancer associated with occupational       repair genes involved in different repair pathways show
exposure, that a significant confounder to be consid-      associations.
ered is tobacco smoking.                                      There is increasing knowledge of the genetic defects
   Oncogenic viruses may be involved in the etiology of    that give rise to the observed variation in, and, more
lung cancer. Some evidence has been provided for the       importantly functional significance of these allelic vari-
involvement of human papilloma viruses, but detection      ants. However, there are numerous conflicting reports
rates of the viruses in bronchial carcinomas are highly    on the association between different polymorphisms
variable, ranging from 0 to 100% in different studies.42   and lung cancer risk. Larger studies are needed in
Regarding other oncogenic viruses such as Epstein–         this area.
Barr virus, human cytomegalovirus, human herpes
virus-8, and simian virus 40, the evidence is scarce.43
                                                           FEMALES AND LUNG CANCER SUSCEPTIBILITY

GENETIC SUSCEPTIBILITY AND LUNG                            The relative lung cancer burden from women is
CANCER ETIOLOGY                                            increasing, partly due to their changing smoking
                                                           habits. Although controversial, the increase in lung
Host factors may influence individual susceptibility to    cancer among females is possibly also partly due to a
tobacco smoke. This may be illustrated by the fact that    higher susceptibility to tobacco smoke carcinogens.
only 1 in 10 lifetime smokers will develop lung cancer.    Several studies have reported the relative risk of lung
Several epidemiologic studies have indicated that there    cancer among females to exceed that of males by a
are genetic factors modifying the risk of individuals to   factor of 1.5 to 2.5.48–50 Although not all epidemiologic
lung cancer. Some degree of familial aggregation of lung   studies have been able to confirm that females are at
cancer is evident in most family studies. One study has    increased risk,51,52 it is clear that biologic factors
reported linkage to chromosome 6q in lung cancer fam-      involved in lung cancer development differ between
ilies, strongly supporting the existence of a gene for     the sexes. Experimental studies have indicated sex
lung cancer.44 The human genome project has resulted       differences in PAH metabolism, DNA repair capacity,
in increasing information becoming available on the        and cell proliferation potential that may support this
existence of polymorphisms in human genes. Suscepti-       hypothesis.
bility to lung cancer may be modulated by host-specific       By analyzing the TP53 gene mutational spectra in a
factors including differences in carcinogen metabolism     large number of lung cancer cases, G:C-to-T:A hotspot
and detoxification, DNA repair, cell cycle control, cell   mutations were found at a higher frequency among
signaling, apoptosis, and inflammation pathways. Sev-      female smokers compared to female never-smokers.
eral studies have been designed to evaluate a large        Similar differences were not found among males.53
number of sequence variants among multiple genes           Since G:C-to-T:A transversions are associated with
of drug-metabolizing enzymes.45 Procarcinogens in          exposure to PAH, this indicates a specific role for PAH
tobacco smoke are activated by several forms of cyto-      in generating this particular signature mutation in
chrome P450 (phase I) and detoxified by glutathione        women. Women have also been reported to have
S-transferase (GST), NADPH:quinone oxidoreductase          increased levels of pulmonary tobacco-smoke-induced
(NQO), N-acetyl-transferase (NAT), and others (phase       DNA damage in the form of PAH-related adducts.54 The
II). Many of these genes exhibit allelism and there is     DNA-adduct level may be a predictor of cancer risk.55
accumulating evidence that some CYP, GST, NQO, and         Higher DNA-adduct levels among females coincide
NAT genotypes are associated with an altered risk of       with a higher level of expression of the smoking-induced
lung cancer.                                               cytochrome P450 1A1 (CYP1A1), which is an important
    The removal and repair of DNA damage plays a key       gene in the metabolic activation of PAH.56 Estrogens
role in protecting the integrity of the genome from the    and their receptors have been hypothesized to be
insults of genotoxic agents such as PAH and NNK found      involved in these sex differences by interfering with the
in tobacco smoke. Lung cancer patients were reported       transcription-activating activity of the aryl hydrocarbon
to have a lower DNA repair capacity, and recent studies    receptor (AHR). AHR is a ligand-activated transcription
have assessed the relationship between single nucle-       factor with high affinity for PAH. In studies with lym-
otide polymorphisms (SNPs) in several DNA repair           phocytes isolated from lung cancer patients, it was
genes and the risk of lung cancer.45–47 Several DNA        found that females might also have a lower capacity to
8 Textbook of Lung Cancer

repair DNA damage,57 which may result in increased                     10. Phillips DH. DNA adducts as markers of exposure and risk.
susceptibility to the manifestation of mutations.                          Mutat Res 2005; 577: 284–92.
                                                                       11. Vineis P, Perera F. DNA adducts as markers of exposure to
   One report has indicated that pulmonary expression
                                                                           carcinogens and risk of cancer. Int J Cancer 2000; 88: 325–8.
of the gastrin-releasing peptide receptor (GRPR), which                12. Calvez FL, Mukeria A, Hunt JD et al. TP53 and KRAS mutation
is involved in lung development during fetal stages, is                    load and types in lung cancers in relation to tobacco smoke:
more frequent among women than men.58 The GRPR                             distinct patterns in never, former, and current smokers. Cancer
gene is induced by smoking and is located on a region                      Res 2005; 65: 5076–83.
of the X-chromosome that appears to escape X-chromo-                   13. Denissenko MF, Pao A, Tang M, Pfeifer GP. Preferential forma-
                                                                           tion of benzo[a]pyrene adducts at lung cancer mutational
some inactivation in females. Activation of the GRPR has
                                                                           hotspots in p53. Science 1996; 274: 430–2.
been associated with an increased proliferative response               14. Hecht SS, Carmella SG, Foiles PG et al. Tobacco-specific nitro-
in human airway epithelial cells. Thus, this represents a                  samine adducts: studies in laboratory animals and humans.
model where smoking may induce the gene to a higher                        Environ Health Perspect 1993; 99: 57–63.
extent among women.                                                    15. Hecth SS. Human urinary carcinogen metabolites: biomarkers
   In summary, tobacco smoking (active smoking or                          for investigating tobacco and cancer. Carcinogenesis 2002; 23:
exposure to environmental tobacco smoke) plays a                       16. Schuller HM. Mechanisms of smoking-related lung and pancreatic
major etiologic role in lung carcinogenesis. More than                     adenocarcinoma development. Nat Cancer Rev 2002; 2: 455–63.
60 compounds in tobacco smoke have been identified                     17. Costa M. Toxicity and carcinogenicity of Cr (VI) in animal
as carcinogenic. Other etiologic factors of minor, but                     models and humans. Crit Rev Toxicol 1997; 27: 431–42.
still significant importance for the disease are air pollu-            18. Waalkes MP. Cadmium carcinogenesis. Mutat Res 2003; 533:
tion, radon, workplace exposure, and viruses. Genetic
                                                                       19. Oller AR, Costa M, Oberdorster G. Carcinogenicity
differences in susceptibility to lung cancer are apparent                  assessment of selected nickel compounds. Toxicol Appl Phar-
and sex differences may be involved.                                       macol 1997; 143: 152–66.
                                                                       20. International Agency for Research on Cancer. Formaldehyde.
                                                                           IARC Monogr Eval Carcin Risk Hum 1982; 4: 131–2.
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    2         Epidemiology of lung cancer: a century of
              great success and ignominious failure
              Peter Boyle, Sara Gandini, Nigel Gray

              Contents Introduction • Phase I: public health success, 1930s onwards • Phase II: understanding
              etiology, losing ground in incidence and mortality • Phase III: descriptive epidemiology of
              lung cancer • Phase IV: public health failure, 1960s onwards

INTRODUCTION                                                  lung cancer since at least the middle of the last century,
                                                              has been of little value in public health terms, since
The present century has witnessed a remarkable                there has been no real action taken to reduce the impact
epidemic of lung cancer. The words of Adler,1 pub-            of this serious disease.
lished in 1912, today make salutary reading:                     In viewing the century of lung cancer epidemiology,
                                                              there are a number of distinct phases that can be identi-
     Is it worthwhile to write a monograph on the sub-        fied. Initially (phase I), there was the great success of
  ject of primary malignant tumours of the lung? In           epidemiology, the basic science of public health, in estab-
  the course of the last two centuries an ever-increas-       lishing the causal link between cigarette smoking and
  ing literature has accumulated around this subject.         lung cancer risk. Following this period, from the mid-
  But this literature is without correlation, much of it      1950s onwards, there was a period (phase II) where
  buried in dissertations and other out-of-the-way            there was an increasing understanding of the etiology of
  places, and, with but a few notable exceptions, no          lung cancer, and simultaneously public health began
  attempt has been made to study the subject as a             losing ground as smoking rates led to great increases in
  whole, either the pathological or the clinical aspect       the incidence and mortality of the disease, particularly
  having been emphasised at the expense of the other,         among men in developed countries. The association
  according to the special predilection of the author.        between tobacco smoking and lung cancer became
  On one point, however, there is nearly complete             widely known, and many groups actively took up the
  consensus of opinion, and that is that primary malig-       movement towards tobacco control. During this period
  nant neoplasms of the lungs are among the rarest            (phase III), the situation stabilized while activists and
  forms of the disease. This latter opinion of the            scientists united to try to bring the adverse effects of
  extreme rarity of primary tumours has persisted for         tobacco smoking to general attention and thereby to
  centuries.                                                  take actions designed to reduce smoking and its harm-
                                                              ful side-effects. It quickly became clear that a great deal
   Lung cancer is currently the most common form of           of ground had been lost, and during phase IV large
cancer worldwide. It is the most common cause of cancer       increases in lung cancer among women became appar-
death in men in North America and in virtually all            ent, indicating the great failure of public health to curb
European countries, west and east, and it is increasingly     the development of the habit among women.
common as a cause of death in developing populations
in Asia, Latin America, and Africa, although compara-
ble high-quality data are not available from many of          PHASE I: PUBLIC HEALTH SUCCESS, 1930s ONWARDS
these populations. From being virtually an unknown
and rare disease at the beginning of the last century,        The association between tobacco smoking and the
public health has documented the development of a             development of lung cancer appears to have been
true epidemic of lung cancer through the 20th century,        suggested in the UK in 1927.2 The first interview study
and has failed to alleviate the situation by positive         on tobacco smoking and lung cancer seems to have
actions. Knowing the cause, which has been the case for       been reported from Vienna,3 where lung cancer rates
                                              Epidemiology of lung cancer: a century of great success and ignominious failure 11

had risen dramatically. Fleckseder3 found 51 smokers           to be conducted and, in 1950, five major contributions
among 54 patients with lung cancer. Thirty-seven of            were made to the literature.7–11
these smoked between 20 and 90 cigarettes daily, while             The data presented by Wynder and Graham10 are
excessive smoking of pipes, cigars, or both was rarer.         capable of transformation to calculate the relative risks
   The same association was alluded to in a report from        (the concept of which was unknown for a few more
the USA4 on a study primarily of a series of                   years). Setting the risk among non-smokers at 1.0, there
79 patients treated by total pneumonectomy. A report           is to some extent or other a dose–response relationship
from Cologne followed one year later,5 based on the            with increasing levels of smoking in all age groups.
postmortem records of 96 patients. The patients (or            Together with the study of Wynder and Graham,10 the
more usually the relatives of fatal cases) were inter-         fifth paper published on this subject during the year
viewed as to patient’s occupation, tobacco consump-            represented a significant contribution not only to knowl-
tion, and exposure to specific ‘inhalants’.                    edge about smoking and cancer but also to the method-
   Reanalysis of Muller’s5 data shows a relative risk of       ology of retrospective epidemiologic studies.11
3.1 among moderate smokers, 2.7 among heavy smokers,               This well-planned, controlled, and well-conducted
16.8 among very heavy smokers, and 29.16 among                 study was initially reported,11 and completed and pub-
excessive smokers. Within the limitations of the study         lished more extensively two years later. It is this latter
(e.g. small numbers, especially among non-smoking              report12 that we shall discuss here. Doll and Hill12 did
cases, and possible inaccuracies in elucidation of pre-        not discuss cigar smoking, but calculated that use of
cise smoking histories), these results were noticeably         one ounce of pipe tobacco was the equivalent of 26.5
similar to results obtained from later case–control stud-      cigarettes, and one ounce per week was equivalent to
ies in the USA and, apart from a lack of increase among        smoking four cigarettes per day. Non-smokers were
heavy smokers, there is the possible appearance of a           defined as people who had never consistently smoked
dose–response relationship.                                    as much as one cigarette per day for as long as one
   A study of smoking habits and occupation based on           year.11
195 postmortem records of lung cancer cases from the               The strongest difference between cases and controls
Pathology Institute at Jena for the years 1930–1941 was        (for both males and females) was found to be the aver-
reported: usable replies were obtained from relatives of       age amount smoked daily over the 10 years preceding
93 men and 16 women. Of the women, 13 were non-                the patient’s illness. Qualitatively similar results were
smokers.6 The authors attempted to collect control             also obtained using the amount smoked immediately
information by interviewing 700 men in Jena between            before the patient’s illness, the maximum amount ever
the ages of 53 and 54, the average age of the lung cancer      smoked regularly, the total smoked since smoking began,
patients at death (53.9 years). This was a study performed     and the average amount smoked daily over the 10 years
in Germany towards the end of the Second World War,            preceding the patient’s illness, over the penultimate 10
and only 270 men from Jena responded to the ques-              years and over the whole of the patient’s life since the
tionnaire. The authors showed great insight in conclud-        age of 15 (even after allowance had been made for
ing that wartime conditions (particularly the rationing        recorded changes in smoking habit).
system) may have favored results from non-smokers.                 Patients who recognized that they inhaled were found
   They reported a statistically significant difference        no more frequently in the lung cancer group than in the
between non-smokers and heavy smokers among lung               control group, although those cases with growths of
cancer patients on the one hand and normal patients on         central origin inhaled less frequently than normal. It
the other. Realizing the possible errors on their mate-        also appeared that lung cancer patients more frequently
rial, they concluded that there was a considerable prob-       had a history of preceding pneumonia or chronic bron-
ability that lung cancer was far more frequent among           chitis, while other respiratory illnesses were referred to
non-smokers than expected. Their data are such that an         with approximately equal frequency by the two
approximate relative risk can be calculated: the risk          groups.
relative to non-smokers was 1.90 among light smokers,              Doll and Hill’s reports11,12 contained a remarkable
9.05 among moderate smokers, and 11.34 among                   amount of information, but the fundamental finding in
heavy/excessive smokers. Again there appears to be a           men was a highly significant difference between the
moderate dose–response relationship.                           proportions of non-smokers and of smokers in the dis-
   The rapid escalation in lung cancer during the 1940s        ease group and in the control group. A less marked
reached a level that permitted more and larger studies         series of differences was reported for women. Highly
12 Textbook of Lung Cancer

significant differences were also shown between the pro-      women,14 in whom lung cancer had increased fivefold
portions of both groups smoking different average             in two decades in the USA. The Secretary for Health of
amounts, i.e. between heavy and light smokers, and this       the time (Mr Joseph Califano) concluded ‘that smoking
result held for males and females. It is apparent from        is the largest preventable cause of death in America’.
the raw data that there is a dose–response relationship          An important factor in the causal relationship between
present.                                                      smoking and lung cancer is the demonstrated dose–
   Less marked but nevertheless distinct differences          response relationship. In epidemiologic studies, the dose
were found when the duration of smoking was consid-           has been measured by:
ered rather than the amount smoked. Lung cancer
cases, as a group, began to smoke earlier; they contin-       •   the number of cigarettes smoked per day at inter-
ued to smoke longer and gave up less often and, when              view;
they did, did so for shorter periods. In males, all these     •   the maximum number of cigarettes smoked per
differences were statistically significant, but, although         day;
the differences were in the same direction in women,          •   the age when smoking commenced;
they did not reach the commonly accepted (5%) level           •   the degree of inhalation of tobacco smoke;
of statistical significance.                                  •   the total number of years smoked;
   These five studies,7–11 but mainly the impact of           •   the total lifetime number of cigarettes smoked;
two,10,11 alerted the medical and scientific community        •   the tar and nicotine levels of the brand of cigarettes
to the serious health hazards associated with cigarette           used;
smoking. Once alerted, the public response to these           •   the number of puffs per cigarette;
studies was a significant, but brief, drop in the per         •   the length of the unburned portion of cigarette.
capita consumption of cigarettes in both the USA and
the UK.                                                          A variety of combinations of these variables can be
                                                              converted into dosage scores.
                                                                 Lung cancer mortality ratios exhibit an inverse rela-
PHASE II: UNDERSTANDING ETIOLOGY, LOSING                      tionship with the age of initiation of the smoking habit.
GROUND IN INCIDENCE AND MORTALITY                             Those who develop the habit at school have a much
                                                              higher risk of lung cancer than those who begin smok-
Throughout the 1950s, a mass of information was               ing at age 25+, in whom the risk is only four to five
published demonstrating the association between lung          times that of non-smokers.
cancer and cigarette smoking, using data derived                 Available data show a strong dose–response relation-
from retrospective studies. Many concentrated on inha-        ship between self-reported inhalation of cigarette smoke
lation and, while some studies demonstrated a higher          and lung cancer mortality. Those who inhale deeply
occurrence of inhalation among lung cancer patients           have risks double those of smokers who do not. The
than among controls, others failed to detect this             American Cancer Society 25 State Study15 reported a
association.                                                  mortality ratio among non-smokers of 1.0, a mortality
   The US Surgeon General was moved by the weight of          ratio of 8.0 among smokers who stated that they did
evidence associating smoking with cancer of the lung,         not inhale, and elevations in this risk among those who
as well as of other sites, to produce an official statement   inhaled slightly (8.9), moderately (13.1) and deeply
on ‘Smoking and Health’ on behalf of the US Govern-           (17.0). Similar results were reported from a Swedish
ment.13 This created a worldwide reaction, since it           study:16 although the mortality ratios among non-
implicated a frightening link between cigarette smoking       smokers (1.0), non-inhalers (3.7), light inhalers (7.8),
and a variety of fatal diseases in a document of impec-       and deep inhalers (9.2) were smaller in magnitude, the
cable scientific authority.                                   same steady pattern was found.
   This report weighed the available evidence, and con-          Although it has been suggested for some time that
sidered that it had been established that cigarette smok-     the risk of developing lung cancer increases with the tar
ing was causally related to lung cancer in men, and judged    and nicotine content of cigarettes there has not been
cigarette smoking in the USA a sufficiently important         any substantial evidence to suggest that individuals
health hazard to warrant remedial action.                     who switch to lower-tar and lower-nicotine cigarettes
   In the 15 years that passed from that initial report,      experience less lung cancer mortality.17 It has been pro-
the body of evidence increased, and extended to include       posed that, if the tar and nicotine contents of tobacco
                                            Epidemiology of lung cancer: a century of great success and ignominious failure 13

were reduced, smokers might increase the number of           (1914–1918). In many countries, such as the USA and
cigarettes smoked per day and effectively vitiate any        the UK, women began to reach the same smoking levels
benefit. On the other hand, those who switch to low-tar      as men during the Second World War (1939–1945).
and low-nicotine brands might inhale smoke more                 Subsequent to this period, cancer was becoming
deeply than smokers of high-tar and high-nicotine ciga-      more frequent, and was developing into an interna-
rettes, and thus exposure to tar and nicotine might be       tional disease that was to become, by the latter part of
reduced.                                                     the 20th century, a significant global public health
   The relationship of tar and nicotine was carefully        problem. An increasing number of forms of cancer
examined with respect to lung cancer in a major study,18     became linked with cigarette smoking: initially oral
in which 897 825 men and women were classified by            cancers, then lung cancer, bladder cancer, laryngeal
levels of tar and nicotine smoked. Brands were consid-       cancer, esophageal cancer, pancreatic cancer, acute
ered to be high in nicotine if they contained between        myeloid leukemia, cervical cancer, kidney cancer, and
2.0 and 2.7 mg of nicotine and high in tar if they con-      gastric cancer. Several of these are of unusually high
tained between 25.8 and 35.7 mg of tar. The medium           frequency in international populations.20
levels of tar and nicotine were set at 17.6 and 25.7 mg
and at 1.2 and 1.9 mg, respectively. Low tar and nico-
tine levels were all those below these limits.               PHASE III: DESCRIPTIVE EPIDEMIOLOGY
   The risk in the high-tar and high-nicotine group of       OF LUNG CANCER
makes was set at 1.0, and the relative risks in the
medium group (risk ratio, RR = 0.95) and low group           The main tobacco-related site is the lung. Lung cancer
(RR = 0.81) were appreciably lower. Similar results were     rates in self-reported non-smokers from various studies
found for females: high (RR = 1.0), medium (RR = 0.79),      are of the order of only 10–15 per 100 000. The IARC
and low (RR = 0.60). These results take into account the     monograph Tobacco Smoking21 gave estimates of the
daily cigarette consumption.                                 proportions of lung cancer deaths attributable to
   In other words, for men smoking the same number of        tobacco smoking in five developed countries (Canada,
cigarettes per day, there appears to be an almost 20%        England and Wales, Japan, Sweden, and the USA):
reduction in the risk of developing lung cancer with the     these ranged between 83% and 92% for males, and
use of cigarettes low in tar and nicotine. In females,       between 57% and 80% for females.
keeping the number of cigarettes smoked per day con-            The most recent, international, cancer incidence data
stant, there appears to be a 40% reduction in risk. The      are available for the period around 1990. The highest
amount of tar and nicotine taken into the body per day       incidence rate in men is recorded among the Afro-
obviously depends on the number of cigarettes smoked         American population of New Orleans in the USA, where
as well as on the tar and nicotine content of individual     the average, annual, age-standardized rate per 100 000
cigarettes. Hammond therefore performed a second             person-years is 110.8 (Table 2.1). Other Afro-American
analysis comparing subjects who smoked 1–19 high-tar         populations in the USA also have remarkably high lung
and -nicotine cigarettes per day with those who smoked       cancer rates in men. Rates are also high among the
20–39 low-tar and -nicotine cigarettes per day. Setting      Maori population of New Zealand, where the incidence
the risk to be 1.0 among the high categories of both         rate is 99.7 per 100 000 (Table 2.1). The incidence rate
males and females, Hammond found risks of 1.6 (males)        is high in Lower Silesia (Poland) and in the west of
and 2.1 (females) among the groups who smoked                Scotland (Table 2.1). There are virtually no regions of
20–39 low-tar and -nicotine cigarettes. He concluded         the world where the annual incidence rates are low: the
that the number of cigarettes smoked per day was rela-       lowest incidence rates are reported from a variety of
tively more important than the tar and nicotine              population groups from the developing world
content.15,18                                                (Table 2.2).
   All these early observations were regarding forms of         Among women, the highest rates are found in
cancer and forms of tobacco smoking that were the            the Maori population group of New Zealand (72.9 per
most common at the period. Cigarette smoking                 100 000) (Table 2.3). High rates are also found among
increased heavily in Europe during the last years of         a variety of populations of North America – both Afro-
Napoleon,19 and the habit spread during the Crimean          American and Caucasian. Notably high rates are
War, accelerated around 1900 and reached many men,           reported from the west of Scotland, where incidence
and increasingly women, during the First World War           rates are high in men as well as in women (Table 2.3).
14 Textbook of Lung Cancer

 Table 2.1 Highest incidence rates of cancer of the trachea, bronchus and lung in men circa 1990

 Registry                                                                                    Cases                          ASRa

 USA, New Orleans: Black (1988–1992)                                                          842                          110.81
 USA, Central Louisiana: Black (1988–1992)                                                    172                          105.62
 USA, Detroit: Black (1988–1992)                                                             2263                          103.23
 USA, San Francisco: Black (1988–1992)                                                       1003                          101.49
 New Zealand: Maori (1988–1992)                                                               387                           99.73
 USA, SEER:b Black (1988–1992)                                                               4964                           99.11
 USA, Atlanta: Black (1988–1992)                                                              892                           97.26
 Poland, Lower Silesia (1988–1992)                                                           7213                           95.52
 Canada, Northwest Territories (1983–1992)                                                    126                           90.26
 UK, Scotland, west (1988–1992)                                                              8877                           88.90
 USA, Los Angeles: Black (1988–1992)                                                         1925                           88.74
 USA, Connecticut: Black (1988–1992)                                                          422                           86.15
 Italy, Ferrara (1991–1992)                                                                   597                           85.73
 USA, New Orleans: White (1988–1992)                                                         1707                           84.01
 Italy, Trieste (1989–1992)                                                                   897                           82.73
     Average, annual, age-standardized rate per 100 000 person-years.
     Surveillance Epidemiology and End Results Program (National Cancer Institute).

 Table 2.2 Lowest incidence rates of cancer of the trachea, bronchus and lung in men circa 1990

 Registry                                                                                        Cases                       ASRa

 India, Karunagappally (1991–1992)                                                                 58                       17.04
 Thailand, Kohn Kaen (1990–1993)                                                                  355                       17.02
 Peru, Lima (1990–1991)                                                                           635                       15.89
 Costa Rica (1988–1992)                                                                           686                       15.63
 India, Bombay (1988–1992)                                                                       1867                       14.48
 Singapore: Indian (1988–1992)                                                                     83                       14.33
 India, Madras (1988–1992)                                                                        789                       12.64
 Peru, Trujillo (1988–1990)                                                                        47                       11.93
 India, Trivandrum (1991–1992)                                                                     69                       10.63
 USA, New Mexico: American Indian (1988–1992)                                                      24                       10.32
 Ecuador, Quito (1988–1992)                                                                       172                       10.13
 India, Bangalore (1988–1992)                                                                     495                        8.06
 Mali, Bamako (1988–1992)                                                                          38                        5.28
 Uganda, Kyadondo (1991–1993)                                                                      20                        4.24
 India, Barshi, Paranda and Bhum (1988–1992)                                                       11                        1.26
  Average, annual, age-standardized rate per 100 000 person-years.

The finding of the incidence rate among women in                                  the world where the incidence rate among women is
Tianjin, China, among the 15 highest incidence rates                              still truly low (Table 2.4).
recorded, is the first clear indication of the rising epi-                           In men in all European countries, except Portugal,
demic of lung cancer, and other cancers, resulting from                           lung cancer is now the leading cause of cancer death. In
the increasing prevalence of cigarette smoking during                             the USA (and in all European countries except a few
recent decades (Table 2.3). There are some regions of                             Scandinavian countries), it is also the commonest tumor
                                                              Epidemiology of lung cancer: a century of great success and ignominious failure 15

 Table 2.3 Highest incidence rates of cancer of the trachea, bronchus and lung in women circa 1990

 Registry                                                                                              Cases                     ASRa

 New Zealand: Maori (1988–1992)                                                                         326                     72.93
 Canada, Northwest Territories (1983–1992)                                                               80                     65.56
 Canada, Yukon (1983–1992)                                                                               39                     47.62
 USA, San Francisco: Black (1988–1992)                                                                  562                     44.33
 USA, Detroit: Black (1988–1992)                                                                       1213                     42.02
 USA, New Orleans: White (1988–1992)                                                                   1115                     41.19
 USA, San Franciso: non-Hispanic White (1988–1992)                                                     3906                     40.42
 USA, Detroit: White (1988–1992)                                                                       4772                     40.17
 USA, Central California: non-Hispanic White (1988–1992)                                               2267                     39.48
 USA, Los Angeles: non-Hispanic White (1988–1992)                                                      6674                     38.58
 UK, Scotland, west (1988–1992)                                                                        5086                     38.47
 USA, SEER:b Black (1988–1992)                                                                         2558                     38.46
 USA, Hawaii: White (1988–1992)                                                                         340                     37.94
 USA, Seattle (1988–1992)                                                                              4413                     37.62
 China, Tianjin (1988–1992)                                                                            3870                     37.00
  Average, annual, age-standardized rate per 100 000 person-years.
  Surveillance Epidemiology and End Results Program (National Cancer Institute).

 Table 2.4 Lowest incidence rates of cancer of the trachea, bronchus and lung in women circa 1990

 Registry                                                                                      Cases                            ASRa

 Malta (1992–1993)                                                                              18                               3.35
 France, La Réunion (1988–1992)                                                                 46                               3.34
 France, Tarn (1988–1992)                                                                       60                               3.19
 Spain, Albacete (1991–1992)                                                                    19                               3.14
 Spain, Tarragona (1988–1992)                                                                   72                               3.09
 Algeria, Setif (1990–1993)                                                                     33                               2.88
 Spain, Granada (1988–1992)                                                                     92                               2.71
 Spain, Zaragoza (1986–1990)                                                                   116                               2.66
 India, Karunagappally (1991–1992)                                                              10                               2.59
 India, Madras (1988–1992)                                                                     142                               2.37
 India, Trivandrum (1991–1992)                                                                  14                               1.89
 India, Bangalore (1988–1992)                                                                  103                               1.67
 Mali, Bamako (1988–1992)                                                                       13                               1.53
 Uganda, Kyadondo (1991–1993)                                                                    4                               0.41
 India, Barshi, Paranda and Bhum (1988–1992)                                                     3                               0.33
     Average, annual, age-standardized rate per 100 000 person-years.

in terms of incidence (although the recent inflation of                        former Czechoslovakia, and the lowest rates being
prostate cancer incidence figures with very early detec-                       reported in southern Europe and in Norway and Swe-
tion of cases is taking prostate cancer above lung cancer                      den.22 This overall pattern of age-standardized lung
in terms of the incidence of the disease). The range of                        cancer mortality rates does not reveal the important
geographic variation in lung cancer mortality in Europe                        and diverging cohort effects occurring in various coun-
is threefold in both sexes – the highest rates being                           tries: for instance, some of the countries in which there
observed in the UK, Belgium, the Netherlands, and the                          are now low rates, such as those in southern Europe
16 Textbook of Lung Cancer

and parts of eastern Europe, experienced a later uptake        chial mucosa was exposed to radon gas and its decay
and spread of tobacco use, and now appear among the            products: this last exposure was reviewed and it was
most elevated rates in the younger age groups. This            concluded that there was ‘sufficient evidence’ that this
suggests that these same countries, including Italy,           occupational exposure caused lung cancer.28 A greater
Greece, France, Spain, and several countries in eastern        risk of lung cancer is generally seen for individuals who
Europe, will have the highest lung cancer rates in men         are exposed at an older age. Investigation of the interac-
at the beginning of the next century, in the absence of        tion with cigarette smoking among atomic bomb survi-
rapid intervention.                                            vors suggests that it is additive,29 but the data from
   The importance of adequate intervention is shown            underground miners in Colorado are consistent with a
by the low lung cancer rates in Scandinavian countries,        multiplicative effect.30
which have adopted, since the early 1970s, integrated             In conclusion, the overwhelming role of tobacco
central and local policies and programs against                smoking in the causation of lung cancer has been
smoking.23,24 These policies may have been enabled by          repeatedly demonstrated over the past 50 years. Cur-
the limited influence of the tobacco lobby in these            rent lung cancer rates reflect cigarette smoking habits of
countries. The experience in Finland provides convinc-         men and women over past decades,31–33 but not neces-
ing evidence of the favorable impact, after a relatively       sarily current smoking patterns, since there is an inter-
short delay, of well-targeted large-scale interventions on     val of several decades between the change in smoking
the most common cause of cancer death and of prema-            habits in a population and its consequences on lung
ture mortality in general.                                     cancer rates. Over 90% of lung cancer may be avoidable
   With specific reference to women, current rates in          simply through avoidance of cigarette smoking. Rates
most European countries (except the UK and Ireland)            of lung cancer in central and eastern Europe at present
are still substantially lower than in the USA, where lung      are higher than those ever before recorded elsewhere;
cancer is now the leading cause of cancer death in             lung cancer has increased tenfold in men and eightfold
females. In several countries, including France, Swit-         in women in Japan since 1950; there is a worldwide
zerland, Germany, and Italy, where smoking is now              epidemic of smoking among young women,34 which
becoming commoner in young and middle-aged                     will be translated into increasing rates of tobacco-re-
women, overall national mortality rates are still rela-        lated disease, including cancer, in the coming decades;
tively low, although appreciable upward trends have            there is another epidemic of lung cancer and tobacco-
been registered over the last two decades. This is par-        related deaths building up in China as the cohorts of
ticularly worrisome in perspective, since smoking prev-        men in whom tobacco smoking became popular reach
alence has continued to increase in subsequent                 ages at which cancer is an important hazard.35 Many
generations of young women in these countries. Thus            solutions have been attempted to reduce cigarette
the observation that lung cancer is still relatively rare in   smoking, and increasingly many countries are enacting
women, with smoking at present accounting for only             legislation to curb this habit.36
approximately 40–60% of all lung cancer deaths, cannot
constitute a reason for delaying efficacious interventions
against smoking by women. The currently more favor-            PHASE IV: PUBLIC HEALTH FAILURE, 1960s
able situation in Europe compared with the USA,                ONWARDS
together with the observation that smoking cessation
reduces lung cancer risk after a delay of several years,       Thus it has been clear for the entire second half of the
should, in the presence of adequate intervention, enable       20th century that cigarette smoking causes lung cancer.
a major lung cancer epidemic in European women to              Current low levels of smoking among physicians and
be avoided.                                                    research scientists in many countries have led many of
   A proportion of lung cancers, varying in various            them unconsciously to overlook tobacco smoking as an
countries and geographic areas, may be due to expo-            important cause of cancer.37 There is, however, a very
sures at work, and a small proportion to atmospheric           substantial body of evidence from many sources that
pollution.25 The effect of atmospheric pollution in            indicates the carcinogenicity of tobacco smoking. Not
increasing lung cancer risk appears to be chiefly con-         only does cigarette smoking greatly increase the risk of
fined to smokers. Lung cancer risk is elevated in atomic       lung cancer in smokers, but the risk of oral cavity can-
bomb survivors,26 in patients treated for ankylosing           cer, laryngeal cancer, esophageal cancer, bladder can-
spondylitis,27 and in underground miners whose bron-           cer, pancreatic cancer, and kidney cancer is also
                                               Epidemiology of lung cancer: a century of great success and ignominious failure 17

increased. The risk of cancer of the cervix and stomach         nor is there evidence that the effect of cigarette smoking
may also be increased, although the evidence for this is        on lung cancer risk is greater in women than in men.
much less consistent.38 These forms of cancer can be            The dominance of the effect of duration of smoking
expected to rise in women as a result of their increased        means that a long period of time will pass between the
levels of cigarette smoking.                                    exposure (large numbers of women smoking) and the
   There is at present a worldwide epidemic of tobacco-         effect (high levels of lung cancer). Lung cancer now
related disease: not only does smoking cause increased          exceeds breast cancer as the leading cancer cause of
levels of many different common forms of cancer, it             death in women in the USA, Canada, Scotland, and sev-
also increases the risk of cardiovascular disease. As           eral other countries. In Canada, breast cancer mortality
mentioned in the previous section, deaths from lung             has remained at least constant for nearly four decades,
cancer, the tumor most strongly linked to cigarette             while lung cancer death rates have increased between
smoking, have increased in Japan by a factor of 10 in           three- and fourfold during the same period. While the
men and 8 in women since 1950. In central and eastern           higher case-fatality of lung cancer may be one factor in
Europe, more than 400 000 premature deaths are cur-             the mortality rates overtaking breast cancer, there is,
rently caused each year by tobacco smoking. In young            increasingly, evidence that there are regions of the
men in all countries of central and eastern Europe, there       world where the gap in the incidence rate is now clos-
are current levels of lung cancer that are greater than         ing. For example, in Glasgow, an area where lung can-
anything seen before in the Western countries, and              cer has been historically high, by 1990 the incidence
these rates are still rising. In Poland – a country severely    rate for lung cancer (115 per 100 000) exceeded that
hit by the tobacco epidemic – the life-expectancy of a          for breast cancer (105 per 100 000) in 1990.40 Among
45-year-old man has been falling for over a decade now          international cancer registries, there are some where the
owing to the increasing premature death rates from              incidence of lung cancer now exceeds the incidence of
tobacco-related cancers and cardiovascular disease.39           breast cancer, and others where there is still a gap. In
Tragically, cigarette smoking is still increasing in central    the SEER (Surveillance Epidemiology and End Results)
and eastern Europe and also in China, where an epi-             Program of the US National Cancer Institute, the inci-
demic of tobacco-related deaths is building up quickly.         dence of lung cancer in both Black and White women
Tobacco smoking is also the most easily avoided risk            increased by over 90% between 1973–1977 and 1988–
factor for cancer.                                              1992: the increase in the incidence of breast cancer was
   The most important determinant of risk of lung can-          around 25% in both racial groups (comparison made
cer is the duration of smoking: long-term cigarette             between incidence rates age-adjusted using the 1970
smokers have a 100-fold increased risk compared with            US population). It is a great worry that there does not
never-smokers. The content of cigarettes (low tar) pro-         appear to be any end in sight to this increase in lung
duces only a threefold variation in risks between the           cancer risk internationally: it is programmed to con-
extremes. (‘Low tar’ is frequently taken to include a           tinue for several decades to come.
number of features, including filter-tips as well as the           Part of the complacency over the effect on women
active tar yield.) Lung cancer is the major tobacco-re-         was also due to the strong tendency for women to
lated tumor and the leading cause of cancer death in            smoke brands of cigarettes that were lower in tar and
men in almost every developed country. Incidence rates          nicotine content than those smoked by men: it was
are around 10–15 per 100 000 in non-smokers and                 assumed that these would have less of a risk for lung
between 80 and 100 per 100 000 in the highest-inci-             cancer than the higher-tar cigarettes that men generally
dence population groups such as Afro-Americans, and             smoked. Marked changes in the rates of the major his-
rates exceeding 200 per 100 000 have been reported in           tologic cell types of lung cancer can now
cities of central and eastern Europe. Since lung cancer         be seen, with particular increases in the risk of
is frequently fatal, mortality rates are high, and conse-       adenocarcinoma.41,42 The changes seen are compatible
quently so are the social costs.                                with increased risk of adenocarcinoma due to increasing
   Women around the world have taken up the ciga-               levels of smoking of ‘light’ cigarettes (low-tar, low-nic-
rette smoking habit with gusto. For many years, it              otine). It appears that abandoning high-tar cigarettes
appeared that their lung cancer rates were low and that         (15–45 mg tar) may have some impact on reducing
tobacco was not having the same effect as on men. This          squamous-cell carcinoma risk, but this is now being
complacency, which crept in during the two decades              balanced by ‘light’ cigarettes increasing the risk of ade-
from the mid-1960s especially, is now exposed as false:         nocarcinoma.
18 Textbook of Lung Cancer

   Cigarette smoking kills half of all those who                    11. Doll R, Hill AB. Smoking and carcinoma of the lung. BMJ 1950;
adopt the habit, with 50% of these deaths occurring in                  ii: 739–48.
                                                                    12. Doll R, Hill AB. A study of the aetiology of carcinoma of the
middle age and each losing an average of 20 years of
                                                                        lung. BMJ 1952; ii: 1271–86.
non-smoker’s life expectancy.43 It kills in over 24 differ-         13. US Public Health Services, Smoking and Health. Report of the
ent ways, with the lung being the commonest cancer                      Advisory Committee to the Surgeon General of the Public
site.43 Lung cancer rates have been declining in men                    Health Service. US Department of Health, Education and Wel-
and increasing in women: cigarette smoking in men has                   fare, Public Health Service, Center for Disease Control, DHEW
been declining while it has been increasing in women.                   Publication 1103: Washington, DC, 1964.
                                                                    14. United States Surgeon General, Smoking and Health. A Report
These two trends are closely related. The move to ‘light’
                                                                        of the Surgeon General. US Department of Health, Education
cigarettes, which is increasingly common, now appears                   and Welfare, Public Health Service, DHEW Publication (PHS)
to be linked to increases in adenocarcinoma of the lung,                79-50066: Washington, DC, 1979.
and shows no sign of being linked to a reduced risk                 15. Hammond EC. Smoking in relation to death rates of one million
overall. There is no such thing as a ‘safe cigarette’.                  men and women. Natl Cancer Inst Monogr 1966; 19: 127–204.
Smokers should be urged and helped to stop smoking;                 16. Cederlof R, Friberg L, Hrubec Z, Lorich U. The Relationship of
                                                                        Smoking and Some Social Covariates to Mortality and Cancer
children and young adults should be convinced not to                    Morbidity. A Ten Year Follow-up in a Probability Sample of
smoke. Tobacco can become an addictive drug: it                         55,000 Swedish Subjects Age 18–69, Parts 1 and 2. Stockholm:
should be left alone.20                                                 Karolinska Institute, 1975.
                                                                    17. Bross IDJ, Gibson R. Risks of lung cancer in smokers
                                                                        who switch to filter cigarettes. Am J Publ Health 1968; 58:
ACKNOWLEDGMENTS                                                     18. Hammond EC, Garfinkel L, Seidman H, Lew EA. Some recent
                                                                        findings concerning cigarette smoking. In: Hiatt HH, Watson
It is a pleasure to acknowledge that this work was con-                 JD, Winsten JA, eds. Origins of Human Cancer. Book A: Inci-
                                                                        dence of Cancer in Humans. New York: Cold Spring Harbor
ducted within the framework of support from the Asso-
                                                                        Laboratory, 1977; 101–12.
ciazione Intaliana per la Ricerca sul Cancro (Italian               19. Bouisson J. Du cancer buccal chez les fumeurs. Montpellier
Association for Research on Cancer).                                    Med 1859; 2: 539–99.
                                                                    20. Boyle P, Veronesi U, Tubiana M et al. School of Oncology Advi-
                                                                        sory Report to the European Commission for the ‘Europe
                                                                        Against Cancer Programme’ European Code Against Cancer.
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                                                                    21. IARC (International Agency for Research on Cancer), Mono-
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    3         Molecular biology of lung cancer
              Thomas Tuxen Poulsen, Hans Skovgaard Poulsen, Helle Pappot

              Contents Introduction • Growth signals and lung cancer • Apoptosis in lung cancer • Aberrant
              anti-growth signaling • Replicative potential and telomerases • Angiogenesis • Tissue invasion
              and metastasis • Conclusion

INTRODUCTION                                                   Normal cells depend on external growth stimulating
                                                               signals to proceed from quiescence to proliferation
It becomes more and more important to understand the           and these growth stimuli are often provided by neigh-
biology of lung cancer as new therapeutic agents are           boring cells in the immediate microenvironment,
emerging in the field of clinical oncology. These agents       for instance by release of diffusible growth factors
are often referred to as targeted therapy or biologic          or expression of cell adhesion molecules. These inter-
therapy. New advances in molecular technologies are            relations between the cell and its environment allow
providing insight into the pathobiology of lung cancer         for establishment of normal tissue homeostasis with
development. It is now known that clinical lung can-           a tight regulation of tissue modeling, growth, and
cers have accumulated numerous clonal genetic and              regeneration.
epigenetic alterations as a multistep process.1 In many           Tumor cells have lost their dependency on growth
research laboratories molecular studies are these days         stimulatory signals from the external environment and
performed in an integrated approach with clinical              are fully capable of proliferating independently. This
investigators to find new ways for early diagnosis, risk       phenotype of growth autonomy is attained by a variety
assessment, prevention, and treatment for this frequent        of molecular changes and gene mutations within the
and deadly disease. In the following, the spectrum of          cell, typically characterized by a state of growth factor
molecular alterations in lung cancer are described as          self-sufficiency, where the cell itself produces the
hallmarks of cancer, subdivided as suggested by Hana-          required growth factors and receptors, resulting in a
han and Weinberg:2                                             self-stimulatory autocrine signaling loop. Aberrant
                                                               expression and signaling by a number of growth factors
•   abnormalities in self-sufficiency          of   growth
                                                               and cognate receptors have been identified, which
                                                               increase the cellular proliferative potential in lung can-
•   evading apoptosis;
                                                               cer. In non-small cell lung cancer (NSCLC) these
•   insensitivity to anti-growth signals;
                                                               include upregulation/mutation of certain receptor
•   limitless replicative potential;
                                                               tyrosine kinases (RTKs), in particular the epidermal
•   sustained angiogenesis;
                                                               growth factor receptor (EGFR, ErbB1) and other mem-
•   tissue invasion and metastasis.
                                                               bers of the ErbB RTK family. In small cell lung cancer
                                                               (SCLC) overexpression of insulin-like growth factor I
GROWTH SIGNALS AND LUNG CANCER                                 (IGF-I) and its receptor as well as a number of neuronal
                                                               growth stimulators is frequently observed.
In tumor cells, activated (proto)oncogenes often encode           An overview of the changes in expression and signal-
molecules involved in aberrant growth factor signaling,        ing of central growth factors and receptors, signal trans-
either by directly promoting cell growth, by mimicking         ducers, and transcription factors in lung cancer is
other growth factors, or by neutralizing growth inhibi-        presented below and summarized in Table 3.1. The
tory signals. Growth factors are proteins that bind to         section will conclude with a presentation of related
receptors (usually on the cell surface) and trigger            experimental therapeutic strategies developed to target
activation of cellular proliferation and/or differentiation.   these mediators for future treatment of lung cancer.
                                                                                             Molecular biology of lung cancer 21

 Table 3.1 Growth signals and lung cancer

 Signaling mediators involved in activating growth signaling in lung cancer

                                         Aberrant activation/mutation frequency

 Oncogene                                NSCLC (%)                             SCLC (%)                        References

 EGFR                                    50–90                                 —                               3, 4
 HER2-Neu                                ∼30                                   —                               33
 IGF-I                                   —                                     >95                             9
 C-Kit/C-Met                             —                                     Up to 70                        12, 13
 K-ras                                   ∼20–30                                —                               15
 Neuropeptides                           16–47                                 All                             17
 C-myc                                   up to 50                              10–40                           23, 24

Epidermal growth factor receptor overexpression                    in hydrolyzation of phosphoinositide 4,5-bisphosphate
and signaling in NSCLC                                             (PIP-2) to generate inositol-3-phosphate (IP3) and
Overexpression of EGFR occurs in 50–90% of all                     diacylglycerol (DAG) (Figure 3.1, the left-hand path-
NSCLC and is particularly common in squamous cell                  way). This results in the release of calcium ions from intra-
carcinoma,3,4 whereas EGFR overexpression is rare in               cellular stores, which affects cell motility and migration
SCLC. The receptor is membrane associated and con-                 by interfering with the activity of actin-modulatory
tains three main regions: an extracellular ligand binding          proteins. The activation of PLC-γ also activates
domain, a hydrophobic membrane spanning region,                    protein kinase C (PKC), which causes attenuation of
and a cytoplasmic part holding the catalytic tyrosine              EGFR signaling by a negative feedback mechanism.
kinase activity. Upon ligand binding, EGFR undergoes               The different pathways by which activated EGFR
a conformational change, leading to dimerization of the            exerts its proliferative, migratory, and anti-apoptotic
receptor and activation of the intracellular catalytic             effects, and the fact that many of the involved signaling
domain by phosphorylation of tyrosine residues. The                modulators have been found to cross-react between
phosphorylated tyrosine residues serve as binding sites            pathways, provide a central, yet complex, role for EGFR
for a number of different downstream signaling mole-               in cell transformation. In NSCLC, increased EGFR sig-
cules and adaptors within the cell. Three major signal-            naling is obtained by an increased gene copy number
ing pathways downstream of EGFR are outlined                       and by activating mutations within the EGFR gene.6
in Figure 3.1. One of the most intensively studied                 One mutated EGFR variant termed EGFRvIII, com-
cascades is the Ras/Raf/ERK pathway (the right-hand                monly found in various malignancies including ∼16%
pathway in Figure 3.1). The effects of this pathway are            of NSCLC, has gained increasing interest in recent
diverse (for a review see reference 5), with a large num-          years. EGFRvIII lacks the extracellular ligand-binding
ber of Ras effectors, but in general Ras signaling upon            domain, rendering the receptor incapable of binding
EGF stimulation has been associated with increased cell            any ligands, yet the receptor is constitutively active
growth and proliferation. One of the three ras genes,              and fully capable of activating downstream modula-
Kirsten-ras (K-ras, p21-ras), is mutated in ∼30% of                tors.7 In recent years, novel activating mutations within
NSCLC. The oncogenic impact of this mutation in lung               the tyrosine kinase domain of EGFR have been identi-
cancer is discussed further below.                                 fied in NSCLC. These mutations have gained massive
   Another central pathway in EGFR signaling involves              interest, since they have been found to correlate with
activation of PI3-kinase and AKT (PKB). This pathway               increased response to treatment with EGFR tyrosine
generally serves to promote cell survival, by inhibition           kinase inhibitors.8
of various cell cycle regulators such as glycogen syn-                Another member of the ErbB family is HER2-Neu
thase kinase 3 (GSK3) and the pro-apoptotic protein                (ErbB2), which is overexpressed in ∼30% of NSCLC.
BAD (Figure 3.1, the middle pathway).                              No ligands for Her2-Neu have yet been identified but
   A final key pathway activated by EGFR involves                  the receptor is a central dimerization partner for the
the activation of phospholipase C-γ (PLC-γ), resulting             other RTKs of the ErbB family. To date, results are
22 Textbook of Lung Cancer

                                                                         EGFR dimer

                                                                   EGF                  EGF


                          PKC              IP3                                                  Ras
                                                                         TK      TK
                                                                                      SHC                   MEK

                                    Ca2+                                                                Cytosol

                                              GSK3                   BAD


                                                  Altered gene expression

                       - Increased cell growth and proliferation
                       - Downregulation of apoptotic response
                       - Increased cell motility/migration

Figure 3.1
EGFR signaling. Upon ligand binding EGFR dimerizes, resulting in a complex signaling response within the cell. Oncogenic EGFR signaling
occurs through three major pathways: the Ras/ERK (right-hand), the PI3-kinase AKT (middle), and the phospholipase C-γ (left-hand)
pathways, resulting in an increased malignant potential of the cells. For further explanation see text.

conflicting with regard to Her2-Neu overexpression                       binding of IGF binding proteins present in the extracel-
and prognosis in NSCLC.                                                  lular fluids and serum to the IGF ligands. As for EGFR,
                                                                         activated IGF-IR signaling is complex but primarily
Overexpression of other growth factor receptors                          occurs through the Ras/Raf/ERK and the PI3-kinase/
and ligands                                                              AKT pathways. A correlation between significantly
The expression level of the mitogen IGF-I is elevated in                 elevated IGF-I serum levels and lung cancer risk has
the majority of SCLC, resulting in a self-stimulatory                    been reported, but results of other studies are
autocrine loop involving the IGF-I receptor which is                     conflicting.10,11
commonly co-expressed in this malignancy.9 IGF sig-                         The RTK c-Kit and its ligand stem cell factor (SCF) is
naling proceeds through binding of IGF ligands (IGF-I                    another receptor/ligand system, upregulated in more
and II) to cell surface RTKs (IGF-IR and -IIR). The bio-                 than 80% of SCLC tumors.12 A study of c-Kit expres-
logic activity of the signaling system is modulated by                   sion in SCLC patients identified c-Kit as a marker for
                                                                                       Molecular biology of lung cancer 23

increased survival13 – an observation which appears          G-protein-coupled receptors, resulting in activation of
contradictory to the oncogenic properties of c-Kit sig-      various downstream signaling pathways including PLC,
naling. However, the patients enrolled in this study were    PI3-kinase, and certain kinases, involved in cellular
receiving chemotherapy targeting actively dividing           focal adhesion. Gastrin releasing peptide (GRP) signal-
cells, and since activation of c-Kit induces cell prolif-    ing via the GRP receptor (GRP-R) has become one of
eration, the active receptor may render the malignant        the most intensively studied neuropeptide signaling
cells more susceptible to cytotoxic treatment, thereby       pathways in SCLC, since different studies have shown
improving overall survival.                                  that blocking GRP or GRPR activity inhibits SCLC cell
   c-Met is yet another RTK often overexpressed in           growth in vitro and in vivo, whereas GRP addition
SCLC. Signaling through this receptor system has             to SCLC cells induces cell proliferation.18,19 The con-
been reported to be associated with tumor growth and         centration of the GRP precursor pro-GRP is highly ele-
metastasis. In contrast to the c-Kit/SCF system, the         vated in the majority of SCLC patients and levels
c-Met ligand hepatocyte growth factor (HGF) is rarely        decrease upon tumor resection, indicating that pro-
co-expressed with the receptor in SCLC,12 but is             GRP serum levels may serve as a detection and moni-
expressed and secreted from surrounding normal lung          toring marker for patients with this disease. Other
fibroblasts. This observation indicates a paracrine rather   neuropeptides highly expressed in lung cancer include
than autocrine activating loop of c-Met expression in        bradykinin, neuron specific enolase and L-Dopa decar-
lung cancer. The importance of paracrine c-Met signal-       boxylase. Whether these molecules play an oncogenic,
ing for lung cancer pathogenesis has been investigated       growth-promoting role in lung cancer and/or whether
further in a study where c-Met-expressing lung cancer        they may potentially serve as clinical markers remains
cells were transplanted into HGF-overexpressing              controversial.
mice, resulting in increased metastatic potential of the        In recent years, the expression of the neuroendocrine
transplanted cells.14                                        transcription factor Achaete–Scute homolog 1 (ASH1)
                                                             in SCLC has gained increased attention. ASH1 is nor-
Activating Ras mutations                                     mally expressed in neuronal progenitor cells during
As mentioned, mutations of the intracellular membrane-       early fetal development of various tissues including the
associated signaling mediator Ras (Figure 3.1, green         central nervous system and the lung. Expression is vir-
pathway) with a high overrepresentation of mutations         tually absent in the normal adult organism, but ASH1
in the K-ras gene are detected in up to 30% of NSCLC,15      is reactivated and highly expressed in SCLC and in
but rarely in SCLC patients. Ras protein becomes             other lung tumors with a neuroendocrine phenotype,
activated by the binding of guanine triphosphate (GTP),      including a minority of large cell and adenocarcinomas.
allowing for transmission of growth stimulatory signals      High expression of ASH1 seems to correlate with poor
to the cell nucleus. Downregulation of Ras signaling         differentiation of these lung tumors, since expression is
occurs by hydrolysis of GTP to GDP, mediated by the          virtually absent in fully differentiated carcinoid tumors.20
GTPase-activating protein (GAP). In NSCLC and other          Furthermore, ASH1 expression is tightly linked to clas-
malignancies, activating point mutations in the K-ras        sic neuroendocrine markers including L-Dopa decar-
gene result in resistance to GAP activity, thereby trap-     boxylase. Although future research is clearly necessary
ping the Ras protein in a constitutively active state,       to clarify the role of ASH1 in lung cancer pathogenesis,
capable of continuous growth promoting signaling.            many studies suggest ASH1 expression as a critical
Controversy exists as to whether K-Ras mutations serve       pathogenic factor in neuroendocrine lung tumors. The
as a marker for poor prognosis in lung cancer, but a         overexpression of ASH1 induces lung tumors and cell
global meta-analysis correlated the presence of point-       hyperplasia in mouse models,21 and one study reported
mutated constitutively active Ras in NSCLC with a poor       significant inhibition of SCLC cell growth after ASH1
prognosis.16                                                 knock out in vitro and in vivo.22

Overexpression of neuropeptides                              Amplification of myc
Highly elevated expression of different neuropeptides        Members of the c-myc, N-myc, and L-myc (proto)onco-
is a hallmark of SCLC and many of these markers              gene family are commonly amplified in SCLC and
have also been detected in some (mainly poorly differ-       NSCLC, resulting in overexpression of Myc transcrip-
entiated) NSCLC tumors.17 Neuropeptides exert their          tion factors.23,24 Myc protein competes with other tran-
effect via binding to seven transmembrane (7TM)              scription factors to bind Max, resulting in activation
24 Textbook of Lung Cancer

and repression of a number of genes. Although the con-       inactive and must be associated with the plasma mem-
tributions of myc amplification to lung cancer patho-        brane to contribute to cell signaling. For this association
genesis remain to be elucidated, recent studies point to     to occur, synthesized Ras protein is post-translationally
a role for myc in promoting cell cycle progression by        modified by addition of a farnesyl group. Farnesylation
activation of key cell cycle molecules responsible for       is mediated by a specific enzyme – the farnesyl
entry into the S-phase of the cell cycle (for a review of    transferase – and targeting this reaction with farnesyl
myc signaling in lung cancer see reference 25). In com-      transferase inhibitors has been investigated clinically
bination with loss of tumor suppressor genes such as         for treatment of lung cancer and other malignancies.
Rb (the properties of which will be discussed in a later     Despite promising preclinical data and reported
section), myc has been shown to significantly contrib-       responses in patients with breast cancer and certain
ute to decreased cell cycle arrest and deregulated tumor     leukemias, the results of the use of farnesyl transferases
growth.26                                                    for treating lung cancer have been disappointing, with
                                                             lack of tumor regression in all of the clinical studies
Experimental therapeutic targeting of growth                 reported to date.28
factors and oncogenes in lung cancer                            The monoclonal antibody imatinib targets a number
In the previous sections, a number of different growth       of RTKs including c-Kit and has been evaluated in two
factors and oncogenes of importance for lung cancer          recent phase II studies for treatment of SCLC. Disap-
biology have been presented. Knowledge gained about          pointingly, both studies report no inhibitory effect on
the properties of these molecules has allowed for            tumor growth, even in patients with c-Kit-positive
the development of novel therapeutics targeting              tumors.29,30 Apart from the clinical studies reported to
key activating, growth promoting, and tumorigenic            date, a number of preclinical investigations have shown
pathways.                                                    promise for anti-growth-signaling targeted therapy
   A research area of major focus in recent years has        of lung cancer. Therapeutic blockade of IGF-I signaling
been therapeutic targeting of EGFR in NSCLC. There           by an IGF-IR-specific tyrosine kinase inhibitor has
are two general strategies for inhibiting signaling via      been reported to enhance the sensitivity of SCLC cells
EGFR. One is to prevent binding of ligand by blocking        to chemotherapy in vitro, correlating with inhibition of
the ligand binding site (commonly with a monoclonal          the anti-apoptotic PKB signaling pathway.31 Finally,
antibody) and the other is to directly inhibit receptor      therapeutics have been developed which target neu-
signaling by blocking activity of the cytoplasmic tyrosine   ronal markers overexpressed in lung cancer, primarily
kinase domain. Belonging to the first group, cetuximab       SCLC. However, a phase I clinical trial using an anti-
is a humanized monoclonal EGFR antibody, which is            body targeting GRP in patients with SCLC reported no
presently under development and testing for treatment        significant therapeutic response.32 In contrast, recent
of NSCLC. The results of a recently published phase          pre-clinical data showed growth suppression of SCLC
I/II clinical trial have shown an effect of cetuximab        cells after knockout of ASH1 in vitro and in vivo.22
in combination with chemotherapy of NSCLC,27 and
further clinical studies are ongoing at present.
   The two most clinically advanced RTK inhibitors           APOPTOSIS IN LUNG CANCER
are erlotinib and gefitinib, and erlotinib recently
obtained FDA approval for second-line treatment              Apoptosis is a morphologically and biochemically
of NSCLC. As previously mentioned, a number of               distinct form of cell death that occurs under various
mutations in the RTK domain of EGFR have been                physiologic and pathologic conditions triggered by
identified in NSCLC.8 Importantly, the presence of           extrinsic and intrinsic cellular and molecular damage. It
RTK mutations seems to correlate positively with the         is characterized by the activation of a specific event of
response to treatment with gefitinib, suggesting that        molecular processes followed by certain morphologic
these mutations may serve as classifiers for selecting the   changes such as shrinkage of the cell, condensation
patients who will benefit from EGFR-RTK inhibiting           of chromatin, and disintegration of the cell into small
treatments.                                                  fragments.
   As previously mentioned, the gene encoding the               Today many of the key players in cellular apoptosis
growth promoting Ras protein is mutated in up to 30%         regulation have been identified and activators and
of NSCLC, making this protein a potential target for         inhibitors have been characterized and can therefore be
therapeutic intervention. Cytoplasmic Ras protein is         targeted by therapeutic agents. Apoptosis is activated
                                                                                           Molecular biology of lung cancer 25

by a family of intracellular cysteine proteases called cas-       formation of a pore that releases mitochondrial inter-
pases. They are synthesized as zymogens and activated             membrane space proteins. After its release, cytochrome
by proteolytic cleavage. They are divided into two dis-           c binds to apoptotic protease activating factor-1 (APAF-1).
tinct classes, initiator caspases, which include caspases         APAF-1 binds to procaspase-9 forming a multiprotein
P8, P9, and P10, and effector caspases, which include             complex, called an apoptosome, which activates effec-
caspases P3, P6, and P7.                                          tor caspases through caspase-9 (Figure 3.2).
   Current knowledge suggests that there are two sepa-               Anti-apoptotic factors such as Bcl-2-related proteins
rate pathways of caspase activation. One starts with              antagonize BAX and BAK. In addition, IAP (inhibitor of
binding of an extracellular ligand to its cell surface            apoptosis protein) binds and inhibits apoptosome-
receptor. The ligands are TNF, FasL, and Trail, and               related caspases. However, this inhibition can be
their respective receptors are TNFRI, FAS, and DR4 and            relieved by the release of another mitochondrial pro-
DR5. The ligand binding triggers initiator caspase acti-          tein, called Smac/Diablo, which binds to the IAP and
vation through a death inducing signaling complex                 releases active caspases. The most widely studied IAP
(DISC), resulting in caspase-P8 activation of effector            is survivin. Activators and inhibitors are influenced
caspases, either directly or through BCL-2 interacting            by several other proteins including p53, RB, PTEN,
domain (BID)-mediated release of cytochrome c from                Raf-ERK, PI3K-PKB, and Hsp70.33,34
mitochondria (Figure 3.2). The other caspase activation              The apoptotic pathways and possible defects have
pathway starts with release of cytochrome c from the              not been studied much in human lung cancer, and
intermembrane space of mitochondria. Two proapop-                 therefore only sporadic, non-conclusive data are avail-
totic family members, BAX and BAK, appear to facili-              able. However, recently it has been shown that DR4
tate cytochrome c release by participating in the                 and DR5 are upregulated in NSCLC, and overexpres-
                                                                  sion of DR5 correlates with a poor prognosis in patients
                                                                  with NSCLC. Bcl-2 expression is higher in SCLC com-
   Death                                                          pared with NSCLC. Furthermore, data have indicated
               Death receptor           Mitochondrial             that the BAX:Bcl-2 ratio might be of importance for
                 pathway                  pathway                 resistance to apoptosis. Caspase-8 and caspase-10 might
                                                                  be deregulated, and differences in deregulation in SCLC
               Death receptor                        Membrane     compared with NSCLC especially concerning caspase-8
                                                                  have been observed, resulting in deregulation of DISC.
              PROCASP 8/10                                        Others have found that the apoptosome signaling might
FADD                                                              be blocked. In addition, it has been indicated that
                                                   Mitochondria   downregulation of caspase-3 is correlated with a poor
                                                                  prognosis in patients with NSCLC.33,35
                                           BID                       Survivin is increased in most NSCLC and it has been
 DISC                                                             shown that absence of its expression might be associ-
                                                                  ated with improved prognosis. In addition, previously
                                                                  unpublished microarray data show that survivin is
                                                 Cytochrome c     upregulated in SCLC in human cell lines, xenografts,
              CASP 8 (CASP10)
                                                                  and resected tumors from patients (Figure 3.3)36
                                                   PROCASP 9      (Poulsen HS, unpublished data).
       CASP3,6,7                                    APAF1
                                                                  Targeting apoptotic pathways
                                                                  Treatment with TNF has been undertaken. However,
                                                                  due to pronounced general toxicity, its potential as a
                                                                  therapeutic drug is limited. Recently TRAIL agonists
        APOPTOSIS           CASP 9
                                                                  have been approved for clinical trials but no data are
                                                                  presently available.
Figure 3.2                                                           Small molecule inhibitors of Bcl-2 have been devel-
Apoptosis. Major pathways to apoptosis: two pathways lead to
apoptosis, an extrinsic pathway through death receptors and an
                                                                  oped and are at the moment being tested in preclinical
intrinsic pathway through the mitochondria. The two pathways      trials. In addition, antisense constructs against survivin
overlap and interact.                                             have been produced and tested in phase I clinical trials.
26 Textbook of Lung Cancer


  Microarray signal




                                 Fetal brain
                             Adrenal gland
                             Salivary gland
                            Skeletal muscle
                             Small intestine

                                                           CPH 54A
                                                      CPH 54A Xeno
                                                           CPH 54B
                                                     CPH 136A Xeno
                                                              GLC 2
                                                              GLC 3
                                                        GLC 3 Xeno
                                                             GLC 14
                                                       GLC 14 Xeno
                                                             GLC 16
                                                             GLC 19
                                                             GLC 26
                                                             GLC 28
                                                            DMS 53
                                                            DMS 79
                                                            DMS 92
                                                           DMS 114
                                                           DMS 153
                                                           DMS 273
                                                      DMS 273 Xeno
                                                           DMS 406
                                                           DMS 456
                                                          H69 Xeno
                                                            NCI 417
                                                       NCI 417 Xeno
                                                           MAR H24
                                                      MAR H24 Xeno
                                                           MAR 86H

                                                                                                                         SCLC tumor 1
                                                                                                                         SCLC tumor 2
                                                                                                                         SCLC tumor 3
                                                                                                                         SCLC tumor 4
                                                                                                                         SCLC tumor 5
                                                                                                                         SCLC tumor 6
                                Normal tissues                        SCLC cell lines and xenografts                       Tumors

Figure 3.3
Survivin in SCLC. Survivin mRNA expression in SCLC cell lines, xenografts, and resected patient tumors compared with normal tissue.

In addition, an adenovirus-based gene therapy approach                   A review of key tumor suppressors, frequently
targeting survivin is under development.37                            mutated in lung cancer is presented below and sum-
                                                                      marized in Table 3.2, followed by an update within the
                                                                      field of tumor suppressor reactivation in experimental
ABERRANT ANTI-GROWTH SIGNALING                                        lung cancer therapy.

Apart from upregulation of growth stimulatory signal-                 Tp53 mutations
ing, cancer cells often lack expression of a number of                The transcription factor p53 is one of the most intensely
tumor suppressors. In contrast to oncogenes, tumor                    studied tumor suppressors. The Tp53 gene is located
suppressor genes act to prevent and control cell growth,              within a region of chromosome 17 (17p13), which is
often via tight control of cell cycle progression. Full               mutated or altered in the majority of lung cancers with
inhibition of tumor suppressor activity often requires                a specifically high prevalence in SCLC and squamous
inactivation of both alleles of a tumor suppressor gene               cell carcinoma.38,39 The types of Tp53 alterations observed
in the cancer cell. This dual inactivation is frequently              in lung cancer range from gross chromosomal changes
accomplished by a two-step process, involving a chro-                 such as LOH, homozygous deletions, and DNA re-
mosomal translocation or deletion resulting in loss of                arrangements, to local point mutations,40 all of which
heterozygosity (LOH), followed by an inactivating point               contribute to Tp53 malfunction or inactivation.
mutation of the remaining allele. In lung cancer cells,                  The p53 protein is a key player in the cellular
LOH of distinct chromosomal regions is frequently                     response to stress, acting as a gatekeeper of the cell
detected and many of these regions harbor genes encod-                cycle. Activation of p53 signaling in normal cells gener-
ing central tumor suppressors, known or speculated to                 ally occurs in response to different types of cellular
be involved in cancer pathogenesis. Tumor suppressor                  stress including DNA damage, aberrant oncogenic
activity may also be inhibited by dominant negative                   growth factor signaling, and exposure to extracellular
mutations, which actively inhibit the activity of wild-               factors such as chemotherapeutics and UV light. The
type protein binding partners within the cell. Finally,               level of p53 protein and activity within the cell is regu-
epigenetic alterations (i.e. mutation-independent mech-               lated at the level of degradation rather than the level of
anisms) have in recent years gained increased attention               synthesis and, under normal conditions, the protein is
in the regulation of tumor suppressor knock-down.                     rapidly degraded within the cell. The cellular enzyme
                                                                                             Molecular biology of lung cancer 27

 Table 3.2 Aberrant anti-growth signaling

 Tumor suppressor gene mutations/inactivations and LOH in lung cancer

                                                             Mutation/inactivation frequency

 Tumor suppressor gene           Chromosome location           NSCLC (%)          SCLC (%)               References

 Tp53                            17p13                         ∼50                ∼80                    43
 RB                              13q14                         ∼30                ∼90                    44, 61
 p16INK4a                        9p21                          ∼70                ∼10                    45, 61
 TGFbRII                         3p22                          ∼44                <75                    48, 62
 LOH 3p                          3p regions                    70–100             >90                    51, 52

MDM2 plays an important role in the downregulation              poorer prognosis in NSCLC. Given the high abundance
of p53. MDM2 serves as a p53 binding partner, which             of p53 mutations in SCLC patients, the limited number
facilitates the attachment of ubiquitin tags to p53,            of patients with intact p53 signaling limits prognostic
thereby targeting it for degradation. Furthermore,              studies in this malignancy. For a detailed review of p53
MDM2-bound p53 activates transcription of the MDM2              mutations in lung cancer, and the clinical impact of
gene, resulting in increased MDM2 levels, p53 ubiquit-          these aberrations, see reference 42.
inylation, and degradation. Upon lowering of the p53
concentration, fewer MDM2–p53 complexes are                     Mutated RB and p16INK4a
formed, resulting in reduced MDM2 transcription and             A central tumor-suppressing signaling cascade, fre-
decreased p53 degradation. As such, the MDM2–p53                quently altered in human lung cancer, is the p16INK4a/
interaction generates an oscillating feedback loop of           CDK-cyclin-D/Rb pathway. The retinoblastoma (RB)
p53 and MDM2 degradation and synthesis within the               tumor suppressor gene located at 13q14 encodes a
cell (Figure 3.4).                                              transcription factor involved in the regulation of G1
   Activation of p53 requires post-translational modifi-        to S-phase transition in the cell cycle. The tumor-
cations (such as acetylation, glycosylation, and addition       suppressing activity of Rb depends on its level of phos-
of phosphate groups), some of which may inhibit p53             phorylation. In its hypophosphorylated state, Rb binds
degradation by inhibiting its binding to MDM2. This is          to and inhibits the activity of different binding partners,
the case upon DNA damage, where activation of differ-           including members of the E2F family of transcription
ent proteins such as ATM-kinase and DNA-dependent               factors. Upon phosphorylation of Rb, E2F is released
kinase facilitates the phosphorylation of p53 at sites          and activated, resulting in transcription of genes respon-
involved in the interaction with MDM2, resulting in             sible for G1 to S-phase cell cycle progression (Fig-
p53 activation (Figure 3.4).                                    ure 3.5). Consequently, Rb in its hypophosphorylated
   Active p53 regulates transcription of a number of            state serves as a tumor suppressor. Phosphorylation of
genes involved in cell cycle control (such as cyclin-           Rb is mediated by different complexes of cell cycle pro-
dependent kinase inhibitors), resulting in cell cycle           teins such as cyclin D and CDK4 and 6. The formation
arrest, thus allowing for repair of damaged DNA by the          of these complexes is inhibited by p16INK4a, which
cellular repair machinery. Activation of p53 also induces       thereby serves as a tumor suppressor upstream of Rb by
apoptosis via activation of a number of apoptotic medi-         indirectly inhibiting its phosphorylation and thereby
ators (including Bax) and inhibits blood vessel forma-          promoting Rb association with its binding partners
tion by activation of genes encoding anti-angiogenic            (Figure 3.5).
factors.                                                           Inactivation of the RB gene by LOH and/or mutation
   A frequent observation in lung cancer cells with             is observed in 90% of SCLC tumors,43 whereas the
mutated p53 is accumulation of p53 within the                   p16INK4a gene is frequently inactivated in NSCLC,44
cell, due to increased stability of the mutated protein.41      resulting in lack of activity of the Rb tumor suppressor
A number of studies have investigated the prognostic            pathway in virtually all lung cancers. These findings
role of p53 mutations in lung cancer patients, and              indicate that inactivation of this pathway is a manda-
although the results are somewhat conflicting, accumu-          tory step in the pathogenesis of pleural malignancies.
lating evidence suggests that p53 mutations result in a         The p16INK4a gene locus is located at chromosome 9p21,
28 Textbook of Lung Cancer

                                                   DNA damage          association was recently confirmed by the introduction
                                                                       of functional TGFβRII into receptor-negative lung can-
                    p14ARF                                             cer cells, resulting in restored sensitivity to TGFβ.48
                                                                       TGFβ signaling is associated with a number of cellular
                             p53 activity                              functions, the best described of which relate to inhibi-
                                                                       tion of the cell cycle. Growth inhibitory effects of TGFβ
                                                 ATM-kinase/DNA        signaling have been associated with inhibition of expres-
                             MDM2 p53            dependent kinase      sion and assembly of some of the cyclin/CDK compo-
                                                                       nents responsible for Rb activation.49
                         MDM2-SYNTHESIS                                Loss of chromosome 3p and related genes
    p14ARF MDM2                                                        Probably the most frequent chromosomal abnormality
                                ACTIVE                                 in lung cancer is loss of regions within chromosome
                                 p53                                   3p. LOH at chromosome 3p has been reported in
                                                                       70–100% of all NSCLC and more than 90% of SCLC.50,51
                                                                       A number of genes within this region have been sug-
                         Altered gene expression                       gested as putative tumor suppressors.
                                                                          The loss of the fragile histidine triad (FHIT) gene
                          - Cell cycle arrest                          located at position 3p14.2 is frequent in lung cancer,
                          - Apoptosis                                  with more extensive genetic lesions occurring in higher-
                          - Anti-angiogenesis`
                                                                       grade tumors compared with low-grade and premalignant
Figure 3.4                                                             lesions.52 Accumulating evidence points to a role of
p53 signaling. In normal cells p53 plays a key role in regulation of   FHIT as a tumor suppressor. Expression of FHIT pro-
the cellular response to a number of stress factors, but the p53       tein in NSCLC cell lines and mouse xenograft models
protein is frequently mutated in lung cancer and other malignan-
cies. Under normal conditions p53 activity is inhibited by the         has been shown to suppress tumor growth and induce
binding of MDM2 to the protein. Upon cellular exposure to              apoptosis,53 and recently FHIT has been found to stabi-
stress, cellular proteins such as p14ARF and specific kinases (i.e.    lize p53 presumably by interaction with MDM2, which
ATM-kinase and DNA-dependent kinase) release p53 from MDM2             thereby becomes incapable of binding and ubiquitiny-
inhibition, resulting in activation of p53. This again may result in
cell cycle arrest, apoptosis, and anti-angiogenic signaling.
                                                                       lating p53.54 This points to a functional role of FHIT in
                                                                       apoptotic signaling, although the exact function of
                                                                       FHIT remains to be fully elucidated.
which is a region frequently subjected to LOH in NSCLC.45                 RASSF1A is a different candidate tumor suppressor
Apart from p16INK4a, the same locus also encodes the                   gene residing at chromosome 3p (position 3p21). This
tumor suppressor p14ARF through an alternative reading                 gene is inactivated in virtually all SCLC and more than
frame. The p14ARF protein is known to bind to MDM2,                    60% of NSCLC.55,56 Apart from allelic loss, the RASSF1A
thereby inhibiting ubiquitinylation and degradation of                 gene has been found to be inactivated by epigenetic
p53 (Figure 3.4). Furthermore, E2Fs are known to acti-                 mechanisms and hypermethylation of distinct regions
vate p14ARF transcription, providing a functional link                 (so called CpG islands) within the promoter of the
between the Rb and p53 tumor suppressor pathways.                      RASSF1A gene, which inhibits gene transcription.
                                                                       Reintroduction of RASSF1A has been found to reduce
Aberrant TGFβ signaling                                                colony formation, suppress anchorage-independent
The transforming growth factor β (TGFβ) receptor                       growth, and inhibit tumorigenicity of NSCLC cells in
system is also commonly altered in lung cancer. In                     vitro and in nude mice.55 Furthermore, RASSF1A has
contrast to the growth factor receptor systems described               been shown to associate with microtubules, and recently
in previous sections, the effects of signaling by TGFβ                 overexpression of RASSF1A has been reported to inhibit
are mostly associated with inhibited cellular prolifera-               motility of NSCLC cells and increase cell adhesion, sug-
tion in many cell types. TGFβ signaling is mediated via                gesting a role for RASSF1A in cell migration and metas-
serine-threonine-kinase receptors that can be divided                  tasis.57 Several other genes reside at the frequently
into two subgroups termed TGFβRI and II. Lack of                       deleted regions of chromosome 3p but much remains
response to TGFβ (termed TGFβ resistance) in SCLC                      to be learned about the role of these genes in tumor
has been correlated with lack of TGFβRII,46,47 and this                suppression. For a review of candidate tumor suppressor
                                                                                                 Molecular biology of lung cancer 29

                 CDK4/6       CYCLIN D                                  to date have all used modified viruses for gene delivery.
                                                                        Although the delivery rates using viral systems have
                                                                        been improved, a major drawback of using viruses for
                                                                        gene delivery is the induction of immune responses
                                      Rb    E2F
                                                                        against the virus in the patients. This results in the pro-
                                                                        duction of antibodies which target the virus for degra-
                                                                        dation and limit the efficiency of repeated treatments.
                  CDK4/6 CYCLIN D                       Rb   P          Novel non-viral delivery vehicles are being developed,
                                                                        which may in the future provide a potent alternative to
                                        ACTIVE                          viral gene therapy. The status within the field of replace-
                                                                        ment gene therapy for lung cancer and delivery vector
                                                                        development has recently been reviewed.59
                                                                           Reintroduction of other tumor suppressor genes in
                                Altered gene expression
                                                                        lung cancer has been evaluated in preclinical studies.
                                                                        Co-delivery and expression of FHIT and TP53 have
                             - Cell cycle progression                   been reported to provide a synergistic tumor-suppressing
                             - Cell proliferation
                             - Anti-apoptosis                           effect in NSCLC in vitro and in vivo.54 Future studies
                                                                        will be necessary to assess the potential of these strate-
Figure 3.5
                                                                        gies for treatment of lung cancer patients.
Rb signaling. The Rb–p16INK4a–tumor suppressor pathway, which is
frequently mutated in lung cancer, acts by inhibiting the
activation of the E2F family of transcription factors responsible for
growth promoting and anti-apoptotic signaling within the cell.          REPLICATIVE POTENTIAL AND TELOMERASES
p16INK4a, which is frequently mutated in NSCLC, acts by inhibition
of the cyclin-CDK4/6 complex responsible for release of E2F from
Rb inhibition. In SCLC, Rb itself is frequently mutated, rendering
                                                                        When cultures of differentiated somatic cells are estab-
the protein incapable of inhibiting E2F signaling. The high             lished in vitro they have a well-defined potential for cell
frequency of Rb and p16INK4a mutations in SCLC and NSCLC,               division. After a number of divisions, the cells are pre-
respectively, suggests that inhibition of this pathway is               determined to enter crisis, a state characterized by
0mandatory in the development of pleural malignancies.
                                                                        extensive cell death and chromosomal aberrations. This
                                                                        phenomenon has been termed the mitotic clock and is
                                                                        part of the tight regulation of normal cell growth. In
genes residing at chromosome 3p which may play a                        contrast, cancer cells propagated in culture have an
role in lung cancer pathogenesis see reference 58.                      unlimited potential for continuous cell division and are
                                                                        said to be immortalized.
Experimental treatments: reintroduction of tumor                           The molecular explanation for the mitotic clock
suppressors                                                             resides in the chromosomal structure and mechanism
Since the loss of activity of certain tumor suppressor                  of DNA replication. Upon cell division, the cell initiates
pathways is a distinctive characteristic of human lung                  DNA replication which proceeds to produce new lead-
cancer, reintroduction of tumor suppressor activity is                  ing and lagging strands from the DNA double helix.
an attractive strategy for therapeutic intervention. For                Since DNA replication can only proceed in one direc-
this purpose, replacement gene therapy by                               tion (3′–5′), only the leading strand of the double helix
delivery of lost tumor suppressor genes to cancer cells                 is continuously synthesized, whereas the new lagging
has become increasingly attractive. Most reports of                     strand is assembled by ligation of smaller DNA frag-
tumor suppressor replacement gene therapy of lung                       ments. The discontinuous replication of the lagging
cancer involve reintroduction of TP53 in NSCLC, where                   strand results in a gap at the 5′ end of the newly syn-
a number of clinical trials have been published. In gen-                thesized DNA strand, resulting in loss of chromosomal
eral, the treatment has been found to be well tolerated                 material during each mitotic cycle.
and responses have been observed in terms of tumor                         The chromosomal ends are termed telomeres
regression and disease stabilization in some of the                     and are composed of six nucleotide repeats. The telo-
enrolled patients. However, the limiting factor of gene                 meres are involved in the correct orientation of the chro-
therapy today remains poor delivery of the therapeutic                  mosomes during cell division. Due to the continuous
gene to the cancer cells. The clinical studies performed                shortening of telomeric DNA following cell division,
30 Textbook of Lung Cancer

lack of telomere maintenance ultimately results in chro-     Experimental therapeutic targeting of telomerase
mosomal degradation and end-to-end chromosome                in lung cancer
fusion, exemplified by the massive cell death observed       Due to the central role of telomerase in the transforma-
during the crisis state of untransformed cells cultured      tion of lung cancer cells, and the lack of telomere main-
in vitro. In order to overcome the limitation of telomere    tenance in normal tissues, blocking the activity of this
shortening, cancer cells activate a program for telomere     enzyme appears an intriguing target for therapeutic
maintenance, which is normally shut down in fully dif-       intervention.
ferentiated normal cells. Most frequently, this is accom-       A number of small molecular inhibitors of telomerase
plished by activation of an enzyme complex known as          activity have been developed and some of these agents
telomerase, but a subset of cancer cells lacks telomerase    have been reported to inhibit the growth of NSCLC
activity and are immortalized by a process known as          cells in vitro, albeit with a delay in growth inhibition of
alternative lengthening of telomeres (ALT). The impli-       several months after the initiation of treatment.65
cations of the telomere-activating machinery in lung            The compound GRN136L is a lipid-modified oligo-
cancer and the development of therapeutic strategies         nucleotide, which binds to the hTERC subunit of telo-
targeting telomere maintenance are discussed below.          merase with high affinity, thereby inhibiting reverse
                                                             transcription by blocking access of hTERT to its RNA
Telomere maintenance in lung cancer                          template. GRN136L has recently been reported to suc-
The core telomerase enzyme comprises an RNA                  cessfully inhibit telomerase activity, leading to telomere
subunit (hTERC) which provides the template for syn-         shortening and resulting in decreased growth of adeno-
thesis of new telomeric DNA facilitated by the catalytic     carcinoma cells in vitro and effective prevention of
subunit human telomerase reverse transcriptase               tumor metastasis in a xenograft mouse model.66
(hTERT). The RNA component hTERC is ubiquitously                Another strategy involves activation of an immune
expressed in many cells, whereas hTERT expression is         response towards telomerase by administration of a vac-
normally confined to undifferentiated cells such as          cine composed of hTERT-derived peptides. Recently a
germ line cells and bone marrow stem cells, identifying      clinical phase I/II study investigating the effect of treat-
the enzyme moiety as the limiting factor for telomere        ment with two hTERT peptides in patients with
maintenance. Indeed, the great majority of SCLC and          advanced NSCLC was published,67 reporting the treat-
NSCLC expresses the enzyme hTERT,60 whereas hTERT            ment to be well tolerated and detecting immune responses
expression and telomerase activity has been found to be      towards telomerase in 11 and tumor response to treat-
repressed in the majority of lung carcinoids, a malig-       ment in 2 of 24 patients. A new clinical trial is being
nancy which is also associated with a longer-term sur-       planned, aiming to investigate the effect of telomerase
vival.61 A number of studies have shown that increased       immunogenic peptides in combination with chemo- and
telomerase activity and increased levels of hTERT            radiotherapy.
mRNA are mainly found in patients with poorly differ-
entiated tumors (such as SCLC) and advanced disease
and correlate with poor survival, suggesting telomerase      ANGIOGENESIS
activity as an important prognostic marker for patients
with lung cancer.62,63                                       The vasculature is crucial for cell function and survival
   A number of alternative splice variants of hTERT mRNA,    in all tissues, since oxygen and nutrients are supplied
many of which lack enzymatic activity, have been identi-     by the vessels. The growth of new blood vessels, called
fied, but the prognostic value and molecular role of these   the process of angiogenesis, is a normal physiologic
mutations in lung malignancies remain to be clarified.       process taking place under organogenesis, which under
   As previously mentioned, a small subset of cancer         these conditions is transitory and carefully regulated.2
cells acquires telomere maintenance without activation       In a similar way tumors must develop angiogenic ability
of telomerase by a process termed ALT. Although this         to progress. This ability appears by activating the angio-
phenomenon remains to be fully elucidated, ALT appears       genic switch. The activation is probably a result of the
to involve recombination of chromosome ends in a             change in the balance of angiogenesis inducers and
mechanism associated with DNA replication.64 No stud-        countervailing inhibitors, e.g. by altered gene transcrip-
ies reporting ALT in lung cancer have been published         tion. Angiogenesis can be described as a result of a
to date, and whether ALT plays a role in lung cancer         dynamic balance between pro-angiogenic factors and
cell immortalization therefore remains to be elucidated.     anti-angiogenic factors.68 Once a tumor has activated its
                                                                                        Molecular biology of lung cancer 31

angiogenic switch it becomes able to grow; in the             VEGFR signaling, ribozymes, and various toxin conju-
absence of this activation the tumor remains in a dor-        gates.72 Furthermore, blocking angiogenesis may
mant state and is unable to grow in size beyond a few         enhance conventional anti-cancer treatments such as
millimeters. Angiogenesis, however, involves more             radiation therapy in situations where tumors are unre-
components than pro- and anti-angiogenic factors only.        sponsive to current anti-growth factor efforts, and the
For succesfull angiogenesis, interactions between tumor       benefits of combining angiogenic inhibitors with radia-
cells, activation of the endothelial cells and mature ves-    tion are being explored. Recent clinical trials have
sels, degradation of the surrounding basement mem-            shown that the anti-VEGF antibody bevacizumab, com-
brane, and invasion and migration of endothelial cells        bined with standard first-line chemotherapy in NSCLC,
into the surrounding connective tissue are needed.            provided a statistically and clinically significant survival
Hereby tumor-associated neovascularization can take           advantage with tolerable toxicity.73 In addition, more
place by establishing continuity with the systemic cir-       recently tested compounds characterized as anti-
culation, allowing tumor survival and growth and, more        vasculature agents have been shown to be effective
seriously, facilitating further metastatic spreading.         against mutiple targets; the efficiency of such com-
   Many different pro- and anti-angiogenic factors have       pounds is currently being investigated in clinical trials
been identified. The angiogenesis-initiating signals          for NSCLC.
are exemplified by vascular endothelial growth factor/
vascular permeability factor (VEGF/VPF) and acidic
and basic fibroblast growth factors (FGF1/FGF2), which        TISSUE INVASION AND METASTASIS
all bind to transmembrane tyrosine kinase receptors
displayed by endothelial cells.69 The typical angiogen-       As mentioned above, cancer cells and tissues often have
esis inhibitor is thrombospondin-1, which binds to            dysregulation of crucial processes and factors, such as
CD36, a transmembrane receptor on endothelial cells           apoptosis, growth factors, angiogenesis, replication
coupled to intracellular Src-like tyrosine kinases.70 In      potential, sensitivity to anti-growth signaling, and
total there are up to nearly one hundred different pro-       invasion and metastasis. Many of these processes are
and anti-angiogenic factors. These include platelet-de-       dependent on proteases, making proteases an interest-
rived endothelial cell growth factor (PE-ECGF),               ing target for new anti-cancer treatments. Proteases
platelet-derived growth factor (PDGF), EGF, angio-            (proteolytic enzymes) are highly involved in invasion
genin, angiotensin II, platelet-activating factor (PAF),      and metastasis by degradation of the extracellular
and the inhibitor angiostatin. Most of the molecules          matrix, e.g. basement membranes. Proteases are involved
involved in angiogenesis are not specific to vascular         in both extra- and intracellular protein degradation.
endothelial cells, but have a broad spectrum of target        Under normal conditions proteolysis is a physiologic
cells, except from VEGF, which activates only endothe-        process leading to, for example, wound healing, but in
lial cells. VEGF is a heparin-binding glycoprotein, which     the malignant tumor proteolysis becomes a harmfull
binds selectively to two high-affinity tyrosine kinase        factor enabling tumor cells to move out, invade adja-
cell surface receptors: VEGFR1 and VEGFR2. These              cent tissues, and thence travel to distant sites where
receptors are found in blood vessels within or near           they may succeed in founding new colonies, metastases
tumors, and the expression is found to be upregulated         (Figure 3.6), which are the cause of 90% of human
in most cancers including lung cancer. VEGF has been          cancer deaths.74 Thus, based on the degradation of
demonstrated to be an important predictor of poor-            extracellular proteins and basement membranes by
prognosis in NSCLC.71                                         proteolytic enzymes, increased invasion and metastasis
                                                              can take place in malignant diseases. The major compo-
Targeting angiogenic factors                                  nents of the basement membrane and the extracellular
Inhibiting angiogenesis through anti-angiogenic and/or        matrix are type IV collagen, laminin, fibronectin, vit-
vascular targeting agents seems logical, as new anti-cancer   ronectin, and proteoglycans. Tumor cells can produce
treatment strategies. In particular, much attention has       a number of proteolytic enzymes which can degrade
focused on targeting VEGF and VEGFR. Compounds                these protein structures, including matrix metallopro-
currently under investigation in cancer therapy include       teinases (MMPs), collagenases, urokinase plasminogen
anti-VEGF/VEGFR antibodies, small molecule VEGFR              activator (uPA), plasmin, cathepsins, and others. MMPs
tyrosine kinase inhibitors, antisense suppression of          are known to play a functional role in the metastatic
VEGF, immunotherapy, viral-directed targeting of              spread of lung cancer.75 Different MMPs are active in
32 Textbook of Lung Cancer


                                                Regional lymph              Survival in            Growth in new
                              Intravasation     node metastasis             circulation            environment

Figure 3.6
Metastasis. This diagram illustrates the importance of proteolysis in cancer, leading to tissue degradation, invasion, and metastasis.

different steps of the invasive and metastatic process,                 have resulted in a substantial insight into important
and a better understanding of the involvement of MMPs                   signaling pathways and mediators contributing to lung
in the invasion and regulation of growth of both pri-                   cancer pathology. Recently, the first novel therapeutic,
mary and metastatic tumors may help to implement                        which directly targets growth-promoting pathways, was
these as anti-cancer therapy targets. Cathepsins have                   approved for treatment of lung cancer and many other
been demonstrated to have a prognostic value in NSCLC                   drugs are presently under clinical investigation. How-
and levels of the receptors for uPA (uPAR) and other                    ever, although some patients respond well to the new
components of the plasminogen activation system are                     treatments, it has become evident that further insight
associated with survival in NSCLC.76                                    into the mechanism of action of many of these novel
                                                                        agents must be gained, in order to better individualize
Targeting proteases and the metastatic process
                                                                        the targeted treatments to the patients who will benefit.
It is expected that inhibition of the metastatic potential
                                                                        Gaining further knowledge into the complexity of
of a tumor by interaction with extracellular protein deg-
                                                                        molecular lung cancer biology, correctly applying this
radation could be an important target, especially during
                                                                        knowledge in the development of novel therapeutics,
early tumor development. Drugs targeting MMPs have
                                                                        and optimization of presently available agents therefore
been in clinical trials, but have shown little or no activ-
                                                                        represent important challenges in lung cancer research
ity in lung cancer. Inhibition of MMPs has especially
                                                                        and clinics for the years to come.
been focused on targeting MMP-2 and -9. In studies on
cell lines and xenografts, the MMP inhibitor batimastat
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48. Anumanthan G, Halder SK, Osada H et al. Restoration of TGF-         65. Damm K, Hemmann U, Garin-Chesa P et al. A highly selective
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    4         Tobacco policy
              Nigel Gray

              Contents Introduction • Basic policy • Developing countries • The future

INTRODUCTION                                                 of malaria and tuberculosis, depressing though it is, is
                                                             partly due to these factors and partly due to the lack of
The single global public health objective in this field is   really effective means of control.
to reduce consumption of tobacco by all possible means          The singular feature of the tobacco problem is that
as quickly as possible. Major successes such as the          someone is selling it. No one is selling tuberculosis. To
decline in British consumption and mortality are cur-        this can be attributed the fact that, five decades after
rently matched by the steep ascent of these two indices      discovering its carcinogenicity, tobacco consumption
in developing countries, particularly China,1 which          worldwide is falling very slowly. Comparisons with the
illustrates the urgency of policy action.                    other industries selling toxic products are unsatisfac-
   It is reasonable to assert that implementation of         tory. There is no pretence that asbestos does not cause
policy lags, sometimes decades, behind policy develop-       asbestosis, nor that drunken driving is merely a plea-
ment, which lags similarly behind the development of         surable habit. The international tobacco industry is
knowledge. In a number of sophisticated countries,           unique in its stubborn refusal to concede the side-
among which are the UK, Norway, Sweden, Australia,           effects of its product, despite revelations3 which make
Canada, and the USA, the proportion of the population        it clear that the industry knew of the carcinogenic and
which continues to smoke has fallen from over a half to      addictive properties of tobacco some decades ago. Once
about a quarter. Mortality declines have usually fol-        having retreated into its legal bunker it is now in the
lowed, but at very different rates. So it is wrong to be     difficult position of facing enormous legal and financial
pessimistic but important to be impatient. Pressing for      consequences if it makes concessions or tells the truth.
activist policies, on the grounds that outcomes take a       Thus the forces of public health and the global tobacco
long time, seems to be an integral part of the duty of the   industry are locked in continuous warfare and pros-
health professions.                                          pects for peace are slight.
   Comprehensive tobacco policy has been well estab-            While no form of tobacco use has been discovered to
lished and understood since the mid-1970s.2 The rec-         be safe, the cigarette is the most ubiquitous, widely
ommendations in this chapter are informed by long            used, and best-studied product. The myriad forms of
experience of successful and unsuccessful policies in        tobacco use seen in India and other parts of Asia are
many diverse countries. Many of the important policy         carcinogenic in many different ways and, being person-
issues and outcomes have never been the subject of ref-      ally grown or based on cottage industry production,
ereed articles in the technical press, so the reader must    each poses specific individual problems. Certainly it is
be satisfied with basic references and must be willing to    easier to develop policies to control cigarette smoking
search newspaper archives for historic detail.               than tobacco/betel chewing as the product is factory
   Tobacco use has been, and is, perhaps the most dif-       made, taxed, exported and imported, and often the
ficult issue faced by public health workers in the 20th      subject of retail licensing.
century. Historic diseases such as smallpox, polio, mea-        The unrepentant nature of the global tobacco indus-
sles, diphtheria, tetanus, whooping cough, rubella, and      try, which is controlled by relatively few major manu-
scarlet fever were conquered in developed countries          facturers, is reflected in the sales statistics. Sales are in
within a decade or so of the arrival of effective control    decline in the most developed countries and the
systems. When vaccines and antibiotics worked, they          expected indices follow. Lung cancer in males, espe-
were used. Failures in developing countries relate to the    cially younger ones, is declining, as is heart disease.1
failure of national and international social organization    By contrast, tobacco exports from the USA are climbing
and rarely to organized opposition. The reappearance         and the antique tobacco monopolies of the previously
36 Textbook of Lung Cancer

communist world are being replaced by modern mass                are the first step. Warnings researched for under-
production systems owned by the same people. Mar-                standability and offering a telephone number to an
keting measures forbidden in the USA, UK, and Europe             information service are better. Warnings with
are rampant in many developing countries.                        graphic pictures are even better.
   Consideration of tobacco policy may conveniently          •   Packet labeling There is a powerful case for generic
focus first on the cigarette. Such consideration should          packaging as a way of interfering with global brand
take note that smoking is a learned habit which is initi-        advertising. Packaging should declare yields of
ated by social forces but sustained by the development           known major carcinogens and other substances,
of addiction in persistent users.                                which may be specified as knowledge develops.
                                                                 Packet inserts are a way of providing the sort of
                                                                 comprehensive information that is given with such
                                                                 substances as aspirin. Tobacco industry claims for
                                                                 the right to compete for adult markets are specious
This is theoretically simple:
                                                                 as adults and children co-exist in society and mea-
•   change the cultural background;                              sures to protect or attract children often impinge
•   change the smoker;                                           on adults and vice versa.
•   change the cigarette;                                    •   Abolition of promotion – in every form Tobacco brand
•   protect the children.                                        names need to be forbidden in advertisements for
                                                                 any other product. Direct and indirect advertising
Changing the cultural background                                 needs to be specifically addressed. This issue
The cultural background against which tobacco smok-              remains difficult because of the cross-border abili-
ing must be considered is a mixture of community law             ties of satellite media. It should be understood that
and community norms. Laws usually arise as a result of           there is no case which can be made in favor of
public opinion at a point in time and are an important           tobacco promotion as the product is seriously and
reflection of community norms, although they do not              chronically toxic when used as the manufacturers
always mirror public opinion in those countries where            intend. Evasion of promotional restrictions is the
the tobacco industry is strongest. The failed battle to          profession of a large number of people, all of whose
introduce strong tobacco legislation in the USA in 1998          arguments should be ignored. Even at point of sale,
shows the difficulties in the path of lawmakers that are         advertisement should be forbidden.
posed by the organized and well-funded opposition of         •   Availability Sales to children, defined as 16–18 in
tobacco manufacturers. This situation, while obvious in          most countries, need to be prohibited and the pro-
the USA, arises in most countries when tobacco policy            hibition policed. Such legislation is widespread,
requires lawmaking, although the opposition may be               but policing is not. Vending machine sales need to
less obvious and behind the scenes.                              be supervised in places inaccessible to children, or
   An important element in the interaction between               forbidden. This policy measure is widely adopted
government, parliaments, and popular opinion may be              but almost nowhere has policing been tried. Until
non-government organizations. Policy frequently arises           that experiment is done and shown to fail this
in the non-government sector, as may the drive for leg-          issue remains high on the agenda for developing
islation. Thus the interactive process of introducing leg-       countries.
islation may be an important part of providing a driving     •   Smoke-free environments These need encourage-
force for implementation. Popular laws are more likely           ment for exemplary as well as risk-avoidance rea-
to be implemented. Opposition to standard compre-                sons. Schools, hospitals, workplaces, and public
hensive laws is to be expected and is routinely led by           transport should be smoke-free, as a minimum.
those with vested interests, supported by the industry,          Smokers in many countries have been remarkably
using arguments now outdated and often ugly when                 accepting of this policy. It is an important down-
exposed to public gaze.                                          ward pressure on smoking rates in all age groups,
                                                                 and probably reduces daily dose as well as encour-
Model legislation                                                aging quitting.
                                                             •   Tax This should be high in the context of individual
•   Health warnings These should state government                income and should be regularly increased; a set
    policy and the facts. Rotating, explanatory warnings         proportion should be allocated to health purposes
                                                                                                      Tobacco policy 37

    including tobacco education.4 Tobacco tax is among        and community involvement. This means that a well-
    the only taxes demonstrated to be popular. There is       organized and co-ordinated anti-smoking movement is
    good reason why the price of a packet of cigarettes       a necessary basis. Such movements are not always large;
    should be several times that of a hamburger.              efficiency and co-ordination are the keys.
•   Regulation of the product It is unacceptable that a
    product as dangerous as tobacco should be unreg-          Changing the smoker
    ulated. Additives need to be demonstrated to be           Changing the smoker to become a non-smoker
    non-toxic in both burnt and unburnt form; and             is a complex multifaceted process requiring analysis of
    upper limits should be set, and continuously              individual society’s smoking patterns. It is accepted
    reviewed, for major carcinogens and toxins. Public        that addiction to tobacco is the major force in maintain-
    health advisors and departments have been slow to         ing smoking status. Progress towards becoming a non-
    act in this field, possibly because of perceived          smoker may be generally and simply summarized:
    complexities. However, the establishment of upper
                                                              Rational information → dissonance → attempts to quit →
    limits for cigarette emissions is relatively straight-
                                                              success → maintenance
    forward and is in need of urgent implementation.
                                                                 Dissonance may be defined as dissatisfaction with
   The importance of legislation is underlined by the         one’s own smoking behavior, and affects a majority of
experience of Norway, the pioneer, in 1975, of compre-        smokers in the USA, for example, but probably a minor-
hensive tobacco legislation. Tobacco consumption              ity in less well-informed societies. Clearly dissonance is
peaked in the mid-1970s, having risen by about 25%            more likely to occur if the victim/person is well
between the mid-1950s and mid-1970s. Since then it            informed, so the place of varied education programs,
has declined by approximately the same amount. The            targeted to the subgroups as well as the totality of smok-
original legislation in Norway was from a unanimous           ers, cannot be doubted, but is country-specific, at least
parliament, but was surrounded by much discussion             to a degree. Other factors can be expected to stimulate
and public interaction. This early legislation did not        dissonance: the smoke-free workplace and public
include severe workplace and public place restrictions,       places; peer group and family pressure; negative peer
and Norwegian prices have risen only slightly, in real        group experiences such as deaths or disease; societal
terms, since the 1980s.5 While it is possible to argue        attitudes and levels of information. Such factors reflect
over the potential benefits of more aggressive pricing,       the cultural background and vary from country to
public education, and smoking opportunity restric-            country.
tions, the Norwegian experience is a testimony to the            Attempts to quit occur frequently in sophisticated
efficacy of good legislation as the basis for a compre-       countries and policy should encourage and provide
hensive anti-tobacco program.                                 support for smokers who make them.
   Community norms are usually well reflected in pub-            The role of nicotine replacement therapy (NRT) is
lic opinion. A comprehensive tobacco policy would             crucial and in need of considerable development. Its
include regular surveys of tobacco consumption, public        value is well established although results are generally
opinion, relevant attitudes among smokers and non-            disappointing by comparison to expectations. Better
smokers, and evaluation of education programs. Opin-          products are needed as is greater availability and more
ion may move slowly, but it does move with time and           support services. It is bizarre that cigarette content is
in the presence of well-directed education programs. It       virtually unregulated while bureaucratic restrictions on
is both logical and true that parental attitudes and          alternative sources of clean nicotine are widespread.
example flow through to youth behavior, so changing           The general global failure of health professionals,
the cultural background implies measuring beliefs and         especially physicians, in support of patients and provi-
recruiting all the potential role models of society as well   sion of therapy is a disturbing reflection of health pri-
as removing the tobacco industry’s ability to promote         orities, which at least means there is hope for potential
its product. It is also logical to believe that education     improvement.
programs work better without opposition, further                 The debate over nicotine addiction6 per se ought not
underlining the importance of complete eradication of         to hold back development of better products and ser-
promotion.                                                    vices. Tobacco is a uniquely toxic way of delivering the
   In summary, changing the cultural background               desired dose of nicotine while NRT appears to be safe
requires an activist and persistent approach to legislation   or relatively so. Up to this time there is no evidence of
38 Textbook of Lung Cancer

mass addiction to nicotine chewing gum, although the          learned in reducing vehicle emissions to the cigarette,
lack of competitive products which will deliver the           and to base regulations upon it.
quick, efficient, ‘fix’ of the cigarette might well explain      It is known8,9 there is great diversity in the levels
this. Nevertheless, policy should be aimed at providing       of major carcinogens in mainstream smoke yields on
support, NRT, and whatever other pharmaceutical aids          the world market, so the evidence that cigarettes
may be developed, since the status quo is an ongoing          with lower carcinogen levels can be made and sold is
disaster which justifies greater effort than it receives.     indisputable – cigarettes low in nitrates and nitro-
Continuing use of NRT in smokers who cut down but             samines are made and sold.
do not abstain is a sensible form of harm reduction,             The policy issues then become the following:
although the obvious goal is abstinence.
   Policy makers should note that the costs of helping        •   Governments must claim power to regulate the
smokers are infinitely less than those of treating them           content of cigarette smoke – this power exists in
and that, while the most immediate mortality, morbid-             some countries.
ity, and cost benefits are achieved by attention to long-     •   Health authorities require suitable advisory sys-
duration heavy smokers, every smoker is at risk sooner            tems involving independent scientists and with
or later, and early intervention is always best.                  mandatory access to industry information.
                                                              •   Initially, major carcinogens such as benzo(a)pyrene,
Changing the cigarette                                            4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
The cigarette is a uniquely efficient nicotine delivery           (NNK), and N-nitrosonornicotine (NNN) should
device which has so far escaped significant production            be targeted. Market analysis would show the range
controls worldwide. This is in contrast to motor vehi-            of yields. Those cigarettes yielding above the median
cles, pharmaceuticals, food, houses, and even sewage              should be removed from the market, or modified,
systems. While the reasons for this disparity are inter-          within a standard period such as 12 months.
esting, as they include corruption on a global scale,         •   Over time this process would allow progressive
there can be no excuse for continuing to allow the                reduction in carcinogens and other toxins, since
tobacco industry alone to decide what will go into the            the starting point is a level found to exist on the
product, and therefore what is present in mainstream              market and already achieved by at least some
smoke.                                                            manufacturers.
   First it is necessary to state that the policy of          •   Nicotine needs special treatment. The first essential
the 1960s, which favored reduction of tar and nicotine            is a new measurement system. However, a measure
levels over time, has not produced the benefits antici-           which measures smoke content will not accurately
pated. Changes in cigarette design7 have brought about            reflect what gets into the smoker’s bloodstream, as
reductions in some carcinogens and increases in others.           it cannot control for compensatory smoking prac-
Mortality benefit, if present, is small, and adenocarci-          tices. Therefore, while control of smoke yield can
noma has increased in the USA and elsewhere. Since tar            be exerted by a measure such as nicotine content
measurement takes no account of the qualitative changes           per liter of smoke, the decision-making process
which have occurred in smoke it is misleading. Over the           which sets the yield levels needs to be informed by
same time, bioavailability of nicotine has been increased         behavioral experiment and analysis.
and, together with compensatory smoking, means                •   The ultimate policy decision – whether mass wean-
the machine-measured levels of nicotine are also mis-             ing of nicotine-dependent populations should be
leading.                                                          attempted by regulatory reduction of dose per cig-
   It can therefore be unequivocally stated that tar and          arette – cannot be made in the light of knowledge
nicotine measures as currently used should be abol-               in 2007. However the goal of reduction in the
ished – the policy question is what they should be                addictiveness of the cigarette is a proper one and
replaced with?                                                    should be pursued as a matter of policy.
   It must be recognized that cigarette design is best        •   In facing the decision to control nicotine yields,
understood by the tobacco industry and is clouded by              policy makers must understand that the rise of
commercial secrecy, and that no governments have                  cigarette smoking was a vast unplanned experi-
applied the necessary research resources to know enough           ment performed by the tobacco industry, initially
to tell manufacturers how to make their product. How-             ignorant of its product’s toxicity. Long-term deci-
ever, it is certainly possible to apply the principles            sions on nicotine policy will require similarly large
                                                                                                       Tobacco policy 39

    experiments based on sensibly considered proba-           ongoing smokers need to be related to those of children
    bilities. The decision to reduce tar and nicotine         to a smoke-free and promotion-free environment.
    was sensible when conceived but subverted by                 Policy is not only about prohibitions and restraints.
    industry manipulation. This mistake should not be         There is a clear need for experimentally based, expen-
    made again but should not prevent innovative reg-         sive, education programs aimed at children. The fact
    ulatory policies.                                         that few of these have been developed outside a few
•   New products containing tobacco ought also to be          richer countries, and even fewer adequately funded, is
    regulated and only tested in situations similar to        not an excuse for failure to change. Every society which
    those which are used for the testing of new phar-         spends money on treating sick smokers would be well
    maceuticals. So far the tobacco industry has not          advised to spend funds of the sort spent on promotion
    produced a successful alternative to the standard         of cola drinks on campaigns aimed at discouraging
    cigarette. They should not be discouraged from            smoking.
    doing so but should not receive marketing advan-
    tages over NRT and other nicotine alternatives.
                                                              DEVELOPING COUNTRIES
Protecting the children
As social norms and fashions have changed over time,          Tobacco use is already built in to many developing
so have the specific stimuli which trigger or contribute      countries and takes many forms. No form of tobacco
to initiation of the smoking habit. Age of onset of ini-      use has been shown to be free of risk and the fact that
tiation varies around the world, beginning earlier in         snuff use in Sweden is less hazardous than tobacco/
developed countries. Cultural differences play an impor-      betel chewing in India is not sufficient to allow fantasies
tant role, as exemplified by the great diversity in smok-     of safe tobacco products to intrude on public policy.
ing rates between men and women in countries such as             The principles set out above are applicable to some
China. Whereas the factors which contribute to initia-        degree with most forms of tobacco use. However, local
tion in particular societies differ, the policy question is   cultures in which the many and strange variants of
what can be done to interfere with the pressures toward       tobacco smoking and chewing persist need to be con-
initiation – or in simple terms, what can be done to          sidered individually. The broad-brush weapons of edu-
protect the children?                                         cation, warning labels, taxation, and restriction where
   The first policy approach is to remove or reduce all       relevant can be considered by policy makers, and locally
the pro-smoking pressures which can be controlled.            suitable policies developed and tried. The after-effects
Formal and informal promotion of tobacco has been             of tobacco use as known are such that no variant of use
dealt with above. Nevertheless, it must be re-empha-          can be neglected.
sized that children are extremely sensitive to promo-            The reappearance of the cigar as a social status
tional pressures and that any presentation of a tobacco       symbol in the USA should warn against complacency.
brand name needs to disappear from the social environ-
ment. This has been substantially achieved in a number
of countries, but has been subverted to a variable degree     THE FUTURE
by cross-border advertising of events such as motor
races and cricket matches sponsored by tobacco inter-         The basic principles of tobacco policy discussed here
ests. Global control of this phenomenon will not be           have been tested and appraised in real societies and
achieved easily, but the battle, slowly being won in          shown to work to a greater or lesser degree. The degree
developed countries, needs to be fought in developing         usually depends on the enthusiasm with which policies
countries as the industry seeks to source such events         are implemented. The force of the vested interests of
from them.                                                    the tobacco industry has been able to slow policy imple-
   Local social pressures need policy attention. The role     mentation, but the fact remains that tobacco use in
of parents, siblings, peer groups, and local and interna-     developed countries had declined substantially and the
tional role models should be the subject of education         tobacco industry is now seeking to replace its lost,
programs and local campaigns, with the specific objec-        dying, and dead smokers in developed countries with
tive of reducing initiating pressures wherever they exist.    new users in the poor and developing world.
What happens in schools, homes, workplaces, and pub-             The political battle over the proposed tobacco settle-
lic places needs detailed consideration. The rights of        ment in the USA in 1998, although seemingly lost at
40 Textbook of Lung Cancer

that time, is a serious and important indication of the            3.   Glantz SA, Slade J, Bero LA et al. The Cigarette Papers. Berke-
degree to which the international tobacco industry has                  ley: University of California Press, 1996.
                                                                   4.   Manley M, Glynn TJ, Shopland D. The Impact of Cigarette
declined in power and influence. It is to be expected
                                                                        Excise Taxes on Smoking Among Children and Adults: Sum-
that the public health principles espoused here will be                 mary Report of a National Cancer Institute Expert Panel.
applied progressively and more rapidly over the next                    Bethesda MD: National Cancer Institute, 1993.
decade. The result can only minimize the tobacco mor-              5.   Bjartveit K, Lund KE. The Norwegian Ban on Advertising of
tality epidemic already set in train by past events, but                Tobacco Products. Has it Worked? Oslo: Norwegian Cancer
while tobacco remains one of the largest causes of                      Society, 1996.
                                                                   6.   Benowitz NL, Henningfield JE. Establishing a nicotine thresh-
avoidable death and disease, it remains one of the major
                                                                        old for addiction. N Engl J Med 1994; 331: 123–4.
global public health targets for all countries.                    7.   Hoffmann D, Hoffmann I. The changing cigarette, 1950–1995.
                                                                        J Toxicol Environ Health 1997; 50: 307–64.
                                                                   8.   Fischer S, Speigelhalder B, Preussmann R. Tobacco specific
REFERENCES                                                              nitrosamines in commercial cigarettes; possibilities for
                                                                        reducing exposure. Relevance to Human Cancer of N-
1.   Peto R, Lopez AD, Boreham J et al. Mortality from smoking          Nitroso Compounds, Tobacco Smoke and Mycotoxins.
     world-wide. Br Med Bull 1996; 52: 12–21.                           International Agency for Research on Cancer. Monograph 105.
2.   Gray N (ed). Lung Cancer Prevention; Guidelines for Smoking        Lyon: 1991 489–93.
     Control. Geneva: Union Internationale Contre le Cancer,       9.   Gray N, Boyle P, Zatonzki W. Tar concentrations in cigarettes
     1977.                                                              and carcinogen content. Lancet 1998; 352: 787–8.
    5         Smoking cessation programs
              Philip Tønnesen

              Contents Introduction • Clinical approach • Stages of motivation • Carbon monoxide in expired air
              • Nicotine replacement therapy • Varenicline • BupropionSR • Other drugs • New drugs • Alternative
              therapies • Smoking reduction • Special considerations for lung cancer patients who smoke
              • Weight gain • Conclusions

INTRODUCTION                                                 he or she has a responsibility to interfere and discourage
                                                             tobacco use.4,5 The first thing is to ask whether or not
This chapter focuses on the proper use of nicotine           the patient is a smoker. Already, by asking, one shows
replacement therapy (NRT), varenicline, and bupropi-         to the patient that one cares about smoking and that
onSR, golden rules in smoking cessation, predictors of       smoking might be of importance in relation to health.
success, and the concept of smoking reduction. It should     It is important that the patient’s smoking be handled in
be remembered that cigarette smoking is an addiction,        a neutral way without anger or condemnation. The
and for that reason smoking cessation cannot be com-         smoker should be informed about the risks of smoking,
pared with treatment of other medical conditions. NRT        and the information should be individualized for the
will produce low success rates when used without             particular patient.
adjunctive behavioral support; however, since most
smokers quit on their own and using over-the-counter
(OTC) NRT, even these low success rates will have an         STAGES OF MOTIVATION
important influence on public health. The degree of
supportive adjunctive behavioral therapy parallels the       Some smokers are contented smokers: they do not con-
actual success rate, while the relative success rate (i.e.   sider quitting and do not think about the dangers of
the odds ratio between NRT and placebo) remains more         smoking. But many smokers would like to quit. Moti-
or less unchanged at around a factor of two.1                vation to do so can be regarded as a cyclic process of
   As a preventive tool, smoking cessation is very cost-     changes, as described by Prochaska and Goldstein.6
effective. Smoking cessation with NRT or bupropionSR         However, these stages do not correlate well with suc-
is approximately eight times more cost-effective per         cess in quitting. It is much more important for patients
saved year compared with 300 medical treatments.2            with smoking-related diseases such as lung cancer to
Also, smoking is the most important etiologic factor in      quit compared with ‘healthy smokers’. Continued smok-
the development of lung cancer, accounting for almost        ing in lung cancer patients has a negative effect on the
85% of all lung cancer cases, and has been strongly cor-     outcome of surgery, chemotherapy, and radiation ther-
related with other cancers, including oral, laryngeal,       apy, and increases the risk of secondary primary lung
and bladder cancer. Around one-third of all cancer           cancers in long-term survivors.
deaths are attributed to tobacco.3 Also, tobacco use is a       The therapist’s approach to the smoker depends on
major contributor to chronic obstructive pulmonary           the motivation to quit. Use of the questions in Table 5.1
disease (COPD) and coronary arteriosclerosis – diseases      is an easy and quick way to classify the motivational
that often prevent lung cancer patients from undergo-        stage of the individual smoker and then to apply the
ing curative surgery.                                        right treatment approach. If the smoker wants to quit
                                                             you should support with advice about NRT and the
                                                             golden rules of smoking cessation, use NRT, vareni-
CLINICAL APPROACH                                            cline, or bupropionSR, clinician-provided assistance
                                                             and skills training, and follow-up visits.7 If the smoker
When a health care provider, i.e. a physician, nurse,        is only interested in cutting down, the smoking reduc-
dentist, or pharmacist, meets with a smoking patient,        tion concept should be applied. Patients who declare
42 Textbook of Lung Cancer

    Table 5.1 Assessment of motivation to quit smoking or to
                                                                CARBON MONOXIDE IN EXPIRED AIR
                                                                In most smoking cessation studies, sustained abstinence
    1.  Will you participate in a smoking cessation             is used as the outcome measure. It consists of the
        course now?                                             smoker’s statement of not smoking now and not having
    Answer ‘Yes’: Start smoking cessation                       smoked since the last visit, together with biochemical
            ‘No’: Continue to 2                                 verification by carbon monoxide (CO) in expired air.
    2. Will you try to cut down your daily number of            CO measurement is an easy and inexpensive way to
        cigarettes now?                                         verify abstinence biochemically. The half-life of CO
    Answer ‘Yes’: Start smoking reduction                       varies between four and six hours, and the cut-off value
            ‘No’: Recommend cessation and give                  between non-smokers and smokers is usually 10 parts
                  brochures                                     per million (ppm). Most non-smokers attain CO values
    3. How motivated are you to quit on a scale from            of 1–4 ppm, and some use a cut-off value of 6 ppm.
        0 to 10?                                                Subjects exposed to passive smoking might attain values
        (0 = not at all motivated;                              of 6–9 ppm.
        10 = extremely motivated)                                   CO levels are most often measured with a portable
    Answer _______ score (0–10)                                 CO monitor (Bedfont Monitor, Sittingbourne, UK) in
    4. How motivated are you to reduce on a scale               expired air after a 15 s breathhold, with a CO value of
        from 0 to 10?                                           less than 6–10 ppm verifying abstinence.10 The result is
        (0 = not at all motivated;                              displayed immediately. Calibrations have to be per-
        10 = extremely motivated)                               formed at least every six months using a 50 ppm CO
    Answer _______ score (0–10)                                 test gas. False-positive values might be observed in sub-
                                                                jects with lactose malabsorption. Although an ethanol
                                                                filter is present, high ethanol concentrations in the
no interest in smoking cessation or reduction should            breath might interfere with measurements. Drifting of
receive brochures and other self-help material about            the zero-point might be observed if many smokers
smoking or smoking cessation. More detailed guide-              are tested consecutively. Without CO monitoring, up
lines for smoking cessation have been published by the          to 10% of failures might state that they do not smoke.
Agency for Health Care Policy and Research in the USA               Plasma, saliva, or urinary cotinine levels are another
and by NICE in the UK.8,9                                       biochemical way to verify smoking abstinence.
   However, there are some basic principles related to
successfull smoking cessation that are important for the
therapist to consider: smokers must stop smoking com-           NICOTINE REPLACEMENT THERAPY
pletely at quit day (even one or two cigarettes per day
during the first one or two weeks of cessation are usu-         The rationale for nicotine substitution is as follows.
ally followed by relapse):                                      When quitting smoking, the administration of nicotine
                                                                decreases withdrawal symptoms in the first months,
•        the use of NRT, varenicline and bupropionSR            thus allowing the subject to cope with the behavioral
         lessens withdrawal symptoms and improves cessa-        and psychologic aspects of smoking (Table 5.2).
         tion outcome;
•        for lung cancer patients aggressive use of NRT,
         varenicline, or bupropionSR should be used;
•        follow-up should be arranged to prevent relapse
         (which is highest during the first three to six         Table 5.2 The principle of nicotine replacement
         weeks, then gradually declines, similarly to other      therapy (NRT)
         addictions);                                            •   Principle: quit cigarettes
•        smoking reduction might be a gateway to smoking         •   Use NRT to reduce withdrawal
         cessation in smokers low in motivation to quit;         •   Break the psychologic addiction
•        if the patient relapses, he or she should be encour-    •   After two to four months, stop NRT
         aged to make another attempt to quit later on and       •   Some might need NRT for longer periods
         then receive retreatment (‘recycling’).
                                                                                                                                  Smoking cessation programs 43

   Withdrawal symptoms (craving for cigarettes, irrita-                                           (i.e. the high peak plasma levels of nicotine reached
bility, anxiety, depression, drowsiness, difficulty in                                            during smoking are not achieved) (Figure 5.1). Patients
concentrating, restlessness, headache, hunger, sleep                                              are weaned off nicotine replacement products (usually
disturbances) are usually assessed on a four-point scale                                          over two to six weeks) when withdrawal symptoms are
(0 = not at all; 1 = mild; 2 = moderate; 3 = severe).11,12                                        lessened owing to decreased dependence. The average
Withdrawal symptoms often appear four to eight hours                                              12-month success rate reported in most studies is about
after quitting, peak during the first week (days 3–5),                                            15–25%.8,9 Predictors that correlate with a lower suc-
and then gradually decline over the next two to four                                              cess rate are higher nicotine addiction, lower age, no
weeks. Nicotine dependence is measured by the Fager-                                              previous quit attempts, previous depression, suffering
ström test of nicotine dependence (FTND), with a pos-                                             from COPD and cardiovascular disease, a smoking
sible scoring of 0–10 (most dependent)13 (Table 5.3).                                             spouse, and low motivation to quit.
   With the nicotine replacement products used today,                                                Nicotine is the drug of choice to assist smoking
lower nicotine levels are attained compared with smoking                                          cessation. Results reported in a Cochrane meta-analysis

                           Table 5.3 Fagerström test for nicotine dependence (FTND)

                           Item                                                                            Answer                                     Score

                           1.                 How soon after you wake up do                                Within 5 min                               3
                                              you smoke your first cigarette?                              6–30 min                                   2
                                                                                                           31–60 min                                  1
                                                                                                           61 min or more                             0
                           2.  Do you find it difficult to refrain from                                    Yes                                        1
                               smoking in places where it is forbidden, i.e.                               No                                         0
                               in church, at the library, in the cinema, etc.?
                            3. Which cigarette would you most hate most                                     The first one in the morning              1
                               to give up?                                                                  Any others                                0
                            4. How many cigarettes per day do you smoke?                                    1–10                                      0
                                                                                                            11–20                                     1
                                                                                                            21–30                                     2
                                                                                                            31 or more                                3
                            5. Do you smoke more frequently during the first                                Yes                                       1
                               hours after waking than during the rest of the day?                          No                                        0
                            6. Do you smoke if you are so ill that you are in bed                           Yes                                       1
                               most of the day (or absent from work)?                                       No                                        0
                                                                                                            Total score                               0–10

                                         35                                                         Figure 5.1
Plasma nicotine concentrations (ng/ml)

                                                                                                    Plasma nicotine levels during cigarette smoking, nicotine nasal
                                         30                                                         spray (NNS) use, and 4-mg nicotine chewing gum use.


                                         20                                          Cigarettes

                                         15                                          NNS

                                                                                     4-mg gum


                                                8    9   12   16   20   24   4   8
                                                         Time (hours)
44 Textbook of Lung Cancer

of 105 trials with 39 503 subjects, who received various       gum whenever it is wanted or needed during the day.
forms of NRT (gum, patch, spray, inhaler, and sublin-          The principal disadvantage of gum use is potential
gual/lozenge), indicated that NRT almost doubled               underdosing, which might explain the lack of effect in
long-term (6–12 months) quit rates.14 The odds ratio           several trials. The approximate dose equivalent for most
for success of NRT compared with controls was 1.8              nicotine patches is approximately 20 pieces of the 2-mg
(95% confidence interval, CI, 1.7–1.9). The odds ratios
for the different nicotine replacement products were
1.6 for gum, 1.8 for patch, 2.4 for nasal spray, 2.1 for        Table 5.5 NRT formulations
inhaler, and 2.1 for sublingual/lozenge (Table 5.4).
Overall, there was no statistical difference between the        Gum
different forms of NRT and this has also been found in          2 and 4 mg content: 0.8–1.2 mg and 1.2–1.5 mg
comparative studies.                                            absorbed, respectively
   The nicotine products described above are self-dos-          Patch
ing systems to be used ad libitum, in contrast to the           15 mg/16 h; 21 mg/24 h
patch, which ‘infuses’ about 1 mg of nicotine per hour
at a constant rate.                                             Inhaler
   There are six different formulations of nicotine             10 mg in one container: 4–5 mg released (2–3 mg
replacement products (Table 5.5) and the determina-             in clinical use)
tion of the most appropriate product should be accord-
ing to patient preference, cost, nicotine dependence,
                                                                Nasal spray
and number of daily cigarettes (Tables 5.6–5.9).                0.5 mg/dose in each nostril
                                                                Sublingual tablet
Nicotine chewing gum                                            2 mg content: 0.8–1.2 mg absorbed
Gum users should only chew a piece five to ten times
until they can taste the nicotine, then let the gum rest        Lozenge
in the cheek for a few minutes, and then chew again             1 mg and 2 mg content: 0.5 and 0.8–1.2 mg
to expose a new surface of the gum. Free nicotine can           absorbed
then be absorbed and reduce side-effects due to
swallowed nicotine. The gum can be chewed for about
20–30 minutes. About 0.8–1.2 mg of nicotine is absorbed
from a piece of 2-mg nicotine gum, and 1.2–1.5 mg               Table 5.6 NRT use: 1
of nicotine from a 4-mg piece15 (Table 5.5). With use
                                                                1–9 cigarettes/day (not-evidence based)
of nicotine gum throughout the day, blood levels of
                                                                • 2-mg gum
one-third (for 2-mg gum) and two-thirds (for 4-mg
gum) of the nicotine obtained through smoking are               • Inhaler
achieved.16,17                                                  • 1-mg lozenge
   A basic advantage of gum is the possibility of               7–9 cigarettes/day
self-titrating the dose, in contrast to the patch, which        • As above, or
delivers a fixed dose. Thus it is possible to use a piece of    • Patch 10-mg/16 h or 7-mg/24 h

 Table 5.4 Efficacy of NRT                                      Table 5.7 NRT use: 2
 •   Meta-analysis controlled trials                            10–20 cigarettes/day
 •   Success rates sustained for one year                       • Patch: 15-mg/16 h or 14-mg/24 h
 •   Odds ratio                 1.77 (95%                       • Gum 2- or 4-mg
                                CI 1.67–1.89)                   • Inhaler
 •   Gum:                       1.66                            • 2-mg lozenge or 2-mg sublingual
 •   Patch:                     1.81
 •   Nasal spray:               2.35                            15–20 cigarettes
 •   Inhaler:                   2.14                            • As above, or
 •   Sublingual/lozenge:        2.05                            • NNS
                                                                                      Smoking cessation programs 45

 Table 5.8 NRT use: 3
                                                          increase the amount of consumed gum might be to
                                                          administer it in fixed-dosage schedules as shown by
 21+ cigarettes/day                                       Killen et al.20
 • Patch: 25-mg/16 h or 21-mg/24 h                           Side-effects of gum consist mainly of mild, transient,
 • Gum: 4-mg                                              local symptoms in the mouth, throat, and stomach due
 • NNS                                                    to swallowed nicotine (i.e. nausea, vomiting, indigestion,
 • Inhaler                                                and hiccups). After adequate instruction, most smokers
 • Sublingual 2-mg or lozenge 2-mg                        can learn to use the gum properly. However, without
 • Gum as rescue in relapse situations                    instruction many will discontinue use or underdose
 • NRT as long-term use if needed                         themselves.
 • Combination of patch and one of the other                 In the Lung Health Study, among 3094 smokers who
    NRTs                                                  were followed for five years, the use of the 2-mg gum
 • NRT in combination with bupropionSR                    appeared safe and did not produce cardiovascular
                                                          problems or other adverse events, even in subjects who
                                                          continued to smoke and still used nicotine gum.21
                                                             It is suggested that smokers be instructed to stop
 Table 5.9 NRT use: 4
                                                          smoking completely, use the nicotine gum on a fixed
 •   Use of NRT in smokers as withdrawal                  schedule (i.e. every hour, from early morning, for at
     suppressor                                           least 8–10 hours), and to use extra pieces of gum when-
 •   Meetings, workplaces, travel                         ever needed.
 •   Few hours: gum, inhaler                                 The optimal duration of treatment is not known;
 •   6 or more hours: gum, inhaler, patch                 however, in most studies, the gum has been used for at
 •   Instruct smoker to try a piece of                    least 6–12 weeks and up to one year. Individualization
     gum/inhaler before travel starts                     of treatment duration is recommended.

                                                          Nicotine transdermal patch
                                                          The nicotine patch is a fixed nicotine delivery system
 Table 5.10 Varenicline use                               that releases about 1 mg of nicotine per hour for 16
 10+ cigarettes/day                                       hours (daytime patch) or for 24 hours (24-hour patch).
 • Varenicline 0.5 mg in morning days 1–3; then           Nicotine substitution is about 50% of the smoking level
    0.5 mg b.i.d. days 4–7                                (21-mg patch/24 h and 15-mg patch/16 h) (Table 5.5).
 • Quit smoking after 1 (–2) week                         The nicotine curve attained in plasma with patches is
 • Varenicline 1 mg b.i.d.                                flat, without the high peaks attained by cigarette
 • Duration: 12 weeks                                     smoking. It is much easier to administer the patch and
 • In quitters after 12 weeks eventually continue         to use it compared with gum, but it is not possible to
    with varenicline up to 6 months                       self-titrate.22 The recommended treatment duration is
 • Side-effects: mild nausea (30%), vomiting (2%)         8–12 weeks.
 • Contraindications: severe renal failure                   In a multicenter smoking cessation trial from the
                                                          USA, examining the effect of 0, 7-mg, 14-mg, and
                                                          21-mg nicotine patches, a dose–response effect of
                                                          increasing nicotine dosages was reported.23 Two large
gum, whereas the mean number of pieces of gum con-        placebo-controlled trials with 600 and 1686 smokers
sumed daily is only around five to six in most studies.   have been published.24,25 The one-year success rate was
Thus underdosing is a plausible explanation for lack of   9.3% in the active patch group versus 5.0% in the pla-
efficacy in several studies.18,19                         cebo patch group in the first study,24 and 9.0% versus
   From these observations, it would be logical to        6.3% in the other study.25 Among 19 studies examining
attempt to raise the consumed dose either by increasing   long-term (i.e. 6–12 months) smoking cessation suc-
the number of pieces of gum chewed or by using the        cess, 10 showed a significant outcome in favor of the
higher-dose (4-mg) gum. In four studies comparing         nicotine patch.22 The pooled success rate was 15.8% for
the 4- and 2-mg gums, the 4-mg gum was superior to        active patches versus 8.8% for placebos (odds ratio
the 2-mg gum for short-term outcome. Another way to       1.98; 95% CI 1.70–2.30).
46 Textbook of Lung Cancer

   Side-effects are mainly mild local skin irritation,       profile closer to cigarettes. After a single dose of 1 mg
occurring in 10–20% of subjects. In only 1.5–2.0% of         nicotine, the peak level is reached within 5–10 minutes,
subjects was the patch terminated owing to more persis-      with average plasma trough levels of 16 ng/ml. Three
tent and severe skin irritation at the patch location.22     published studies with the NNS indicate that the
   Because of its ease of use, the patch may be the first    one-year success rates for active NNS versus placebo,
choice of nicotine delivery system today. Transdermal        respectively, were 26% and 10%, 27% and 15%, and
nicotine replacement does increase success in smoking        27% and 17%.28,29
cessation with minimal adjunctive support.                      This strong spray induces localized side-effects, such
                                                             as sneezing, nasal secretion and irritation, and conges-
Nicotine inhaler                                             tion, watery eyes, and coughing. Up to 5% of subjects
An inhaler consists of a mouthpiece and a plastic tube       rate these side-effects as unacceptable; however, most
with a porous plug impregnated with nicotine, which          symptoms decrease within a few days after the spray is
releases nicotine vapor when air is drawn through the        initiated. Highly nicotine-dependent smokers might be
plug. Most of the nicotine is absorbed through the           the target group for this delivery mode of nicotine.
mouth and throat. Each inhaler contains 10 mg of nico-          The NNS should be used for three months, but has
tine (Table 5.5). In clinical use, each inhaler releases     been used for up to one year in some studies. The dose
approximately 2–3 mg of nicotine, and the number of          is from 10 to 40 puffs in each nostril per day.
inhalers used daily averages five or six. Thus, nicotine
levels comparable to those found during use of the           Nicotine sublingual tablet/lozenge
2-mg nicotine gum are attainable (i.e. relatively low        The 2-mg sublingual tablet should be placed under the
concentrations).                                             tongue, where it will disintegrate within 20 minutes.
   Few controlled trials have been conducted with nico-      The 1-mg and 2-mg lozenges should be sucked at until
tine inhalers. The efficacy and safety of the nicotine       a strong taste appears, they should then rest in the
inhaler were examined in a double-blind, clinical,           cheek for a few minutes and then the cycle is repeated
smoking cessation trial.26 The first published study was     for 15–20 minutes. The nicotine released from the tab-
a one-year, randomized, double-blind, placebo-con-           let will be absorbed through the oral mucous mem-
trolled trial that enrolled 286 smokers. The success rates   brane and the dose delivered is comparable with the
for smoking cessation were 15% and 5% at 12 months           2-mg nicotine chewing gum.30 Side-effects are similar
(p < 0.001) for active and placebo, respectively. The        to those from the nicotine gum. Many subjects with
mean nicotine substitution based on determinations           dentures who cannot use nicotine gum can use tablets
after one to two weeks of therapy was 38–43% of smok-        or lozenges.
ing levels. The treatment was well accepted, and no             The tablet/lozenge should be used for three months,
serious adverse events were reported. Three other stud-      but duration of treatment should be individualized
ies have confirmed the above finding, with odds ratios       for up to one year or longer. One tablet per hour is
in favor of active treatment of 1.6, 2.2, and 1.6.27 The     the recommended dosage up to 20/day, with a maxi-
inhaler may replace some of the habit patterns associ-       mum dose up to 40 tablets/day in highly dependent
ated with smoking (e.g. oral and handling reinforce-         smokers.
ment), along with providing nicotine replacement. At
least four inhalers should be used per day, the optimal      Combination of two different NRTs
number being 4–10 per day and the duration of use            Relatively few studies have been published about the
three months, with another 3–9 months of use and             combination of two NRT products. A short-term
downtitration if needed. With rapid and frequent puff-       increase in success has been observed in some, and a
ing, it is possible to increase the dose.                    trend towards a statistically significant 12-month
                                                             increase has been found in meta-analysis.14
Nicotine nasal spray                                            A dose–response effect has been observed with both
The nicotine nasal spray (NNS) consists of a multidose,      the nicotine gum and patch. Even 22- and 44-mg
hand-driven, pump spray with nicotine solution. Each         patches have been tested with promising results after
puff contains 0.5 mg nicotine; thus a 1-mg dose is deliv-    four weeks of treatment, i.e. success rates of 45% and
ered if both nostrils are sprayed as recommended             68%. In two studies the degree of nicotine substitution
(Table 5.5). The NNS is a strong and rapid means of          was compared to outcome and in both higher success
delivering nicotine into the body with a pharmacokinetic     rates were found with increasing degree of substitution.
                                                                                           Smoking cessation programs 47

In the CEASE study comprising 3575 subjects, a higher         of 19 placebo-controlled studies reported a doubling of
success rate was achieved with 25-mg 16-hour patches          quit rates with an odds ratio of 2.06 (95% CI 1.8–2.4)
compared with 15-mg nicotine patches.31                       in favor of bupropionSR.35
   Overall, in clinical use the combinations of different        The recommended dosing for bupropionSR is
NRT administration forms seem safe with few side-             150 mg a.m. for one week prior to the quit date, in order
effects. Also, concomitant use of NRT and cigarette           to establish adequate blood levels. Therapy should then
smoking seems safe, with nicotine concentrations similar      continue with 150 mg bid for 7–12 weeks.
to those found during normal cigarette smoking.                  Common adverse events from bupropionSR are
                                                              insomnia (up to 40%) and dry mouth. These side-
                                                              effects usually decline during the first week of therapy.
                                                              In clinical trials the treatment was stopped due to
                                                              adverse events in 10–12% of subjects. The most serious
Varenicline affects the central nicotine receptors by
                                                              adverse event was epileptic seizures, which were
binding to the nicotine receptor as an agonist with some
                                                              reported in 0.1% of patients, and allergic reactions
antagonist action. This means that varenicline mimicks
                                                              (1–2%), with 0.1% cases of serious hypersensitivity.35,36
the effect of nicotine, but also prevents the pleasure
                                                              The formulation is slow release to prevent high peak
from cigarette smoking by preventing nicotine from
                                                              concentrations as seizures are concentration-dependent.
binding to the receptor. In two studies with 1025 and
                                                              BupropionSR is contraindicated in individuals with an
1027 smokers with similar design, varenicline 1 mg bid
                                                              increased risk of seizures (e.g. epilepsy, earlier head
was compared with bupropionSR 150 mg bid versus
                                                              trauma, anorexia nervosa). A reduced dose – that is,
placebo for three months.32,33 The quit rate after 1 year
                                                              one tablet daily – is recommended in patients with
was 22% and 23% for varenicline, 16.4% and 15% for
                                                              severe liver impairment. As bupropionSR is metabo-
bupropionSR, and 8.4% and 10.3% for placebo, i.e.
                                                              lized in the liver, interactions occur with several drugs.
there were significantly higher quit rates for varenicline
                                                              Similarly, it is important not to increase the dose above
versus placebo and bupropionSR.
                                                              300 mg, and to administer the daily dose in divided
   A relapse prevention study reported that, in subjects
                                                              form, with an interval of at least eight hours. The last
who had quit after 3 months, prolongation of vareni-
                                                              dose should not be taken later than 6 p.m. if insomnia
cline use for another three months resulted in a higher
                                                              is a problem. Post-cessation weight gain is reduced by
quit rate after one year.34 The major side-effect was
                                                              2–3 kg during the drug treatment period.
nausea in approximately 30% of cases, with 2–3% dis-
                                                                 There are few studies comparing bupropionSR
continuing the drug due to nausea and vomiting. How-
                                                              with NRT or looking at the combination effect; however,
ever, in most subjects the nausea was not a major
                                                              the combination seems safe and is recommended for
problem. No drug interactions have been found, and
                                                              hard-core smokers such as lung cancer patients.
no significant contraindications have been reported,
                                                                 BupropionSR is of similar efficacy to NRT and is
except severe renal failure. Varenicline has no effect on
                                                              generally well tolerated in smoking cessation. As bupro-
post-cessation weight gain.
                                                              pionSR has a more severe side-effect profile, more con-
   Overall, varenicline is a new, effective, and safe agent
                                                              traindications, and is only available on prescription,
for smoking cessation. Also, varenicline tends to be more
                                                              I regard NRT as first-line medication and bupropionSR
effective than bupropionSR. Varenicline should be con-
                                                              as a second-line drug, but this is a matter of personal
sidered a first-line drug in lung cancer patients.
                                                              judgment and in most guidelines bupropionSR is a
   The dosing should be varenicline 0.5 mg a.m. for
                                                              first-line medication. The dosing should be bupropi-
3 days, 0.5 mg bid for another 3 days, then quit ciga-
                                                              onSR 150 mg a.m. for 6 days, then quit cigarettes from
rettes from day 7 and continue with 1 mg varenicline
                                                              day 7 and continue with 150 mg bid for 7–12 weeks
bid for 12 weeks and, if needed, up to six months.
                                                              and, if needed, up to six months (see Table 5.11).

                                                              OTHER DRUGS
BupropionSR, an amino-ketone, is an antidepressant that
differs from tricyclic antidepressants and serotonin re-      Nortriptyline, a tricyclic antidepressant, has been shown
uptake inhibitors, and the effect on smoking is not cou-      to be as effective as NRT and bupropionSR in smoking
pled to the antidepressive effect per se. A meta-analysis     cessation. A meta-analysis of four trials found an odds
48 Textbook of Lung Cancer

 Table 5.11 BupropionSR use
                                                              It might be used as a secondary drug, especially in
                                                              smokers afraid of or not accepting weight gain. Rimona-
 10+ cigarettes/day                                           bant has been marketed as a weight-reducing agent due
 • BupropionSR 150 mg in the morning                          to the low efficacy in smoking cessation.
    for 7 days                                                   Several nicotine vaccines are under development.
 • Quit smoking after 7 days                                  The principle is to produce antibodies in the blood that
 • Increase dose: bupropionSR 150 mg b.i.d.                   prevent most of the inhaled nicotine from cigarettes
 • Duration: 7–12 weeks                                       from reaching the brain. Phase II studies have found
 • Side-effects: sleep disturbances, seizures in              that it is possible to induce a long-term antibody level
    1:2000                                                    in humans with a safe vaccine and that high antibody
 • Contraindications: epilepsy, increased risk of             response is associated with smoking cessation.40
    seizures, impaired liver function

                                                              ALTERNATIVE THERAPIES

ratio of 2.8 (1.7–4.6) for one-year quit rates for nortrip-   Other ‘popular’ interventions often used are acupunc-
tyline versus placebo at a dose of 50–75 mg daily.37          ture and hypnosis. However, there is no evidence to
There are contraindications, common anticholinergic           support an effect from hypnosis or other alternative
side-effects, and particularly cardiac conduction distur-     therapies. A meta-analysis comparing active versus
bances and a decrease in orthostatic blood pressure.          control acupuncture found that acupuncture was no
However, at the relatively low dose used for smoking          more effective than placebo.41 One study reported no
cessation, nortriptyline seems to be relatively well toler-   effect for laser therapy in 320 adolescents.42
ated and is a second-line agent or even first-line agent,
especially in countries that cannot afford the more
expensive first-line drugs or where they are not mar-         SMOKING REDUCTION
keted. Several other antidepressants including selective
serotonin re-uptake inhibitors have not been found to         Many smokers would prefer to reduce the number of
be effective in smoking cessation, e.g. doxepin, fluox-       cigarettes smoked daily instead of quitting completely.
etine, sertraline, moclobemide, and venlafaxine.              The aim of smoking reduction is to widen access to ces-
   Clonidine, an α2-noradrenergic agonist, has been           sation by including smokers not currently able or will-
used as a smoking cessation agent. Six studies were           ing to stop abruptly, wanting to reduce smoking, or
included in a meta-analysis comprising 722 subjects,          unable or unwilling to quit. As shown below, by the
and the odds ratio of success with clonidine versus pla-      concept of smoking reduction it is possible to recruit a
cebo was 1.89 (95% CI 1.30–2.74).38 However, a high           new segment of smokers who are not interested in
incidence of adverse effects (median 71%) occurred            abrupt cessation. The reduction process should be
(e.g. dry mouth, sedation, dizziness, and symptomatic         looked at as a gateway to complete cessation.
postural hypotension). In my opinion – due to the high           The definition of smoking reduction is a decrease in
incidence of adverse events – clonidine is an obsolete        the number of cigarettes (or tobacco) smoked daily. A
drug in this area.                                            50% reduction or more in daily cigarettes has been
                                                              chosen arbitrarily in most studies.43,44
                                                                 Several randomized controlled trials have been pub-
NEW DRUGS                                                     lished. In eight studies, two using nicotine inhalers
                                                              and six using nicotine chewing gum for half to one
Rimonabant is a cannabinoid type 1 receptor antagonist        year, comprising 2424 smokers, a reduction (>50%)
with a central action and has been tested in smoking          was reported in 15.9% of smokers using nicotine prod-
cessation trials. Preliminary results showed an increased     ucts compared with a reduction in 6.7% of placebo
three month quit rate with rimonabant, with relatively        users.45 Surprisingly, after one year a smoking cessation
low absolute abstinence rates.39 Rimonabant more or           rate of 8.4% was found among nicotine users versus
less prevents post-cessation weight gain; however,            4.1% in placebo users. A reduction of more than 50%
when the drug is ceased weight increases. The role            after 3–4 months had a strong predictive value for
of rimonabant in smoking cessation has to be defined.         quitting at one year. Also, participation in reduction
                                                                                        Smoking cessation programs 49

trials increased the motivation to quit smoking,           surgery and during chemotherapy and radiation ther-
thus not undermining the motivation to stop smoking        apy if the patient has stopped smoking.
completely.                                                   The period of diagnosis and therapy might elicit
   Another way to attain smoking reduction and reduce      depressive reactions and put a heavy strain on the
the harm of smoking could be through tobacco product       patient’s and family’s mental and social situations. Many
modification.46 For the group of smokers not motivated     family members of lung cancer patients are often smok-
to quit smoking a less hazardous cigarette might be an     ers and do not quit spontaneously during this period.54
advantage. Also, smokeless tobacco (chewing tobacco        It might also be that lung cancer patients are more
and snuff) might be an alternative with tobacco smoking,   nicotine dependent.55 Overall, this calls for a more
with fewer health risks compared with smoking.47 Epi-      intensive and aggressive effort to get these patients to
demiologic studies in Sweden have found much less          successfully quit smoking. A nurse-managed program
harm in snuff users compared with cigarette smokers.48     reported an abstinence rate of 40% after six weeks.54 A
   The smoking reduction concept should be offered to      combination of nicotine patch with another NRT prod-
smokers who are not motivated to quit. They should be      uct should be the rule, and also a longer duration of
prescribed NRT – nicotine gum or inhaler – for three       treatment with the possibility to continue long term
months and recommended to reduce the number of             with NRT. A combination of NRT and bupropionSR
cigarettes by at least 50% during the first 1–2 weeks      might also be an option. However, as many of these
and then to try to reduce further. If the smoker has not   smokers have tried NRT previously, varenicline might
reduced by more than 50% after three months, NRT           be the right option for these dependent smokers. Sched-
should be stopped as the chance of quitting then is low.   uled visits with smoking cessation counseling and
In smokers who have reduced by more than 50%, NRT          support are important, to be combined eventually with
should be continued for up to one year, and after six      telephone calls.
months they should be recommended to try to stop              In healthy smokers higher quit rates have been
smoking completely.                                        obtained if spouses are also enrolled in the same pro-
   In summary, smoking reduction seems to have a role      gram and quit smoking, and this might also prove to be
for smokers not motivated or able to quit, as a gateway    the case for lung cancer patients. For the small fraction
to complete cessation. There is limited evidence that      of lung cancer patients with the lowest performance
smoking reduction is followed by an improvement in         status, where only supportive therapy is prescribed and
health, in contrast to the use of smokeless tobacco        who have an expected short survival time, I would not
products.                                                  actively suggest smoking cessation.
                                                              The clinics involved with the diagnostics and therapy
                                                           of lung cancer should be able to cover smoking
SPECIAL CONSIDERATIONS FOR LUNG                            cessation, and the health-care workers should have an
CANCER PATIENTS WHO SMOKE                                  adequate knowledge about smoking cessation.52 It is
                                                           important that a specific budget is allocated to each
In this group of patients as many as 80% quit smoking      clinic for a smoking cessation service.
during the time of diagnosis.49 However, up to 50% of
patients undergoing curative surgery for lung cancer
relapse and smoke after five years, thus increasing the    WEIGHT GAIN
risk of a secondary primary lung cancer.50,51 In healthy
smokers a high relapse rate is observed during the first   A weight gain of 3 to 6 kg for abstainers after one year
month after quit day, in contrast to cancer patients       is found in most studies.56,57 In 10% of males and 13%
where most relapses occur between one and six months       of females the weight increase is more than 14 kg, i.e.
after quit day.52,53                                       they are ‘supergainers’. About half of the participants
   An increasing proportion of lung cancer patients        are afraid of gaining weight and it may be a more
undergo chemotherapy and this proportion will prob-        significant problem for females. Weight gain can be
ably further increase during the next decade due to        regarded as a withdrawal symptom due to increased
increased public focus on this disease. Thus, in the       hunger and increased caloric intake. NRT products are
future most patients will undergo treatment with sur-      only partially able to reduce the post-cessation weight
gery and/or chemotherapy. The importance of smoking        gain while bupropionSR has a slightly greater effect, i.e.
cessation is due to a decreased complication rate after    a reduction in post-cessation weight gain of 2–3 kg.57
50 Textbook of Lung Cancer

For lung cancer patients the increase in weight might                 3. Peto R, Lopez AD, Boreham J et al. Mortality from tobacco in
be an advantage if they are underweight. The increase                    developed countries 1950–2000. Oxford: Oxford University
                                                                         Press, 1994.
in appetite might also be an advantage for patients with
                                                                      4. World Health Organisation (WHO). European partnership to
decreased appetite.                                                      reduce tobacco dependence: WHO evidence based recommen-
                                                                         dations on the treatment of tobacco dependence. Geneva:
                                                                         WHO, 2001.
CONCLUSIONS                                                           5. IASLC Workshop. Prevention and early detection of lung
                                                                         cancer. Clinical aspects. Proceedings. Elsinore, Denmark,
In summary, NRT, varenicline, and bupropionSR                         6. Prochaska JO, Goldstein MG. Process of smoking cessation.
almost double the one-year cessation outcome, and,                       Implications for clinicians. Clin Chest Med 1991; 12:
combined with counseling and behavioral strategies,                      727–35.
are important adjuncts for maintaining long-term smok-                7. American College of Chest Physicians, American Thoracic Soci-
ing cessation. Nicotine gum, patch, and inhaler are first                ety, Asia Pacific Society of Respirology, Canadian Thoracic
                                                                         Society, European Respiratory Society International Union
line drugs, while NNS nasal spray is for the more heav-
                                                                         Against Tuberculosis and Lung Diseases. Smoking and health:
ily dependent smokers. The patch might not be the first                  a physician’s responsibility. A statement of the joint committee
choice for heavily dependent smokers. The duration of                    on smoking and health. Eur Respir J 1995; 8: 1808–11.
NRT treatment is approximately three months, with                     8. USDHHS. Tobacco and the Clinician: Interventions for Medical
individual variations.                                                   and Dental Practice. NCI 94-3693. Rockville, MD: US Depart-
   NRT is a very cost-effective treatment compared with                  ment of Health and Human Services, Public Health Service,
                                                                         National Institutes of Health, 1994.
several other medical treatments, and should be much
                                                                      9. National Institute for Clinical Excellence (NICE). Guidance on
more widely implemented in the future. If the smoker                     the use of nicotine replacement therapy (NRT) and bupropi-
has failed using NRT, varenicline or bupropionSR is the                  onSR for smoking cessation. National Institute for Clinical
choice.                                                                  Excellence Technology Appraisal Guidance No 39, 2002. Avail-
   As lung cancer patients might be more nicotine-                       able from
dependent and have more difficulty in stopping smok-                 10. Jarvis MJ, Russell MA, Saloojee Y. Expired air carbon monox-
                                                                         ide: a simple breath test of tobacco smoke intake. BMJ 1980;
ing, a more aggressive therapeutic approach should be
                                                                         281: 484–5.
used, i.e. higher doses of NRT, a combination of two                 11. American Psychiatric Association. Diagnostic and Statistical
NRT formulations, varenicline, bupropionSR plus NRT,                     Manual of Mental Disorders–IV. Washington, DC: APA,
a longer duration of therapy (6–12 months), and more                     1994.
support visits. Family members who smoke should also                 12. Hughes JR, Gust SW, Skoog K et al. Symptoms of tobacco with-
be enrolled in a cessation program.                                      drawal. A replication and extension. Arch Gen Psychiatry 1991;
                                                                         48: 52–9.
   Most lung cancer patients have used NRT previously,               13. Fagerström KO, Heatherton TF, Kozlowski LT. Nicotine
varenicline seems to be the drug of choice as it seems                   addiction and its assessment. Ear Nose Throat J 1991; 69:
more effective than bupropionSR, with fewer adverse                      763–8.
effects and almost no contraindications or interactions.             14. Silagy C, Lancaster T, Stead L et al. Nicotine replacement
Also, varenicline tends to be more effective when com-                   therapy for smoking cessation. Cochrane Database Syst Rev
                                                                         2004; 3: CD000146.
pared with bupropionSR.
                                                                     15. McNabb ME, Ebert RV, McCusker K. Plasma nicotine
   Physicians and other health-care providers have                       levels produced by chewing nicotine gum. JAMA 1982; 248:
an obligation to discourage tobacco use in their                         865–8.
patients and to deliver up-to-date assistance in smok-               16. McNabb ME. Chewing nicotine gum for 3 months: What hap-
ing cessation.                                                           pens to plasma nicotine levels? Can Med Assoc J 1984; 131:
                                                                     17. Tønnesen P, Fryd V, Hansen M et al. Two and four mg nicotine
                                                                         chewing gum and group counseling in smoking cessation: an
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    Lancet 1992; 340: 324–9.                                              46.   Bates C, McNeill A, Jarvis M, Gray N. The future of tobacco
29. Blondal T, Franzon M, Westin A et al. Controlled trial of nico-             product regulation and labelling in Europe: implications for the
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52 Textbook of Lung Cancer

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    6         Current status of lung cancer screening
              James L Mulshine

              Contents Introduction • Current evidence • Technical innovations with CT imaging • Recommendations
              from professional societies • Recent developments • Conclusion

INTRODUCTION                                                  concern about CT-based lung cancer detection being not
                                                              only prohibitively expensive but possibly dangerous.15–17
Lung cancer screening is the crucible where providing         Against this charged back drop, it is timely to review the
an expensive new service with the potential for harm in       status of early lung cancer detection.
vast numbers of variably at-risk individuals collides
with the consequences of the world’s most lethal can-
cer. With over 160 000 annual deaths, lung cancer             CURRENT EVIDENCE
accounts for 30% of cancer deaths in the USA.1 Regional
or distant metastatic spread is evident in at least three-    A number of CT screening pilot studies have been
quarters of lung cancer cases at time of initial diagnosis    reported over the last few years (Table 6.1). While there
resulting in a 5-year survival rate of 15%. For surgically    are different eligibility criteria and case work-up
resected cancer, the 5-year survival rate exceeds 60%.        approaches, these single-arm studies have been consis-
By comparison, localized breast and prostate cancer are       tent for several critical parameters. Frequency of stage I
detected at rates of 63 and 82%, so correspondingly           detection with CT screening is about 80%, which is
their 5-year survival rates are much better at 87 and         considerably higher than the national experience of
98%, respectively. For women, there has been a 600%           17%.1 This published experience is too recent to have
increase in the frequency in lung cancer over the last        long-term clinical outcomes except for a recently pre-
eighty years, and lung cancer death rates in United           sented Japanese series. From 1975–1993, the Anti-lung
States women are the least favorable in the world.2 Unlike    Cancer Association performed 26 338 screening chest
cardiovascular disease, the risk of developing lung           X-rays,18 and in the detected cases 42% were stage I
cancer remains elevated after smoking cessation.3–5           lung cancer with an average primary size of 3 cm and
   Lung cancers are being diagnosed at least as frequently    33% were stage III/IV. During 1993, this group began
in the over 45 million former smokers as in current           using CT and, by 2002, 15 342 scans had been per-
smokers,3 and smoking cessation strategies are of no          formed. With CT screening, 78% of the detected cases
utility in the growing cohort of former smokers. The          were stage I with a mean diameter of 1.5 cm and the
progress in cardiovascular disease has not been matched       rate of detection for stage III/VI disease had decreased
in lung cancer outcomes, so this cancer has recently          to 14%. With this transition, the overall 5-year survival
emerged as the dominant cause of death in tobacco-            improved from 49% with chest X-ray-detected cases to
exposed individuals.6 Tobacco-related diseases are the        84% with CT-detected cases. This experience is consis-
leading cause of premature death and account for half         tent with the early reports from the International-Early
of health-care costs in our society, so better approaches     Lung Cancer Action Project (I-ELCAP), whose screen-
to lung cancer management are critical.7                      ing experience with current and former smokers was
   Promising reports with high-resolution computed            presented with prevalence evaluation of over 26 000
tomography (CT) detection have renewed interest in            subjects and follow-up incidence data from 19 700
early lung cancer screening.4,8–11 No major lung cancer       subjects.19,20
screening trial has been completed here in decades and           The critical endpoint of a randomized trial is sig-
the recent United States Preventive Services Task Force       nificant cancer-related mortality reduction in the
(USPSTF) analysis acknowledges the methodologic lim-          screened population compared to a control population.
itations of the previous chest X-ray screening trials.12–14   The randomized trial design addresses the potentially
Lingering debate about those earlier trials has fostered      confounding influence of overdiagnosis. The term
54 Textbook of Lung Cancer

 Table 6.1 Distillation of the pilot CT screening results for non-small cell lung cancer

                              No of subjects           Number of CT-detected          Mean size of      Percent stage I
                                                       lung cancers tumors            primary (mm)      cancers

 cohorts8,37,38,67,71             13 122                          112                      16.5              79
 cohorts33,37,38,67,71              9 401                          54                      14.8              81

‘overdiagnosis’ refers to clinical outcome events not                optimal size range for finding lung cancers before lym-
adjusted for disease that would remain clinically covert             phatic dissemination must be even smaller. Neverthe-
until death from other causes. If there is considerable              less, the evidence for more favorable outcomes in
overdiagnosis, an apparently favorable screening result              managing smaller primary lung cancers is growing.29–36
in regard to stage or 5-year survival would not lead to              From the experience in Tokyo, Rochester (MN), New
a significant lung cancer mortality reduction in the                 York City, and Milan, it is evident that centers of excel-
screened arm. With current information it is not pos-                lence can deliver high-quality lung cancer screening
sible to establish a reliable estimate of the magnitude of           care and measures reducing the number of invasive
overdiagnosis, but emerging clinical and biologic infor-             diagnostic procedures improve cost efficiencies.8,33,37–40
mation suggests that these small screen-detected lung                   Professional groups such as the Society for Thoracic
cancers may behave like symptom-detected lung                        Surgery have developed national registries as a tool
cancers.21,22                                                        for improving quality outcomes in thoracic surgery
   Furthermore, the term ‘overdiagnosis’ is used loosely             (, and these measures may
and may be construed to include the situation where a                allow favorable management outcomes to become more
clinically aggressive lung cancer is detected by CT                  generalized.4,41 Currently, the best approach to reducing
screening. However, in certain situations overdiagnosis              overtreatment, and with it the morbidity and mortality
also refers to the patient who expires first of a co-morbid          of screening case management, is an area of uncertainty,
condition related to tobacco yeast. In the decades since             but clear research opportunities exist and preliminary
the last major NCI-sponsored lung cancer screening tri-              studies in this regard are being undertaken.42–45
als, the influence of competing risks has diminished                    An important finding at both Mayo Clinic and Cor-
related to both improved coronary artery disease out-                nell is that smoking cessation counseling in the setting
comes and the increasing number of former smokers                    of lung cancer screening is associated with favorable
perhaps mitigating the influence of overdiagnosis.6,23–25            quit rates.46,47 Tobacco control has been the dominant
Finally, overdiagnosis could also be construed as cases              public health response for improving lung cancer out-
where lethal iatrogenic complications occur in the course            comes.48 Linking smoking cessation with early detec-
of clinical management of screen-detected lesions.26                 tion research efforts may improve the cost economy of
Overtreatment refers to the use of an intervention that              lung cancer screening.
may entail greater morbidity than benefit of screening                  In light of the reports suggesting spiral CT can detect
that may be accrued to an individual choosing to undergo             small, early lung cancer, the NCI rapidly initiated the
lung cancer screening.                                               National Lung Cancer Screening Trial (NLST) to evalu-
   The best clinical management for small CT-detected                ate whether CT screening leads to a significant improve-
primary cancers is emerging to be different from the                 ment in lung cancer-related mortality. This urgency
standard management recommended for a chest X-ray-                   was heightened by the concern that widespread ad hoc
detected lung cancer.27,28 For example, an anatomic                  CT screening, despite being a non-reimbursed service,
lobectomy with mediastinal dissection is the appropri-               could preempt the opportunity for conducting a formal
ate operation to manage a chest X-ray-detected lung                  randomized trial. Based on favorable initial data, many
cancer, but is it the best way to remove a 7 mm periph-              people believe that lung cancer screening will be a
eral primary lung cancer? Since even with subcentime-                sensitive test for early disease. While this may be true
ter screen-detected primary cancers, the frequency of                for many individuals, from a public health policy per-
regional nodal involvement remains around 10%, the                   spective it is also necessary to place emphasis on the
                                                                                    Current status of lung cancer screening 55

specificity of a screening test. The specificity of the         amount of data generated in this process is daunting.
screening test will affect the resultant costs to society, in   Currently, the average size of incident primary cancers
terms of morbidity and dollars, in regard to overdiag-          detected at one center is under 1.0 cm.27,52,53 The gap
nosis, overtreatment, false positives, and adverse events       between the technical capabilities of the hardware in
associated with appropriate treatment. Conventional             acquiring vast amounts of imaging data and the avail-
wisdom is that these factors can only be assessed in a          ability of validated software to harness this improved
prospective, randomized trial with a control group and          imaging capability highlights the importance of research
a lung cancer mortality endpoint.                               into CAD for early cancers. A potential benefit of high-
   The NLST, which has already completed full accrual,          er-resolution imaging is that the evaluation may be
uses multi-detector-row scanners (at least four rows)           more sensitive in finding smaller primary cancers. This
for the 25 000 volunteers on the CT arm of that trial.          size reduction may further decrease the frequency of
The control group of 25 000 receives annual chest X-ray         metastatic disease as well as interval-detected cancer.27–
screening. The NLST subjects will receive annual                   A particular problem in this regard is the reliable
screening for three years, and follow-up will continue          detection of curable small cell lung cancer cases.
for a few years until a mortality endpoint is reached.             CAD has not had a major clinical impact on breast
The Dutch national randomized CT screening trial will           cancer imaging,54 but this is a two-dimensional data situ-
use 16-detector scanners and computer-assisted-detec-           ation. With the anatomically more precise, three-dimen-
tion (CAD) tools for their entire study population and          sional spiral CT, this situation could be different for lung
compare outcomes with a standard care control arm.              cancer. The additional information provided by the third
Other European trials including studies in France and           dimension greatly improves the precision of measure-
Italy are coming online. Investigators from the Ameri-          ment and of volume comparisons across time.55–57
can and European trials will have periodic meetings to             If CT screening is validated to be effective, many
standardize elements of data acquisition so that com-           more lung CT scans will be performed. Even with
parison of results from the various trials may be more          screening high-risk cohorts, the frequency of cancer in
productive.                                                     a high-risk population will typically be about 1% or
   While breast cancer screening trials were conducted          less, so software to allow efficient work flow is essential
over several decades with relative stability of the imag-       to leveraging the productivity of thoracic radiologists.
ing detection tool,49 the dynamic pace of innovation            However, to reliably establish clinically relevant fea-
with spiral CT and its consequences have imposed an             tures such as the irregular boundary of small pulmo-
unprecedented challenge to the randomized trial design          nary lesions abutting normal adjacent structures, the
concept.50,51 Thoughtful analysis of the relative utility of    amount of imaging information required by a CAD sys-
different trial designs, large databases, and other             tem may exceed the amount of imaging information
resources in permitting adaptive public health progress         that it is reasonable to expect a radiologist to review.
is a profound strategic challenge, but one that merits          This disconnection will be most evident when CAD is
more serious attention.19,41                                    being applied to evaluate very small lesions, where
                                                                human vision has limited capabilities and determining
                                                                the ‘ground truth’ will be problematic. Therefore, devel-
TECHNICAL INNOVATIONS WITH CT IMAGING                           oping and validating CAD applications for cancer
                                                                screening are great challenges, but standardized image
Over the last decade, there have been substantial               evaluation tools may prove essential in moving popula-
improvements in the speed and quality of CT imaging.            tion-based lung cancer screening into routine care
Ten years ago, a typical single-detector CT scanner             settings.54,58–60 For this reason, the NCI developed the
acquiring one centimeter thick views (slices) along the         Lung Image Database Consortium (LIDC) to accelerate
entire axial length of the thorax took several minutes          the maturation of image-processing tools for CAD. The
and consequently the respiratory motion of chest struc-         key aspect of this cooperative group is to create a large,
tures seriously compromised image resolution. Since             well-characterized database of images and clinical out-
then there have been several generations of multi-de-           comes data for CAD algorithm research and validation.
tector CT scanners; the latest 64-detector-row scanners         This resource could expedite such projects as the utility
will image the entire thorax using 0.625 mm slice thick-        of volumetrically determined growth rates for identi-
nesses in several seconds. This thinner slice thickness         fying potential cancerous pulmonary nodules53,61 or
may allow for markedly better image resolution, but the         studies on the natural history of newly reported
56 Textbook of Lung Cancer

ground-glass opacities (or non-solid nodules).39,42,62              defining the risk features of the screened cohort,66
Rapid progress with CT-based imaging is expected to                 by reducing the screening intensity in following up
continue. To extract clinically significant information             screen-negative populations,67 as well as from further
from such a detail-rich image, computer-assisted tools              innovation with the imaging technology.
will be crucial. The further pragmatic issues encoun-
tered in the breast cancer screening efforts in regard to
radiologists’ workload, reimbursement, and profes-                  RECOMMENDATIONS FROM PROFESSIONAL
sional liability may also be ameliorated if validated               SOCIETIES
computer-aided diagnosis methods are developed.63,64
   A major concern about widespread CT screening                    The American Cancer Society (ACS) updated its state-
relates to its cost, especially in light of one study which         ment on testing for early lung cancer and recommended
projected enormous costs from models assembled using                against testing for early lung cancer in the asymptom-
assumptions based on early screening reports.15 More                atic population of at-risk individuals.68 However, this
extensive use of non-invasive imaging techniques in the             revised statement recommends that individuals at high
work-up of screen-detected lesions may explain why                  risk for lung cancer, due to significant exposure to
the cost features of some screening management                      tobacco smoke or occupational exposure, should dis-
approaches are less expensive.65 Only 13% of the                    cuss with their physician the potential benefits and
screened cases require further follow-up, with most of              harm to inform their testing decision. ACS further rec-
those cases evaluated by serial CT imaging for nodule               ommends that such testing be done only in experienced
growth rate.52,53,61 Further potential for cost savings and         centers linked to multidisciplinary specialty groups for
morbidity reductions can be achieved by carefully                   diagnosis and follow-up.69

 Table 6.2 Points to consider for clinicians in discussing lung cancer screening and its implications with individuals considering
 spiral CT screening

 •    The risk and benefits of lung cancer screening should be discussed, including potential morbidity,
      mortality, and associated medical costs
 •    No data are available from the two randomized trials evaluating for improvement in lung cancer-related
      mortality and results are expected in several years
 •    Results from observational studies of CT screening among high-risk patients (i.e. those with a history of
      heavy smoking) indicate a high rate of diagnosis of lung cancer in stage I (a relatively curable stage)
 •    The risk:benefit issues around lung cancer screening may be different for current smokers compared to
      former smokers.
      • For current smokers, smoking cessation remains the single most important measure to improve one’s
           overall but especially cardiovascular health prospects
      • For former smokers, the elevated risk of developing lung cancers persists for the rest of their lives
 •    CT screening reveals many non-calcified nodules, only a fraction of which will be found to be lung cancer
 •    The approach to diagnostic evaluation of suspicious nodules should be refined to maximize information
      yield from non-invasive procedures while minimizing iatrogenic risk
 •    Referral to a facility that is experienced and committed to providing high-quality integrated screening care
      is essential. At such a facility there would be experienced and credentialed clinicians from
      multidisciplinary fields (including thoracic surgeon, pathologist, pulmonologist)
 •    The surgeon selected to perform the lung cancer operation should not only be specifically trained to
      provide such care but should also perform lung cancer operations frequently
 •    Facilities providing lung cancer screening care should provide objective information about the quality of
      their outcomes
 •    There is a persistent increased risk of subsequent lung cancers after curative resection of lung cancer, so
      ongoing surveillance is essential
 •    Participation in research to optimize CT screening management should be strongly encouraged
                                                                                     Current status of lung cancer screening 57

   The conclusions from the USPSTF analysis, based on            RECENT DEVELOPMENTS
a review of the literature published as of January 2003,
( are as          The New England Journal of Medicine recently published
follows:                                                         a landmark experience in using spiral CT in over 31 000
                                                                 individuals at risk for lung cancers from 38 institutions
   The USPSTF recommends neither for nor against
                                                                 across three continents.73 Over the last 15 years, the
   using chest x-ray, computed tomography (CT scan),
                                                                 group at Cornell, together with their collaborators, has
   or sputum cytological examination to look for lung
                                                                 systematically explored the best approach to finding
   cancer in people who have no symptoms to suggest
                                                                 and operating on early lung cancer. In a series of peer-
   the disease. If screening is being considered, doctors
                                                                 reviewed publications they have defined innovative
   and patients should discuss the pros and cons of
                                                                 uses of spiral CT, image processing techniques, and
   screening before going ahead with x-ray, CT scan, or
                                                                 internet-based clinical trial co-ordination, driving prog-
   sputum cytologic examination to screen for lung
                                                                 ress in the detection and management of early lung
   cancer. Patients should be aware that there are no
                                                                 cancer. There is controversy about the benefit of CT-
   studies showing that screening helps people live lon-
                                                                 based screening for lung cancer, but there should be no
   ger. They should also know that false-positive test
                                                                 argument about the core strategy of attempting to
   results are common and can lead to unnecessary
                                                                 improve our ability to routinely find early, localized
   worry, testing, and surgery.12
                                                                 lung cancer.
This statement represents a change from their previous              In community-based populations, finding early lung
recommendation against screening and this reflects the           cancer is a daunting process since disease prevalence is
accumulation of more persuasive though not yet defin-            relatively low. Finding economic approaches to detect
itive data regarding the utility of lung cancer screening.       and confirm the occurrence of lung cancer in this set-
As a reflection of the extraordinary pace of this field, a       ting is a critical public health challenge. The Cornell
number of relevant reports have been published since             group has described a successful approach to this and
the completion of the USPSTF literature review on new            has integrated minimally invasive diagnostic and surgi-
cohorts,18,38,39 efficiency of the diagnostic work-up,27,53,70   cal techniques as feasible for early lung cancer manage-
outcomes,72,73 and cost-effectiveness.45,65                      ment. In addition, they have worked with a number of
   In this dynamic setting, clinicians have a major chal-        the most respected thoracic pathologists in the world
lenge in staying abreast to provide current information          (mostly from IASLC) to review these cases and, in their
to their patients. Issues to consider in discussion with a       recent publication, reported that the cases found by CT
patient who may be considering lung cancer screening             screening fulfill standard criteria for fully fledged aggres-
are complex. In light of recent reports about health lit-        sive lung cancers.74 This supports recent tumor biology
eracy there is a major communications challenge in res-          information suggesting that these screen-detected
ponsibly educating about lung cancer screening (see              tumors behave like routinely detected lung cancers.22 and http://               Of the more than 400 cancers recently reported in the                         Cornell study, 85% of the detected cases were stage I.
   Since the clinical management for lung cancer screen-         The 10-year survival analysis, after three years of median
ing has a higher probability of morbid and mortal com-           follow-up, shows that over 90% of the people undergo-
plications than cancer screening for other organs, a             ing operations were projected to be alive and lung can-
mortality reduction benefit found by the NLST may not            cer free. All eight individuals who for personal reasons
result in improved national outcomes with lung cancer            declined surgery died of lung cancer.
if screening care delivery systems for early lung cancer            A key enabler of this large study consortium was the
are not in place.41 The choice is between organized              use of a web-based early lung cancer management sys-
screenings, where screening services are provided in             tem developed by the Cornell group which allowed
centers committed to excellence in early cancer man-             research to go on in the setting of clinical care. The cur-
agement, or ad hoc screening, where the specifics of             rent I-ELCAP results convincingly demonstrate that
screening care are left to be refined by market forces.          systematic efforts to find early lung cancer can be asso-
We recently tried to organize a series of issues that            ciated with very favorable outcomes and their organiza-
should help physicians organize their dialog with                tional process accelerates early lung cancer research. A
subjects considering lung cancer screening.72                    challenging debate is proceeding about the sufficiency
58 Textbook of Lung Cancer

of the I-ELCAP data to change national health-care                     7. Leaf C. Why we’re losing the war on cancer and how to win it.
policy on lung cancer screening. This is a profoundly                     Fortune 2004; 149: 76–96.
                                                                       8. Henschke CI, McCauley DI, Yankelevitz DF et al. Early Lung
important scientific, medical, and political process.
                                                                          Cancer Action Project: overall design and findings from base-
However, the IASLC could play a pivotal role in gener-                    line screening. Lancet 1999; 354: 99–105.
ating the research data to inform the process. There are               9. Henschke CI, Yankelevitz DF, McCauley DI et al. Guidelines
many steps in moving to responsible management of                         for the use of spiral computed tomography in screening for
early lung cancer and we need better information about                    lung cancer. Eur Respir J Suppl 2003; 39: 45s–51s.
all of them. How do we identify the optimal cohort,                   10. Kaneko M, Kusumoto M, Kobayashi T et al. Computed tomog-
                                                                          raphy screening for lung carcinoma in Japan. Cancer 2000; 89:
how do we do the diagnostic work-up, how do we do
the most appropriate removal of the primary cancer,                   11. Mulshine J. Screening for lung cancer: in pursuit of pre-meta-
how frequently do we do follow-up CT scans to find                        static disease. Nature Rev Cancer 2003; 3: 65–73.
synchronous primaries, etc. These and many more                       12. Humphrey LL, Teutsch S, Johnson M. Lung cancer screening
issues need to be addressed with research using state-                    with sputum cytological examination, chest radiography and
of-the-art imaging tools. Since the progress in improv-                   computer tomography: an update for the U.S. Preventive Task
                                                                          Force. Ann Intern Med 2004; 140: 740–53.
ing imaging tools is moving so fast, it is a major challenge          13. Strauss G, Dominioni L. Varese meeting report. Lung Cancer
for our research processes. This is a part of the discus-                 1999; 23: 171–2.
sion about early detection research that merits much                  14. Fontana RS, Sanderson DR, Woolner LB et al. Screening for
more serious and urgent research attention. The con-                      lung cancer. A critique of the Mayo Lung Project. Cancer 1991;
tentious discussion surrounding screening trial design                    67: 1155–64.
                                                                      15. Mahadevia PJ, Fleisher LA, Frick KD et al. Lung cancer screen-
has distracted us from a profound emerging opportu-
                                                                          ing with helical computed tomography in older adult smokers:
nity to much more successfully manage lung cancer.                        a decision and cost-effectiveness analysis. JAMA 2003; 289:
                                                                      16. Swensen SJ, Jett JR, Midthun DE, Hartman TE. Computer
CONCLUSION                                                                tomographic screening for lung cancer: home run or foul ball?
                                                                          Mayo Clin Proc 2003; 78: 1187–8.
CT screening for lung cancer detection has consider-                  17. Brenner DJ. Radiation risks potentially associated with low-
                                                                          dose CT screening of adult smokers for lung cancer. Radiology
able promise. Yet many individuals seeking lung cancer
                                                                          2004; 231: 440–5.
screening services, such as the lower-risk subject out-               18. Kakinuma R. Low-dose helical CT screening for lung cancer:
lined in the introductory vignette, may have a greater                    the Japanese experience and perspective. Proc IASLC Work-
chance of iatrogenic harm that screening benefit. While                   shop 2003: 18.
definitive trials are in progress, the opportunity should             19. Henschke CI, Yankelevitz D. Lung cancer screening with spiral
not be lost to conduct further essential research to gen-                 CT: how can it work: reviewed. Oncology 2004; 18: 584–7.
                                                                      20. Wisnivesky JP, Mushlin AI, Sicherman N et al. The cost-effec-
eralize a potential mortality reduction benefit evident in                tiveness of low-dose CT screening for lung cancer: preliminary
a lung cancer screening trial to routine care settings.                   results of baseline screening. Chest 2003; 124: 614–21.
                                                                      21. Bianchi F, Hu J, Pelosi G et al. Screening spiral CT-detected
                                                                          lung cancers have a malignant phenotype by cDNA microarray
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    J Clin 2003; 53: 27–43.                                         73. International–Early Lung Cancer Action Program Investigators.
69. Smith RA, Cokkinides V, Eyre HJ. American Cancer Society            Survival of patients with Stage I lung cancer detected on CT
    Guidelines for the Early Detection of Cancer, 2004. CA Cancer       screening. N Engl J Med 2006; 355: 1763–71.
    J Clin 2004; 54: 41–52.                                         74. Flieder DB, Vazque M, Carter D. Pathological findings of lung
70. Libby DM, Smith JP, Altorki NK et al. Managing the small pul-       tumors diagnosed on baseline CT screening. Am J Surg Pathol
    monary nodule discovered by CT. Chest 2004; 125: 1522–9.            2006; 30: 606–13.
    7         Histopathology of lung tumors
              Elisabeth Brambilla, Sylvie Lantuejoul

              Contents Introduction • Squamous cell carcinoma • Adenocarcinoma • Small cell carcinoma
              • Large cell carcinoma • Adenosquamous carcinoma • Sarcomatoid carcinoma
              • Typical and atypical carcinoid • Conclusions

INTRODUCTION                                                 lung cancers, and is even more frequently seen by
                                                             electron microscopy.
With 169 500 new cases per year in the United States
and 182 000 new cases per year in Europe, lung cancer
is the most common worldwide diagnosed cancer and            SQUAMOUS CELL CARCINOMA
the major cause of mortality,1 with157 400 cancer
deaths2 in the USA and 190 000 cancer deaths in the          A malignant epithelial tumor showing keratinization
European Union in 2001. Although cancer incidence            and/or intercellular bridges that arises from bronchial
began to decline in men in the USA from 1980,3 its rate      epithelium.11
is increasing in women,2 as a consequence of the                Squamous cell carcinoma (SCC) accounts for approx-
increasing proportion of women who smoke.                    imately 30% of all lung cancers in the United States12
   The international standard for histologic classifica-     and 45% in Europe. Twenty years ago it was the most
tion of lung tumors is that proposed by the World            frequent histologic type of lung cancer in Europe, and
Health Organization (WHO) and the International              it has progressively decreased, while adenocarcinoma
Association for the Study of Lung Cancer (IASLC;             has increased in incidence. Over 90% of SCC occurs in
Table 7.1).4 The four major histologic types of lung         cigarette smokers. Two-thirds of SCCs present as cen-
cancer are squamous cell carcinoma, adenocarcinoma,          tral tumors, whereas one-third present as peripheral
the incidence of which is increasing at the expense of       tumors, although the primary bronchial site may be
squamous cell carcinoma, small cell carcinoma (SCLC),        easily detected at histology.13,14 The morphologic fea-
and large cell carcinoma. These major types have been        tures that characterize squamous differentiation include
subclassified into subtypes, the clinical significance of    intercellular bridging and keratinization (or individual
which might be extremely important, such as the bron-        cell keratinization or squamous pearl formation). These
chioloalveolar carcinoma (BAC) as a variant of adeno-        differentiated features are readily apparent in well-dif-
carcinoma.4                                                  ferentiated tumors, and are difficult to detect in poorly
   Although lung cancer can be divided into many sub-        differentiated ones.15 However, this spectrum of differ-
types, the most important distinction is between SCLC        entiation has not been demonstrated to correlate with
and non-small cell lung carcinoma (NSCLC). Clinical          prognosis in lung SCC. Segmental bronchi more often
importance has been given to this distinction because        than lobar and mainstem bronchi are the primary site
of the major clinical differences in presentation, meta-     of SCC.16
static spread, and response to therapy of SCLC. How-            Variants described in the WHO classification include
ever, this is an extremely simplistic means of distinction   papillary, clear cell, small cell,17 and basaloid subtypes.4
between these subtypes which is not recommended              This last variant has a dismal prognosis as compared to
because it may override the clinical significance of spe-    poorly differentiated SCC.18,19 In a recent evaluation of
cific subtypes like BAC. Histologic heterogeneity is an      a large series of cases where basaloid carcinoma appeared
important feature of the pathology of lung cancer,           to have a shorter survival than other types of NSCLC
which consists of a mixture of histologic types that rep-    (p = 0.005) the basaloid variant of SCC did not differ
resent a derivation of lung cancer from a pluripotent        from pure basaloid cases with regard to survival.20
stem cell.5–10 This histologic heterogeneity is apparent     Papillary SCC often shows a pattern of exophytic endo-
on light microscopic examination in at least 30% of          bronchial growth.21,22
62 Textbook of Lung Cancer

 Table 7.1 WHO histologic classification of tumors             Table 7.1 Continued
 of the lung
                                                               Salivary gland tumors
 Malignant epithelial tumors
                                                                 Mucoepidermoid carcinoma                8430/3
 Squamous cell carcinoma                             8070/3
                                                                 Adenoid cystic carcinoma                8200/3
   Papillary                                         8052/3
                                                                 Epithelial-myoepithelial carcinoma      8562/3
   Clear cell                                        8084/3
   Small cell                                        8073/3    Preinvasive lesions
   Basaloid                                          8083/3      Squamous carcinoma in situ              8070/2
                                                                 Atypical adenomatous hyperplasia
 Small cell carcinoma                                8041/3
                                                                 Diffuse idiopathic pulmonary
   Combined small cell carcinoma                     8045/3
                                                                 neuroendocrine cell hyperplasia
 Adenocarcinoma                                      8140/3
                                                               Mesenchymal tumors
   Adenocarcinoma, mixed subtype                     8255/3
                                                                Epithelioid hemangioendothelioma         9133/1
   Acinar adenocarcinoma                             8550/3
                                                                Angiosarcoma                             9120/3
   Papillary adenocarcinoma                          8260/3
                                                                Pleuropulmonary blastoma                 8973/3
   Bronchioloalveolar carcinoma                      8250/3
                                                                Chondroma                                9220/0
     Non-mucinous                                    8252/3
                                                                Congenial peribronchial                  8827/1
     Mucinous                                        8253/3
                                                                myofibroblastic tumor
     Mixed non-mucinous and                          8254/3
                                                                Diffuse pulmonary lymphangiomatosis
     mucinous or indeterminate
                                                                Inflammatory myofibroblastic tumor       8825/1
   Solid adenocarcinoma with mucin                   8230/3
                                                                Lymphangioleiomyomatosis                 9174/1
                                                                Synovial sarcoma                         9040/3
     Fetal adenocarcinoma                            8333/3
                                                                   Monophasic                            9041/3
     Mucinous (‘colloid’) carcinoma                  8480/3
                                                                   Biphasic                              9043/3
     Mucinous cystadenocarcinoma                     8470/3
                                                                Pulmonary artery sarcoma                 8800/3
     Signet ring adenocarcinoma                      8490/3
                                                                Pulmonary vein sarcoma                   8800/3
     Clear cell adenocarcinoma                       8310/3
                                                               Benign epithelial tumors
 Large cell carcinoma                                8012/3
   Large cell neuroendocrine carcinoma               8013/3
                                                                 Squamous cell papilloma                 8052/0
      Combined large cell                            8013/3
                                                                    Exophytic                            8052/0
      neuroendocrine carcinoma
                                                                    Inverted                             8053/0
   Basaloid carcinoma                                8123/3
                                                                 Glandular papilloma                     8260/0
   Lymphoepithelioma-like carcinoma                  8082/3
                                                                 Mixed squamous cell and glandular       8560/0
   Clear cell carcinoma                              8310/3
   Large cell carcinoma with                         8014/3
   rhabdoid phenotype                                          Adenomas
                                                                  Alveolar adenoma                       8251/0
 Adenosquamous carcinoma                             8560/3
                                                                  Papillary adenoma                      8260/0
 Sarcomatoid carcinoma                               8033/3       Adenomas of the salivary gland type
   Pleomorphic carcinoma                             8022/3    Ta   Mucous gland adenoma                 8140/0
   Spindle cell carcinoma                            8032/3         Pleomorphic adenoma                  8940/0
   Giant cell carcinoma                              8031/3         Others
   Carcinosarcoma                                    8980/3       Mucinous cystadenoma                   8470/0
   Pulmonary blastoma                                8972/3
                                                               Lymphoproliferative tumors
 Carcinoid tumor                                     8240/3      Marginal zone B-cell lymphoma           9699/3
   Typical carcinoid                                 8240/3      of the MALT type
   Atypical carcinoid                                8249/3      Diffuse large B-cell lymphoma           9680/3
                                                 (Continued)                                            (Continued)
                                                                                                         Histopathology of lung tumors 63

    Table 7.1 Continued
                                                                              the mixed subtype. For this reason the adenocarcinoma
                                                                              mixed subtype was moved to the top of the list of ade-
       Lymphomatoid granulomatosis                              9766/1        nocarcinoma subtypes in the 2004 WHO classification,
       Langerhans cell histiocytosis                            9751/1        although it was not recognized in the 1981 WHO
    Miscellaneous tumors                                                      classification.23 The acinar and papillary subtypes are
      Harmatoma                                                               recognized by their architectural pattern of tumor cell
      Sclerosing hemangioma                                     8832/0        growth and invasion. A substantially different defini-
     Clear cell tumor                                           8005/0        tion has been given to bronchioloalveolar carcinoma
      Germ cell tumors                                                        (BAC subtype), which should be restricted to tumors
        Teratoma, mature                                        9080/0        that grow in a purely lepidic fashion without invasion
         Immature                                               9080/3        of stroma, blood vessels, or pleura. The solid type is a
        Other germ cell tumors                                                poorly differentiated carcinoma presenting intracyto-
      Intrapulmonary thymoma                                    8580/1        plasmic mucins that should be of at least five mucin
      Melanoma                                                  8720/3        droplets in two different high-power fields. Mucin
    Metastatic tumors                                                         stains recommended are PAS (periodic acid–Schiff)
                                                                              with diastase digestion and Kreyberg staining with
    From WHO Classification of Tumors, 2004.
                                                                              alcian blue.
    Behavior is coded /0 for benign tumors, /3 for malignant tumors, and /1
    for borderline or uncertain behavior.                                         Several additional unusual variants have also been
                                                                              recognized, such as well-differentiated fetal adenocar-
                                                                              cinoma,24 mucinous (‘colloid’) adenocarcinoma,25 muci-
ADENOCARCINOMA                                                                nous cystadenocarcinoma,26–28 signet ring carcinoma,29
                                                                              and clear cell adenocarcinoma.4 Two unusual gross
A malignant epithelial tumor with glandular differentiation                   patterns of adenocarcinoma include the endobronchial
or mucin production, showing acinar, papillary, bronchi-                      polypoid adenocarcinoma30 and pseudomesothelioma-
oloalveolar, or solid with mucin growth patterns, or a mixture                tous adenocarcinoma.31–33
of these patterns.                                                                Bronchioloalveolar carcinoma is uncommon, and
   Adenocarcinoma can be classified into:                                     probably restricted to fewer than 5% of all lung malig-
                                                                              nancies.12 In the new 1999 WHO/IASLC classification,
•     adenocarcinoma mixed subtype;                                           BAC is defined as a tumor showing lepidic growth
•     acinar adenocarcinoma;                                                  along pre-existing alveolar septa with intact elastic and
•     papillary adenocarcinoma;                                               basal lamina frames, without invasive growth. It should
•     bronchioloalveolar carcinoma;                                           be noticed that some increased fibrotic collagen deposit
      – non-mucinous                                                          of alveolar walls is accepted, as long as no myofibro-
      – mucinous                                                              blastic proliferation is visible. The lack of invasive
      – mixed non-mucinous and mucinous                                       growth is added as an essential criterion4 based on clin-
      – solid adenocarcinoma with mucin production.                           ico-pathologic data indicating that in patients with less
     Variants are:                                                            than a 2 cm tumor, BAC may be curable by economic
•       fetal adenocarcinoma;                                                 surgical resection.34 As a result of the narrow criteria for
•       mucinous (‘colloid’) carcinoma;                                       BAC, the term ‘adenocarcinoma, mixed subtype’ is used
•       mucinous cystadenocarcinoma;                                          for tumors that have BAC and an invasive component.
•       signet ring adenocarcinoma;                                           In such cases the invasive patterns present (acinar, pap-
•       clear cell adenocarcinoma.                                            illary, or solid) should be mentioned. It is common to
                                                                              observe central scars in pulmonary adenocarcinoma
   Adenocarcinomas account for about 30% of lung
                                                                              that contain invasive components and a focal BAC-like
cancers in Europe and the USA.12 Most primary pulmo-
                                                                              pattern at the periphery of the tumor.
nary adenocarcinomas, in contrast with metastases, are
                                                                                  As a consequence of this revised definition of BAC,
highly heterogeneous and consist of a mixture of histo-
                                                                              the literature dealing with these tumors need complete
logic subtypes. Most adenocarcinomas are histologi-
                                                                              re-evaluation. Indeed, previous to the last classification,
cally heterogeneous, consisting of two or more of the
                                                                              BAC included tumors with obvious invasive growth.23,35,36
histologic subtypes and whilst a majority of the lung
                                                                              More than 50% of tumors previously classified as BACs
adenocarcinomas diagnosed are classified today into
                                                                              presented focal central desmoplastic scarring tissue or
64 Textbook of Lung Cancer

intra-alveolar complex papillary growth while the lepidic     •   lobar consolidation;
growth started around the edge of the scar.37 For tumors      •   diffuse (pseudopneumonic) consolidation pattern.
showing malignant tumor cell nests in a desmoplastic
stromal reaction, the diagnosis is adenocarcinoma mixed          The typical radiologic appearance of BAC (pure BAC
subtype and the various subtypes present should be            or BAC component) is the ground glass pattern by CT
mentioned (such as acinar, papillary, or BAC). These are      and an ill-defined, aerated, spongy density on gross
no longer considered as pure BAC.13,37 In addition, fill-     examination. In contrast, a grossly circumscribed nod-
ing of alveolar lumens by papillary or micropapillary         ule at growth examination and a pure solid appearance
structures is considered to be papillary adenocarcinoma,      on CT is typical of purely invasive adenocarcinoma
but not bronchioloalveolar carcinoma.                         (acinar, papillary, solid). In between, a mixture of
   BAC has two major cytologic subtypes, non-mucinous         these growths and CT appearances is seen in mixed
and mucinous,4 and are rarely mixed, consisting of an         subtype adenocarcinoma with both invasive (often cen-
association of mucinous and non-mucinous cells.4 The          trally located) components and BAC component (often
majority of BACs are mucin-producing, followed by the         peripheral). When BAC and other adenocarcinomas
non-mucinous type, while about 12% are a mixture of           present with multiple nodules they can be unilateral or
both.37,38                                                    bilateral. Unilateral nodules are classified as T4 by the
   Non-mucinous BACs consist of Clara cells and type          TNM classification and multiple nodules in another
II pneumocytes; the latter cell type is a common stem         lobe are classified as M1. Lobar consolidation and dif-
cell for distal bronchioles and alveoli identified in fetal   fuse pseudopneumonic condensation patterns are dif-
lung and is nowadays considered as the lung adenocar-         ficult to distinguish grossly or radiologically from
cinoma stem cell.39 The non-mucinous BACs are more            infective pneumonia. All cases of adenocarcinoma
likely to be solitary38 than the mucinous type. These         presenting with a diffuse or pseudopneumonic consol-
tumors are composed of cuboidal cells proliferating           idation pattern have been shown to correspond to
along alveolar septa and showing a hobnail appearance.        mixed subtype adenocarcinoma with BAC component.
Specific nuclear inclusions are patent in half of the non-    They are more frequently of the mucinous cell type,
mucinous tumor cells that are stained with diastase-          with varying amounts of acinar, papillary, and solid
digested PAS and immunohistochemically for surfactant         components.
apoprotein. On electron microscopy, these inclusions
form a network of 40-nm diameter microtubules.40,41           Prognostic correlations with solitary small
   The mucin-producing BACs tend to be more multi-            peripheral lung nodules
centric and characteristically have mucin production.38       Several important clinico-pathologic studies have
They may cause lobar consolidation resembling pneu-           shown the clinical significance of BAC.34,42,43 Noguchi
monia on gross examination. Histologically, these             et al34 reported that, in a large series of 236 peripheral
tumors consist of tall columnar cells with abundant api-      lung adenocarcinomas less than 2 cm in size, the
cal cytoplasmic mucin and small, basally oriented, regu-      patients achieved 100% 5-year survival. These were
lar bland nuclei lining thin alveolar septa. Alveolar and     pure BACs, in contrast to patients with ‘invasive BAC’
bronchiolar spaces are filled with abundant mucin.            who experienced higher mortality and a 5-year survival
   According to the 1999 WHO/IASLC classification, a          of 75%, while the purely invasive form had a 5-year
final diagnosis of BAC can only be achieved on exami-         survival of 52%. Suzuki et al42 demonstrated that the
nation of a surgical resection specimen. Small biopsies       size of the fibrotic scar was correlated with survival in
obtained by bronchoscopy or fine needle sampling may          a series of 100 peripheral adenocarcinomas less that
show a lepidic growth pattern suggesting the possibility      3 cm in size: a 5-year survival of 100% was recorded
of BAC, but are not sufficient to exclude the presence of     for patients with a scar size of 5 mm or less, in contrast
an invasive growth.                                           to 70% for patients with scars 5 to 15 mm in size
                                                              and 40% for patients with a central scar greater than
Pathoradiologic correlations                                  15 mm. In this study, the size of central fibrosis was
There are several growth presentations for the most           an independent prognostic factor on multivariate anal-
common adenocarcinoma mixed subtype with BAC:                 ysis (p = 0.01), as significant as vascular invasion
                                                              (p = 0.024) and lymph node metastasis (p = 0.024).
•   a solitary nodule;                                        Yokose et al43 studied multiple pathologic factors for
•   multiple nodules;                                         prognostic assessment in 200 patients: 100% 5-year
                                                                                          Histopathology of lung tumors 65

survival was associated with at least one of the following     because of difficulties in reproducibility of these sub-
features:                                                      types and lack of confirmation that these patients have a
                                                               different prognosis.48,49
•   a pattern of lepidic growth of more than 75%;
                                                                  SCLC has a distinctive histologic appearance. The
•   a central scar measuring 5 mm or less;
                                                               tumor cells have a small size, not exceeding that of
•   lack of destruction of the elastic fiber framework
                                                               three lymphocytes. They have a round or fusiform
    by tumor cells.43
                                                               shape, scant cytoplasm with a nuclear to cytoplasmic
   The most significant determinants of shorter survival       ratio of 9 to 10, a finely granular nuclear chromatin
in the multivariate analysis were vascular invasion            (‘salt and pepper’ appearance), and absent or incon-
(p < 0.001) and more than 25% papillary or invasive            spicuous nucleoli.4 Owing to the scarcity of cytoplasm,
growth (p = 0.043). Size and grade/pattern of stromal          nuclear molding and smearing of nuclear chromatin is
invasion44,45 also influence survival. This has practical      frequent, caused by crush artifacts. There is usually
consequences: all small (≤3 cm) tumors with a predom-          extensive necrosis and a mitotic rate exceeding 20 and
inant BAC component should be entirely sampled seri-           reaching 100 mitoses per 2 mm2 area. Most often, the
ally, and included so that potential foci of invasion are      growth pattern consists of diffuse sheets, although
detected.                                                      endocrine differentiations with rosettes, palisading, rib-
   BAC is not a unique feature for lung adenocarcinoma         bons, and organoid nesting might be seen.50 Basophilic
since about 15% of digestive mucinous carcinoma                encrustation of vessel walls is known as the Azzopardi
metastases might mimic the histologic appearance of            effect in necrotic areas.50
BAC. Thyroid transcription factor-1 (TTF-1) immuno-               Depending on the biopsy specimens, the tumor cell
staining restricted to primary lung adenocarcinoma is          size of SCLC might appear larger, which is often the
of great help in this distinction.                             case in well-fixed open biopsies.
                                                                  Fine needle aspiration (FNA) biopsy and core biopsy
                                                               may provide excellent material for assessment of the
SMALL CELL CARCINOMA                                           diagnosis of SCLC, essentially because cytologic fea-
                                                               tures of SCLC have a high diagnostic value and the
A malignant epithelial tumor consisting of small cells with    architecture is not critical for the diagnosis. The small
scant cytoplasm, ill-defined cell borders, finely granular     cell proliferation, with nuclear moulding, the very high
nuclear chromatin, and absent or inconspicuous nucleoli.       nuclear to cytoplasmic ratio, and the ‘salt and pepper’
The cells are round, oval, and spindle-shaped.                 quality of chromatin are extremely useful for this diag-
   SCLC accounts for 25% of all lung cancers in                nosis on FNA. The diagnostic markers (NE markers,
the USA as well as in Europe.12 Two-thirds of SCLCs            TTF-1, absence of CK34βE12 expression) are of pri-
are proximal and present as a perihilar tumor. They            mary help in the diagnosis of SCLC. There is an excel-
occur in a bronchial location, infiltrating the bronchial      lent yield of these markers on FNA and/or biopsy.
submucosa and subsequently leading to bronchial
obstruction by circumferential compression. SCLCs are          Combined small cell lung cancer
not commonly observed on a surgical specimen since             The frequency of combined SCLC depends on the
extensive lymph node metastasis is common and the              extent of histologic sampling, and the extent of the
tumor is not surgically curable. Macroscopically the           associated component. Combined SCLC represents
tumor is soft, friable, white-tan, and extensively necrotic.   about 10%49 of SCLC if small biopsies are considered.
Extensive lymph node metastasis is very frequent and           However, in a recent study on surgically treated SCLC,
less than 5% of cases present as a solitary coin               using a conservative estimate of 10% of tumors show-
lesion.46,47                                                   ing associated NSCLC for subclassifying a tumor as a
   The 1999 WHO/IASLC classification presents only             combined variant of SCLC, 28% of the cases of SCLC
two types of SCLC: SCLC (with pure SCLC histology)             showed a combination with NSCLC, more commonly
and combined SCLC (combined with any non-small cell            with large cell lung carcinoma followed by adenocarci-
type) (see Table 7.1).4 The two subtypes oat cell carci-       noma and squamous cell carcinoma.48,49,51–53 SCLC can
noma and intermediate cell type, that were proposed            also be associated, although rarely, with spindle cell
in the 1981 WHO classification, as well as the category        carcinoma,54,55 giant cell carcinoma,54 and carcinosarco-
of mixed small cell, large cell, proposed in 1988 by           ma.56 Immunohistochemistry might help to differenti-
the IASLC, were discarded from the new classification          ate associated components, such as cytokeratin antibody
66 Textbook of Lung Cancer

cocktails, which tend to stain NSCLC components, a                              of SCLC from LCNEC (Table 7.2). Crush artifact is
good example of which is cytokeratin 1, 5, 10, 14 rec-                          common in small biopsy specimens owing to scarcity of
ognized by 34βE12.57 However, evidence is lacking                               stromal protection; this can also be seen in carcinoid
that pure and combined SCLC behaves differently with                            tumors, lymphocytic infiltrates, or poorly differentiated
regard to prognosis and response to therapy.51 Follow-                          NSCLC. In these cases, cytology specimens might be
ing chemotherapy, a mixture of large cells, squamous                            helpful because the morphology may be more diagnos-
cells, adenocarcinoma or giant cells with SCLC may be                           tic than on a small biopsy specimen. Immunohis-
seen in 15 to 45% of the cases.52,58–60                                         tochemistry for neuroendocrine differentiation, keratins,
                                                                                and common leukocyte antigen (lymphoid marker) can
Differential diagnosis                                                          be useful in marking SCLC versus lymphoid cells,
Because SCLC has distinctive clinical properties with                           respectively.64 TTF-1 has been shown to be of great
an aggressive clinical course, frequent widespread                              help in distinguishing between SCLCs, which are 85%
metastasis of presentation, common paraneoplastic                               positive for TTF-1 nuclear staining, and other prolifer-
syndrome, and responsiveness to chemotherapy, histo-                            ating small cells such as the small cell variant of
logic classification of lung cancer often is simplified                         squamous cell carcinoma and basaloid carcinoma, both
into SCLC versus NSCLC. A constellation of criteria is                          of which are always TTF-1 negative.57,65 The most use-
applied for the distinction between SCLC and large                              ful and specific neuroendocrine markers for distinction
cell neuroendocrine carcinoma (LCNEC) including cell                            of SCLC in formalin-fixed, paraffin-embedded tissue
size, nucleoli, nuclear-to-cytoplasmic ratio, nuclear                           sections are chromogranin A, synaptophysin, and neu-
chromatin pattern, nuclear molding, cell shape (fusi-                           ral cell adhesion molecule, especially the 123C3 clone
form versus polygonal), and Azzopardi phenomenon                                and CD56.61,66–70 Keratin (AE1/AE3) and epithelial
(Table 7.2).4,23,61,62                                                          membrane antigen (EMA) as well as TTF-1 stain virtu-
   Disagreement among expert lung cancer pathologists                           ally all SCLCs in open lung biopsy and transbronchial
over this distinction occurs in up to 10% of cases,10,63                        biopsy specimens.57,61,65,66 In contrast, a specific set of
owing to the fact that sometimes LCNEC may adopt the                            cytokeratins never expressed in neuroendocrine prolif-
nuclear features of SCLC. With the new description of                           erations (CK 1, 5, 10, 14) called 34βE12 is always absent
LCNEC, the main differential resides in the distinction                         in pure SCLC. In the cases where common cytokeratins

 Table 7.2 Light microscopic features for distinguishing small cell carcinoma and large cell neuroendocrine carcinomaa

 Histologic feature                                 Small cell carcinoma                                  Large cell neuroendocrine

 Cell size                                          Smaller (less than diameter                           Larger
                                                    of 3 lymphocytes)
 Nuclear/cytoplasmic ratio                          Higher                                                Lower
 Nuclear chromatin                                  Finely granular, uniform                              Coarsely granular or vesicular,
                                                                                                          less uniform
 Nucleoli                                           Absent or faint                                       Often (not always) present,
                                                                                                          may be prominent or faint
 Nuclear molding                                    Characteristic                                        Less prominent
 Fusiform shape                                     Common                                                Uncommon
 Polygonal shape with                               Uncharacteristic                                      Characteristic
 ample pink cytoplasm
 Nuclear smear                                      Frequent                                              Uncommon
 Basophilic staining of                             Occasional                                            Rare
 vessels and stroma
  From Travis WD, Linnoila RI, Tsokos MG, et al.61 Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma.
 An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 15: 529–533, 1991; with permission.
                                                                                        Histopathology of lung tumors 67

 Table 7.3 Histochemical differential diagnosis between
                                                                 Because lung cancers are classified according to the
 small cell lung carcinoma (SCLC), basaloid carcinoma, and
                                                              best differentiated component, areas of large cell carci-
 large cell neuroendocrine carcinoma (LCNEC)
                                                              noma are frequently observed in poorly differentiated
                                                              adenocarcinoma or squamous cell carcinoma, and due
                 NE markers      TTF-1       Cytokeratins     to the common heterogeneity of these cancers it is dif-
                                             1, 5, 10, 14     ficult to specifically and appropriately classify many
 SCLC                 +            +              −           lung cancers in which only small pieces of tissue are
 Basaloid             −            −              +           available. In such cases, the best diagnosis might be
 carcinoma                                                    ‘non-small cell carcinoma’ and specification of the most
 LCNEC                +           +/−             −           obvious component.5,80,81

                                                              Large cell neuroendocrine carcinoma
                                                              LCNEC is a variant of large cell carcinoma. It is a high-
are negative in a suspected SCLC, the pathologist             grade non-small cell neuroendocrine carcinoma that
should exclude other possibilities such as chronic            differs from atypical carcinoid and small cell carcinoma.
inflammation, lymphoma (CD45 positive), primitive             Histologic criteria include:
neuroectodermal tumor, or small cell round sarcoma.
One difficulty resides in the fact that about 25% of          (1) neuroendocrine morphology (organoid, palisading,
SCLCs express the antigen CD99/MIC-2, as do primi-                trabecular, or rosette-like growth patterns;
tive neuroectodermal tumors and small round cell sar-         (2) non-small cell cytologic features (large size, polyg-
coma. It is important to recognize that this distinction          onal shape, low nuclear to cytoplasmic (N/C) ratio,
is based primarily on light microscopy (Table 7.2).4              coarse or vesicular nuclear chromatin, and obvious
Since no single monoclonal antibody can reliably                  nucleoli);
distinguish SCLC from NSCLC,70,71 a set of reliable           (3) high mitotic rate (≥11 per 2 mm2) with a mean of
markers should be considered (Table 7.3).                         60 mitoses per 2 mm2;
                                                              (4) frequent necrosis; and
                                                              (5) at least one positive neuroendocrine immunohis-
LARGE CELL CARCINOMA                                              tochemical specific marker or neuroendocrine
                                                                  granules by electron microscopy.4,61
Large cell carcinoma is a tumor that shows no differen-
tiation pattern to allow classification into squamous cell       It is difficult to diagnose LCNEC based on small
carcinoma, adenocarcinoma, or small cell carcinoma.           biopsy specimens because of frequent lack of neuroen-
These poorly differentiated tumors most often arise in        docrine morphology without a substantial sampling of
the lung periphery, although they may be located cen-         the tumors. Some criteria have been proposed based on
trally. They frequently appear at gross examination as        cytology.82
large, necrotic tumors. Histologically, these consist of         The term combined LCNEC is used for tumors associ-
sheets or nests of large polygonal cells with vesicular       ated with other histologic types of NSCLC, such as
nuclei and prominent nucleoli.23 Although they are            adenocarcinoma or squamous cell carcinoma (Table 7.1).4
undifferentiated by light microscopy, features of             Any combination of LCNEC with SCLC is diagnosed as
squamous cell or adenocarcinoma might be found on             SCLC combined.4 A variety of criteria must be used to
electron microscopy examination.6,7,72                        separate SCLC from LCNEC (Table 7.2).
   There are several variants of large cell carcinoma, some
of which have high clinical significance, recognized in       Differential diagnosis
the new WHO/IASLC histologic classification of lung           In 10% of the cases of NSCLC lacking neuroendocrine
cancer (Table 7.1).4 These include LCNEC,4,61,73 basaloid     morphology, immunohistochemical neuroendocrine
carcinoma,18,19,74 lymphoepithelial-like carcinoma,75–77      markers or neuroendocrine granules by electron micros-
clear cell carcinoma,78 and large cell carcinoma with         copy can be demonstrated. Such tumors are called non-
rhabdoid phenotype.79 Lymphoepithelial-like carci-            small cell carcinomas (adenocarcinoma, squamous cell
noma is described as an EBV (Epstein–Barr virus)              carcinoma, or large cell carcinoma) with neuroendocrine
dependent epithelial proliferation more commonly seen         differentiation (NSCLC-NED).4,61 Although Iyoda et al83
in the upper respiratory tract.                               found that the tumor size of large cell carcinoma with
68 Textbook of Lung Cancer

neuroendocrine differentiation was significantly larger      show no staining in small cell, large cell and LNEC
than that for LCNEC, the survival was not different          whereas it stains quite all basaloid carcinoma. TTF-1 is
in this series from patients with LCNEC. At the present      never present in basaloid carcinoma, but is present in
time, the clinical significance of the diagnosis of NSCLC-   the majority of SCLC and LCNEC (Table 7.3).57,95 p63
NED is not known. Whether these tumors are responsive        is expressed in most cells of all basaloid carcinomas.
to SCLC chemotherapy regimens84–86 or whether expres-
sion of neuroendocrine markers may be an unfavorable
prognostic factor87–94 remains to be determined.             ADENOSQUAMOUS CARCINOMA

Basaloid carcinoma                                           Adenosquamous carcinoma accounts for 0.6 to 2.3% of
Basaloid carcinoma is the most prominent variant of          all lung cancers96–100 and is defined as a lung carcinoma
large cell carcinoma after LCNEC.4,18,74 Basaloid carci-     having at least 10% of squamous cell or adenocarci-
noma represents 3 to 4% of NSCLCs in Europe, almost          noma components.4 Adenosquamous carcinoma should
always occurs in males, and most of these tumors             not be confused with mucoepidermoid carcinoma, a
develop in proximal bronchi where they frequently            malignant epithelial tumor characterized by the pres-
have an endobronchial component. Two-thirds of these         ence of squamoid cells, mucin-secreting cells, and cells
tumors arise from long areas on the bronchial mucosa         having intermediate type, identical to the same tumors
and show prolonged and laterally extended in situ car-       encountered in the salivary glands. Mucoepidermoid
cinoma. About half of the tumors present with a pure         carcinoma of high-grade malignancy is differentiated
basaloid pattern that belongs to a variant of large cell     from adenocarcinoma by a variety of features including
carcinoma. The remaining cases have minor (less than         a mixture of mucin-containing cells and squamoid cells,
50%) components of squamous cell carcinoma or, more          transition areas from classic low-grade mucoepider-
rarely, adenocarcinoma and are thus classified as            moid carcinoma, and lack of keratinization.
squamous cell carcinoma (basaloid variant) or adeno-
carcinoma, respectively. These tumors consist of a lobu-
lar, trabecular, or palisading gross pattern of relatively   SARCOMATOID CARCINOMA
small monomorphic cuboidal to fusiform cells with
moderately hyperchromatic nuclei, finely granular            This group of lung carcinomas is poorly differentiated
chromatin, absent or only focally conspicuous nucleoli,      and expresses a spectrum of pleomorphic, sarcomatoid,
scant cytoplasm but a nuclear to cytoplasmic ratio lower     and sarcomatous elements. They express the features and
than that of SCLC, and a high mitotic rate from 20 to        the biological behavior of epithelial cells that adopt an
100 mitoses per 2 mm2. Neither intercellular bridges         epithelial to mesenchymal transition in certain condi-
nor individual cell keratinization are present which         tions of culture in vitro. Pleomorphic carcinomas tend
allows them to be distinguished from poorly differenti-      to be large peripheral tumors invading bronchial
ated squamous cell carcinoma. Patients with basaloid         lumens, forming endobronchial growth. They often
carcinoma have a significantly shorter survival than         invade the chest wall and are associated with a poor
those with poorly differentiated squamous cell carci-        prognosis.54 Because of the characteristic histologic het-
noma which deserves this differential diagnosis.18,19,74     erogeneity of this tumor, adequate sampling is required
                                                             and should consist of at least one section per centime-
Differential diagnosis                                       ter of the tumor diameter. To enter in this category a
Since comedo type necrosis is common, palisading is a        pleomorphic carcinoma should have at least a 10%
characteristic feature of basaloid carcinoma, and rosettes   component of spindle or giant cells associated with, but
can be identified in about one-third of cases, the main      distinctly identifiable from, other histologic types
differential diagnosis resides in separation from LCNEC.     such as adenocarcinoma or squamous cell carcinoma.4
Immunohistochemical stains for neuroendocrine mark-          A few giant cells disseminated in an otherwise recogniz-
ers are negative in basaloid carcinoma and positive in       able squamous cell adenocarcinoma or SCLC have no
LCNEC. No secretory granules have been seen by elec-         value for classification in the category of sarcomatoid
tron microscopy in basaloid carcinoma. Two antibodies        carcinoma.
are helpful to make the distinction on small biopsies           Rarely carcinomas present with a pure giant cell or
between basaloid carcinoma, SCLC, and LCNEC. The             spindle cell pattern and deserve the terms giant cell or
specific cytokeratins 1, 5, 10, 14 recognized by 34βE12      spindle cell carcinoma. Giant cell carcinoma consists of
                                                                                        Histopathology of lung tumors 69

huge, bizarre, pleomorphic and multinucleated tumor           not affect their clinical outcome.13 Compared with TC,
cells that engulf numerous inflammatory cells, particu-       atypical carcinoid (AC) presents with a larger tumor
larly polymorphonuclear leukocytes, in their cytoplasm.101–   size, higher rate of metastases, and a significantly
    They are discohesive and separated by significant         reduced survival. Most series where the diagnosis was
infiltration of inflammatory cells. This tumor is defined     based on actual accepted criteria reported a mortality of
as a carcinoma by light microscopy, but immunohis-            27 to 47%.104,112–114
tochemical and epithelial markers such as keratins               Carcinoid tumors are most often centrally located
are also quite helpful in confirming their epithelial         with a polypoid endobronchial obstructive component.
nature.4                                                      When peripheral carcinoids occur they are more often
                                                              of the spindle cell type. Both TC and AC are character-
Carcinosarcoma                                                ized histologically by an endocrinoid, organoid growth
Carcinosarcoma is a tumor composed of a mixture of            pattern and uniform cytologic features, consisting of
carcinoma and sarcoma. A heterologous component               moderate eosinophilic, finely granular cytoplasm, a
should be demonstrated such as cartilage, bone, or            nucleus with a finely granular chromatin (Table 7.4),
skeletal muscle – heterologous elements which do not          and inconspicuous nucleoli that can be discretely more
display cytokeratin staining.4 Experience proves that         prominent in AC. A variety of histologic patterns may
these cases are extremely rare while observations of          occur in AC and TC, including trabecular, palisading,
pseudochondromatous or pseudo-osseous patterns in             rosette-like, papillary, sclerosing papillary, glandular,
sarcomatoid carcinoma are frequent: in these cases the        paragangliomatous, spindle cell, and follicular pat-
pseudosarcomatous components also express keratins.           terns.61 More rarely, the tumor cells of pulmonary carci-
                                                              noid tumors may have oncocytic, acinic cell-like, signet
Pulmonary blastoma                                            ring, mucin-producing, or melanocytic features.61
Pulmonary blastomas are defined as biphasic tumors               The most distinguishing feature between typical car-
consisting of an association of a glandular component         cinoid and atypical carcinoid is the rate of mitosis and
that resembles well-differentiated fetal adenocarcinoma       the presence or absence of necrosis. Typical carcinoids
and a primitive sarcomatous or mesenchymal compo-             show less than 2 mitoses per 2 mm2 area of viable tumor
nent.4 Well-differentiated fetal adenocarcinoma is no         (per 10 high power field) and no necrosis. The pres-
longer regarded as the epithelial pattern of monophasic       ence of between 2 and 10 mitoses per 2 mm2 or necro-
pulmonary blastoma but, rather, as a variant of adeno-        sis73 defines the diagnosis of atypical carcinoids. The
carcinoma.4                                                   presence of features such as cell pleomorphism, vascu-
                                                              lar invasion, and increased cellularity are of no help in
                                                              separating TC from AC and in allowing stratification of
TYPICAL AND ATYPICAL CARCINOID                                patients for prediction of survival.73 TC may well show
                                                              focal cytologic pleomorphism, as do paragangliomas in
Carcinoid tumors accounts for 1 to 2% of all invasive         the head and neck area.61,112 The necrosis in AC usually
lung malignancies.12 The majority of patients are             consists of small foci centrally located within organoid
asymptomatic at presentation.104 Symptoms include             nests of tumor cells.
hemoptysis, postobstructive pneumonitis, dyspnea, para-
neoplastic syndromes including carcinoid, Cushing’s           Immunohistochemistry
syndrome,104–106 and acromegaly.107 There is no gender        Nearly 80% of TC and AC stain for pan-
predilection.104,108 There is no association with smoking     cytokeratins and, as other pulmonary neuroendocrine
since 40% of patients with carcinoid are non-smokers,         tumors, they always express cytokeratins 8, 18, and
which is the proportion within the normal population.         19.115 From a more practical standpoint, expression of
The mean age is 55 years, with a range up to 82 years.104     cytokeratins 1, 5, 10, and 14 has never been observed
This is the most common lung tumor in childhood.109           along the whole spectrum of neuroendocrine tumors of
   The treatment of choice of pulmonary carcinoids is         the lung.116
surgical resection.104,110 Patients with typical carcinoid       Neuroendocrine markers are present in all carcino-
(TC) have an excellent prognosis and rarely die from          ids. Chromogranin A is present in neurosecretory gran-
their tumors.104,111 However, metastases do not disqual-      ules and synaptophysin is contained in synaptic
ify the diagnosis of typical carcinoid. Five to ten percent   vesicles.68 They all express CD 56/NCAM, which belong
of TCs have regional lymph node involvement that does         to the immunoglobulin superfamily of transmembrane
70 Textbook of Lung Cancer

 Table 7.4 Typical and atypical carcinoid: distinguishing features

 Histologic or clinical feature           Typical carcinoid                          Atypical carcinoid

 Histologic patterns: organoid,           Characteristic                             Characteristic
 trabecular, palisading, and
 spindle cell
 Mitoses                                  Absent or <2 per 2 mm2 area                2–10 per 2 mm2 or area of viable
                                          of viable tumor (10 high power             tumor (10 high power fields
                                          fields on some microscopes)                on some microscopes)
 Necrosis                                 Absent                                     Characteristic, usually focal or
 Nuclear pleomorphism,                    Usually absent, not sufficient             Often present
 hyperchromatism                          by itself for diagnosis of AC
 Regional lymph node                      5–15%                                      40–48%
 metastases at presentation
 Distant metastases at                    Rare                                       20%
 Survival at 5 years                      90–95%                                     58%
 Disease-free survival                    90–95%                                     35%
 at 10 years

adhesion molecules, and to date, as for other neuroen-               hemangiomas may resemble carcinoids, especially with
docrine tumors of the lung, NCAM remains the most                    a papillary or pseudoglandular pattern. The demonstra-
useful immunohistochemical marker, even on crushed                   tion of neuroendocrine markers and absence of TTF-1
biopsies or small specimens, in the differential diagno-             expression distinguish carcinoids from sclerosing
sis with papillary adenocarcinoma and sclerosing                     hemangiomas.124 Carcinoids may be confused with
hemangioma. In contrast, as widely reported, NSE                     paragangliomas, but this lesion remains very rare in the
immunostaining is of little help in the diagnosis of                 lung, and the lack of cytokeratin expression in the latter
neuroendocrine tumors in general because of its lack of              has a discriminative feature. Glomus tumors and other
specificity.69,117                                                   smooth muscle tumors may mimic carcinoids, from
   TTF-1 expression was demonstrated to be negative                  which they are distinguished by the presence of smooth
in the spectrum of neuroendocrine hyperplasia, tumor-                muscle actin and the absence of neuroendocrine mark-
lets, and typical and carcinoid tumors.118 However,                  ers. Adenocarcinoma enters the differential diagnosis
other authors have reported some TTF-1 expression in                 because a gland-like pattern occurs in carcinoids. Mucin
nearly one-third of TC and AC,119,120 predominantly in               production is not a definitive distinguishing feature
a peripheral location.121 This discrepancy could be                  since carcinoids may disclose mucin formation. TTF-1
related to differences in immunohistochemical tech-                  expression and the absence of neuroendocrine markers
niques or in assessing the threshold of positivity. TTF-1            in adenocarcinoma are of great help. The solid type
expression has not been demonstrated in cDNA expres-                 adenoid cystic carcinoma may be mistaken for carci-
sion profiling, whereas it is in high-grade NE tumors of             noid, but is negative for neuroendocrine markers.
poor prognosis.122
   Concerning the proliferation antigen Ki 67 in carcino-
ids, staining is observed in less than 10%, and an index             CONCLUSIONS
higher than 4%, more frequently observed in AC, seems
to be related to a shorter survival.123,124                          Histologic subclassification of lung tumors is essentially
                                                                     based on light microscopy in order to achieve the wid-
Differential diagnosis                                               est application through the world and assume compa-
Carcinoids differ from tumorlets by the size of the latter,          rability and consistency of data. However, techniques
which do not exceed 5 mm in diameter. Sclerosing                     including immunohistochemistry, electron microscopy,
                                                                                                      Histopathology of lung tumors 71

tissue culture, and molecular biology might provide                         clinical features, histopathology, and survival. Arch Pathol
valuable information on carcinogenesis, histogenesis,                       Lab Med 1990; 114: 468–74.
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and differentiation. It is well recognized that immuno-
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    San Francisco and Tokyo: Churchill Livingstone, 1997.                      differentiation is an independent prognostic factor in chemo-
75. Butler AE, Colby TV, Weiss L et al. Lymphoepithelioma-like                 therapy-treated nonsmall cell lung carcinoma. Cancer 1996;
    carcinoma of the lung. Am J Surg Pathol 1989; 13: 632–9.                   77: 1284–91.
76. Chan JK, Hui PK, Tsang WY et al. Primary lymphoepithelio-            93.   Skov BG, Sorensen JB, Hirsch FR et al. Prognostic impact of
    ma-like carcinoma of the lung. A clinicopathologic study of                histologic demonstration of chromogranin A and neuron spe-
    11 cases. Cancer 1995; 76: 413–22.                                         cific enolase in pulmonary adenocarcinoma. Ann Oncol 1991;
77. Pittaluga S, Wong MP, Chung LP et al. Clonal Epstein–Barr                  2: 355–60.
    virus in lymphoepithelioma-like carcinoma of the lung. Am J          94.   Pujol JL, Simony J, Demoly P et al. Neural cell adhesion mol-
    Surg Pathol 1993; 17: 678–82.                                              ecule and prognosis of surgical resected lung cancer. Am Rev
78. Katzenstein AL, Prioleau PG, Askin FB. The histologic spec-                Respir Dis 1993; 148: 1071–5.
    trum and significance of clear-cell change in lung carcinoma.        95.   Sturm N, Rossi G, Lantuejoul S et al. Expression of thyroid
    Cancer 1980; 45: 943–7.                                                    transcription factor-1 (TTF-1) in the spectrum of neuroendo-
79. Cavazza A, Colby TV, Tsokos M et al. Lung tumors with a                    crine cell lung proliferations with special interest in carcino-
    rhabdoid phenotype. Am J Clin Pathol 1996; 105: 182–8.                     ids. Hum Pathol 2002; 33: 175–82.
80. Chuang MT, Marchevsky A, Teirstein AS et al. Diagnosis of            96.   Fitzgibbons PL, Kern WH. Adenosquamous carcinoma of the
    lung cancer by fibreoptic bronchoscopy: problems in the his-               lung: a clinical and pathologic study of seven cases. Hum
    tological classification of non-small cell carcinomas. Thorax              Pathol 1985; 16: 463–6.
    1984; 39: 175–8.                                                     97.   Ishida T, Kaneko S, Yokoyama H et al. Adenosquamous carci-
81. Haratake J, Horie A, Tokudome S et al. Inter- and intra-pa-                noma of the lung. Clinicopathologic and immunohistochemi-
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    diagnosis. Diagn Cytopathol 2001; 24: 58–64.                         99.   Sridhar KS, Raub WA Jr, Duncan RC et al. The increasing
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    tion of pulmonary large cell neuroendocrine carcinoma and                  Am J Clin Oncol 1992; 15: 356–62.
    large cell carcinoma with neuroendocrine morphology. Can-           100.   Takamori S, Noguchi M, Morinaga S et al. Clinicopathologic
    cer 2001; 91: 1992–2000.                                                   characteristics of adenosquamous carcinoma of the lung. Can-
84. Gazdar AF, Kadoyama C, Venzon D et al. Association between                 cer 1991; 67: 649–54.
    histological type and neuroendocrine differentiation on drug        101.   Addis BJ, Dewar A, Thurlow NP. Giant cell carcinoma of the
    sensitivity of lung cancer cell lines. Monogr Natl Cancer Inst             lung – immunohistochemical and ultrastructural evidence of
    1992; 191–6.                                                               dedifferentiation. J Pathol 1988; 155: 231–40.
85. Graziano SL, Mazid R, Newman N et al. The use of neuroen-           102.   Chejfec G, Candel A, Jansson DS et al. Immunohistochemical
    docrine immunoperoxidase markers to predict chemotherapy                   features of giant cell carcinoma of the lung: patterns of expres-
    response in patients with non-small-cell lung cancer. J Clin               sion of cytokeratins, vimentin, and the mucinous glycoprotein
    Oncol 1989; 7: 1398–406.                                                   recognized by monoclonal antibody A-80. Ultrastruct Pathol
86. Linnoila RI, Jensen SM et al. Neuroendocrine (NE) differen-                1991; 15: 131–8.
    tiation in non-small cell lung cancer (NSCLC) correlates with       103.   Ginsberg SS, Buzaid AC, Stern H et al. Giant cell carcinoma of
    favorable response to chemotherapy. Proce Am Soc Clin                      the lung. Cancer 1992; 70: 606–10.
    Oncol 1989; 8: 248.                                                 104.   McCaughan BC, Martini N, Bains MS. Bronchial carcinoids.
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105. Pass HI, Doppman JL, Nieman L et al. Management of the                  the lung, from neuroendocrine cell hyperplasia to small cell
     ectopic ACTH syndrome due to thoracic carcinoids. Ann Tho-              carcinoma. Histopathology 2003; 42: 156–66.
     rac Surg 1990; 50: 52–7.                                         117.   Bergh J, Esscher T, Steinholtz L et al. Immunocytochemical
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     bronchial adenoma. Am J Surg 1973; 126: 671–7.                          lung cancers. Am J Clin Pathol 1985; 84: 1–7.
107. Scheithauer BW, Carpenter PC, Bloch B et al. Ectopic secre-      118.   Sturm N, Rossi G, Lantuejoul S et al. Expression of thyroid
     tion of a growth hormone-releasing factor. Report of a case of          transcription factor-1 (TTF-1) in the spectrum of neuroendo-
     acromegaly with bronchial carcinoid tumor. Am J Med 1984;               crine cell lung proliferations with special interest in carcino-
     76: 605–16.                                                             ids. Hum Pathol 2002; 33: 175–82.
108. el-Naggar AK, Ballance W, Karim FW et al. Typical and atyp-      119.   Folpe AL, Gown AM, Lamps LW et al. Thyroid transcription
     ical bronchopulmonary carcinoids. A clinicopathologic and               factor-1: immunohistochemical evaluation in pulmonary neu-
     flow cytometric study. Am J Clin Pathol 1991; 95: 828–34.               roendocrine tumors. Mod Pathol 1999; 12: 5–8.
109. Lack EE, Harris GB, Eraklis AJ et al. Primary bronchial tumors   120.   Oliveira AM, Tazelaar HD, Myers JL et al. Thyroid transcrip-
     in childhood. A clinicopathologic study of six cases. Cancer            tion factor-1 distinguishes metastatic pulmonary from well-
     1983; 51: 492–7.                                                        differentiated neuroendocrine tumors of other sites. Am J Surg
110. Stamatis G, Freitag L, Greschuchna D. Limited and radical               Pathol 2001; 25: 815–19.
     resection for tracheal and bronchopulmonary carcinoid            121.   Du EZ, Goldstraw P, Zacharias J et al. TTF-1 expression is
     tumour. Report on 227 cases. Eur J Cardiothorac Surg 1990;              specific for lung primary in typical and atypical carcinoids:
     4: 527–32.                                                              TTF-1-positive carcinoids are predominantly in peripheral
111. Warren WH, Gould VE. Long-term follow-up of classical                   location. Hum Pathol 2004; 35: 825–31.
     bronchial carcinoid tumors. Clinicopathologic observations.      122.   Jones MH, Virtanen C, Honjoh D et al. Two prognostically
     Scand J Thorac Cardiovasc Surg 1990; 24: 125–30.                        significant subtypes of high-grade lung neuroendocrine
112. Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid                 tumours independent of small-cell and large-cell neuroendo-
     tumors of the lung. J Thorac Cardiovasc Surg 1972; 64:                  crine carcinomas identified by gene expression profiles.
     413–21.                                                                 Lancet 2004; 363: 775–81.
113. Bonato M, Cerati M, Pagani A et al. Differential diagnostic      123.   Costes V, Marty-Ane C, Picot MC et al. Typical and atypical
     patterns of lung neuroendocrine tumours. A clinico-patholog-            bronchopulmonary carcinoid tumors: a clinicopathologic and
     ical and immunohistochemical study of 122 cases. Virchows               KI-67-labeling study. Hum Pathol 1995; 26: 740–5.
     Arch A Pathol Anat Histopathol 1992; 420: 201–11.                124.   Devouassoux-Shisheboran M, Hayashi T, Linnoila RI, et al. A
114. Paladugu RR, Benfield JR, Pak HY et al. Bronchopulmonary                clinicopathologic study of 100 cases of pulmonary sclerosing
     Kulchitzky cell carcinomas. A new classification scheme for             hemangioma with immunohistochemical studies: TTF-1 is
     typical and atypical carcinoids. Cancer 1985; 55: 1303–11.              expressed in both round and surface cells, suggesting an ori-
115. Brambilla E, Brambilla C. Hétérogénéité des cancers bron-               gin from primitive respiratory epithelium. Am J Surg Pathol
     chiques. Problèmes d’histogénèse. Rev Mal Resp 1986; 5:                 2000; 24: 906–16.
116. Sturm N, Rossi G, Lantuejoul S et al. 34β E12 expression
     along the whole spectrum of neuroendocrine proliferations of
    8         Clinical diagnosis and basic evaluation
              John J Mullon, Eric J Olson

              Contents Introduction • History • Physical examination • Imaging • Diagnostic techniques
               • Overview of basic evaluation • Future developments

INTRODUCTION                                                 HISTORY

Lung cancer is the most lethal of all malignant diseases     Lung cancers are clinically silent for the majority of
worldwide and remains the leading cause of cancer-           time as they theoretically grow from a single malignant
related death in the United States.1 Lung cancer is          cell to a potentially detectable lesion. The vast majority
responsible for the overall increase in cancer mortality     of patients diagnosed with lung cancer are symptomatic
noted over the second half of the 20th century in            at the time of diagnosis. In only about 10% of cases is
the USA, which since 1999 has exceeded heart disease         lung cancer discovered incidentally in an asymptomatic
as the leading cause of death in those less than 85 years    patient, for instance as a solitary pulmonary nodule on
of age.1 Although the overall death rates due to lung        a routine chest radiograph. Smoking history,5 concur-
cancer have decreased in the USA and western Europe          rent chronic obstructive pulmonary disease (COPD),6
since 1991, largely due to reductions in tobacco             and previous exposures to certain environmental and
smoking,2,3 global lung cancer incidence and mortality       occupational carcinogens,7 including environmental
rates are expected to continue to rise as a result of        tobacco smoke,8 predict a higher risk for bronchogenic
the ongoing tobacco use in countries with developing         carcinoma. Ethnic and racial differences also contribute
or transitional economies.4 Three- to five-year disease-     to the smoking-related risk of lung cancer, with African
free rates for resected stage I lung cancer as high as       Americans and native Hawaiians within the USA at
60 to 90% are reported, but less than 20% of all             higher risk.9 Local tumor growth, regional extension,
lung cancers are stage I at the time of diagnosis and        metastases, paraneoplastic phenomenon, or a combina-
five-year survival rates for all stages of lung cancer       tion of mechanisms may cause tumor-associated symp-
remain approximately 15%.1 It is imperative that             toms (Table 8.1). There are no characteristics of clinical
clinicians be familiar with the evaluation of lung           presentation which absolutely distinguish NSCLC and
cancer given its tremendous worldwide public health          SCLC.
impact and the prognostic importance of early cancer
detection.                                                   Local effects
   Lung cancer outcome depends on the cell type              The most common initial symptom of lung cancer is
and stage of disease at presentation based on the            cough, which occurs in 45–75% of patients,10 and may
TNM classification. Accordingly, the essential aspects       be productive in up to 27%.11 Bronchorrhea, the expec-
of lung cancer evaluation are the histologic distinction     toration of large-volume, thin, mucoid secretions, may
of small cell (SCLC) and non-small cell (NSCLC) types        be seen with advanced bronchioloalveolar carcinoma
and accurate determination of the extent of disease so       (BAC), but is rare. Due to the location of vagal afferent
that appropriate treatment can be initiated. The evalu-      cough receptors, which principally line the airway
ation of lung cancer begins with a careful history and       mucosa, cancer types with a predilection for central air-
physical exam, followed by testing to obtain a tissue        way involvement (notably SCLC or NSCLC in the form
diagnosis and stage the extent of disease. This chapter      of squamous cell carcinoma) may cause cough earlier in
will review aspects of clinical presentation, imaging,       their course, whereas peripherally located tumors such
and diagnostic testing for bronchogenic carcinoma.           as adenocarcinoma or large cell carcinoma may only
Details regarding staging are discussed elsewhere in         cause cough as a late symptom. In addition to bronchial
this text.                                                   mucosa tumor invasion, causes of cough may include
76 Textbook of Lung Cancer

 Table 8.1 Aspects of lung cancer presentation
                                                             cancer patient with a normal chest X-ray may be due to
                                                             pulmonary thromboembolism or, less commonly,
 Asymptomatic                                                tumor microembolism. Lung cancer presents with
 Symptomatic                                                 hemoptysis in many patients as a result of tumor necro-
   Effects of local tumor growth                             sis, mucosal ulceration, tumor erosion into pulmonary
      Cough                                                  vasculature, postobstructive pneumonia, and pulmo-
      Bronchorrhea                                           nary thromboembolism. Retrospective studies reveal
      Fever, chills, purulent sputum                         that bronchogenic carcinoma accounts for 19–29% of
      production (postobstructive pneumonitis)               cases of hemoptysis.14,15 In patients with a normal chest
      Dyspnea                                                radiograph and hemoptysis, only 2–9% are subse-
      Hemoptysis                                             quently found to have lung cancer.16 Hemoptysis is
      Chest pain                                             commonly blood-streaked sputum, although large cen-
      Wheeze                                                 tral tumors may lead to massive hemoptysis that can
      Stridor                                                result in death by asphyxiation. Tumor involvement of
   Effects of regional tumor extension                       the parietal pleura, chest wall, and mediastinum leads
      Hemidiaphragm paralysis                                to chest pain as an initial complaint in 25–50% of
      Hoarseness                                             patients.17 Other causes of pain include rib cage metas-
      Dysphagia                                              tases, pulmonary embolism, and postobstructive pneu-
      Bronchoesophageal fistula                              monitis. Pneumothorax is a rare cause of chest pain and
      Pericardial effusion/tamponade/                        dyspnea in lung cancer patients.
      Lymphangitic carcinomatosis                            Regional extension effects
      Pulmonary nodules                                      Direct mediastinal extension by lung cancer or metasta-
      Tumor microembolism                                    ses to mediastinal lymph nodes can lead to a variety of
      Pleural effusion                                       presentations due to the diversity of adjacent structures.
      Superior vena cava syndrome                            Phrenic nerve involvement by tumor may cause ipsilat-
      Pancoast syndrome                                      eral diaphragmatic paralysis demonstrated on chest
   Metastatic effects                                        X-ray by hemidiaphragm elevation often in the setting
      Adrenal                                                of a centrally located mass. If lung cancer is not initially
      Liver                                                  identified as the etiology of diaphragm paralysis, it is
      Central nervous system                                 unlikely to become the explanation over time.18 Hoarse-
      Bone                                                   ness, a finding at presentation in 5–18% of lung cancer
   Paraneoplastic effects                                    patients,17 is usually attributable to unilateral left vocal
      See Table 8.2                                          paralysis resulting from damage to the left recurrent
                                                             laryngeal nerve anywhere along its intrathoracic course.
                                                             Extrinsic esophageal compression by tumor or metas-
postobstructive pneumonitis/atelectasis, tumor cavita-       tatic lymph nodes may cause dysphagia. Postprandial
tion, or pleural effusion. Although cough is a non-          coughing raises the possibility of bronchoesophageal
specific symptom frequently present in patients with         fistula. Pericardial involvement, which may be present
co-existent smoking-related airways disease, a change        in 20% of patients,17 occurs by hematogenous, lym-
in the character of a chronic cough, such as new hemop-      phatic, or direct extension routes, and may cause
tysis or co-existent fever and chills, should raise suspi-   asymptomatic pericardial fluid/thickening detected
cion of an additional process such as lung cancer. Lung      radiographically, tachyarrhythmias, or pericardial tam-
cancer is overall an unusual cause of chronic cough,         ponade.
occurring in less than 2% of patients,12 and is even less       In addition to its characteristic tendency to spread to
likely in the setting of a normal chest radiograph.13        hilar and mediastinal lymph nodes, lung cancer may
One-third to one-half of patients initially report dysp-     metastasize within the lung in several patterns. One
nea that may arise from large airway obstruction,            type is lymphangitic carcinomatosis, which usually
postobstructive pneumonitis/atelectasis, pleural effu-       appears on chest radiography as focal or diffuse reticu-
sion, lymphangitic metastases, pericardial effusion, or      lar or reticulonodular interstitial infiltrates and Kerley B
concurrent illnesses such as COPD. Dyspnea in a lung         lines, possibly combined with central adenopathy and
                                                                                   Clinical diagnosis and basic evaluation 77

pleural effusions. By high-resolution chest computed           The cytologic yield increases to 65% and 70% on the
tomography (CT), this process characteristically appears       second and third attempts, respectively. Pleural fluid
as irregular nodular thickening along bronchovascular          cytology is more sensitive than closed pleural biopsy,
bundles and interlobular septa, consistent with the role       primarily because pleural metastases tend to be focal
of lymphatics in this form of dissemination.19 Intrapul-       and percutaneous biopysy is performed blindly. Pleural
monary metastases may also appear as single or multi-          biopsy adds very little to the overall diagnostic yield
ple nodules/masses in one or both hemithoraces. A              when combined with cytology.21 Therefore, a second
management dilemma occurs in patients with other-              thoracentesis is usually performed rather than closed
wise resectable lung cancer who have one or more               pleural biopsy if malignant effusion is suspected. Low
radiographically indeterminate lung nodules. The dif-          pleural fluid pH (<7.30) and glucose (<60 mg/dl) val-
ferential diagnosis is broad, but includes synchronous         ues predict higher pleural fluid cytology yields, but also
lung cancers, granulomatous processes, silicotic nod-          predict poor response to pleurodesis and short survival
ules, metastatic extrapulmonary malignancies, Wegen-           time.22
er’s granulomatosis, and others. An individualized                Malignant cells in pleural fluid indicate T4 or stage
approach to these situations is generally recommended.         IIIB disease in NSCLC and this eliminates further con-
Lung cancer microembolism to the pulmonary arterial            sideration of surgical resection. It is important to
system, a rare form of intrathoracic metastasis, pro-          remember, however, that the mere presence of a pleural
duces dyspnea and is very difficult to diagnose ante-          effusion does not categorically preclude surgery for
mortem. Diagnosis has been occasionally accomplished           NSCLC. Other conditions that can cause pleural fluid
by cytologic examination of blood drawn through a              without direct tumor involvement of the pleura include
wedged pulmonary artery catheter.                              postobstructive pneumonitis/atelectasis, pulmonary
                                                               embolism, or illnesses unrelated to the tumor, such as
Pleural effusion                                               congestive heart failure, non-obstructive pneumonia,
Ten percent of all lung cancers metastasize to the pleura,     and cirrhosis. Therefore, the physician must thoroughly
with adenocarcinoma being the most common.17,20                evaluate pleural effusion in NSCLC patients with other-
Malignant pleural effusions due to lung cancer are gen-        wise potentially resectable disease. Unfortunately, series
erally on the same side as the main tumor. They may be         have demonstrated that only 5–10% of lung cancer
moderate to large in size, bloody, and recurrent follow-       patients with cytologically negative pleural effusions are
ing thoracentesis. Pleural effusions develop in the set-       ultimately found to have operable disease.23
ting of malignancy from local effects of the tumor
(pleural metastases, lymphatic obstruction, bronchial          Superior vena cava syndrome
obstruction with pneumonia or atelectasis, chylotho-           Several well-known syndromes result from regional
rax), systemic effects (pulmonary thromboembolism,             growth of lung cancer. Obstructed venous flow due to
hypoalbuminemia), or as complications of therapy. The          extrinsic compression of the superior vena cava (SVC)
main mechanism for malignant pleural effusion forma-           by adjacent bronchogenic carcinoma causes the SVC
tion is altered lymphatic drainage. Metastatic tumor           syndrome.24 Overall, approximately 2–4% of patients
implants on the pleural surface may alter capillary            suffering from bronchogenic carcinoma will develop
permeability and further increase pleural fluid forma-         the SVC syndrome;25 however occurrence is as high as
tion. In most cases, metastatic involvement of the pleura      20% in those with SCLC due to its propensity to develop
is thought to begin with hematogenous seeding of the           in the central airways.26 Clinical manifestations result
visceral pleura followed by subsequent movement                from venous hypertension above the level of the obstruc-
and attachment of tumor cells to the parietal pleural          tion. Symptoms and signs typically include headache
surface.                                                       and facial fullness (which may be worse in the recum-
   Malignant effusions are usually exudative (effusion         bent position), swelling and ruddiness of the face, neck,
meets at least one of the following criteria: pleural fluid/   and upper extremities, distended neck veins, and
serum total protein ratio >0.5, pleural fluid/serum lac-       prominent/tortuous collateral venous drainage over the
tate dehydrogenase [LDH] ratio >0.6, or pleural fluid          upper torso (Figure 8.1). Chest radiography may reveal
LDH > two-thirds of the upper limits of normal of the          mediastinal widening or a right perihilar mass. The dif-
serum). The fluid may appear serous, serosanguinous,           ferential diagnosis also includes lymphoma, metastatic
or frankly bloody. The initial thoracentesis of a malig-       extrathoracic malignancies, granulomatous mediastinal
nant effusion reveals malignant cells 50% of the time.         inflammation/fibrosis, postirradiation fibrosis, and aortic
78 Textbook of Lung Cancer

                                                                 imaging (MRI) in staging is recommended and is supe-
                                                                 rior to CT in determining the extent of local invasion.33
                                                                 A magnetic resonance angiogram (MRA) is likewise
                                                                 superior to both MRI and CT in assessing vascular
                                                                 involvement.34 The majority of cases of Pancoast’s syn-
                                                                 drome are due to NSCLC, but SCLC, metastatic extra-
                                                                 pulmonary cancer, and infectious conditions (bacterial,
                                                                 mycobacterial, and fungal) have also been implicated.
                                                                 Tissue diagnosis is recommended and transthoracic
                                                                 needle aspiration is frequently and successfully employed
                                                                 in this regard. Pancoast’s tumors are generally found to
Figure 8.1                                                       be stage IIB, IIIA, or IIIB lesions.
Tortuous, prominent, collateral venous drainage over the upper
torso in superior vena cava syndrome. (Courtesy of JH Ryu MD,
Mayo Clinic, Rochester, MN.)                                     Metastatic effects
                                                                 Approximately 40–50% of NSCLC patients present with
                                                                 metastatic disease that precludes surgical resection. SCLC
                                                                 has an even greater propensity to metastasize earlier in
aneurysms. Although the treatment goal remains                   its course. Consequently, SCLC is considered a systemic
prompt initiation of palliative chemotherapy or radia-           disease at time of diagnosis, even if it appears limited to
tion, SVC syndrome is no longer regarded as a medical            the chest. Lung cancer dissemination may occur via lym-
emergency.27 Diagnostic studies can be safely executed           phatic, hematogenous, or interalveolar routes. Metasta-
and a tissue diagnosis should be obtained before start-          ses to nearly every organ have been described, but the
ing therapy. Overall treatment with radiation and/or             most common sites of involvement are the lung, adrenals,
chemotherapy is effective in approximately 60% of                liver, central nervous system, and bone. Clinical mani-
cases of SVC syndrome due to NSCLC; however recur-               festations depend upon the extent of specific organ dys-
rence occurs in almost 20%.28 The presence of SVC                function induced by metastases. Quoted frequencies of
syndrome is a poor Prognostic indicator for patients             metastases differ depending upon whether initial presen-
with NSCLC, with a median survival of five months.29             tation or autopsy series are cited.

Pancoast’s syndrome                                              Adrenal
Pancoast’s syndrome is characterized by a tumor situ-            Adrenal metastases are common in lung cancer. They
ated in the extreme apical region of the hemithorax              are usually asymptomatic and initially detected as uni-
called the superior sulcus, in conjunction with ipsilat-         lateral adrenal gland enlargement on staging chest CT
eral shoulder and medial scapular discomfort. Pancoast           extended to the upper abdomen. In two series totaling
initially described the syndrome of shoulder and arm             576 NSCLC patients, 4–7.5% were found to have an iso-
pain in the distribution of the eighth cervical and first        lated unilateral adrenal mass, and approximately 30–40%
and second thoracic nerve trunks, Horner’s syndrome,             of the adrenal lesions were found to be malignant.35,36
and ipsilateral hand atrophy and weakness associated             Adrenal adenomas occur in 2–10% of the general pop-
with superior pulmonary sulcus tumors.30 Most patients           ulation and typically appear on CT as homogeneous,
do not have all of these signs and symptoms until late           low attenuation (due to fat content), well-circumscribed
in the course of the disease. Tumor invasion of the              lesions <3 cm in diameter.37 The differential diagnosis
adjacent chest wall, brachial plexus, and sympathetic            for benign adrenal enlargement includes adrenal ade-
ganglion is the cause for the clinical manifestations.           nomas, nodular hyperplasia, and hemorrhagic cyst.
The clinical findings vary depending on the extent to            Chemical shift MRI has been shown to be 96% sensitive
which the adjacent structures are involved. Shoulder             and 100% specific for distinguishing adenomas,38 and
pain is the most common symptom, occurring in up to              more recently 18F-fluoro-2-deoxy-D-glucose positron
88% of patients, with arm weakness noted in 40% and              emission tomography (18F-FDG-PET) has been shown
Horner’s syndrome in 30%.31 Superior sulcus tumors               to be 93% sensitive and 90% specific for detecting adre-
may manifest on chest radiography as unilateral apical           nal metastases in patients with known lung cancer.39
thickening (>5 mm), an apical mass (Figure 8.2), or              A positive result on 18F-FDG-PET, although highly
bony destruction.32 The use of magnetic resonance                suspicious, does not confirm the presence of adrenal
                                                                                   Clinical diagnosis and basic evaluation 79

(a)                                      (b)                                 Figure 8.2
                                                                             (a) Posteroanterior and (b) lateral chest radio-
                                                                             graphs, and (c) CT appearance of a large right
                                                                             superior sulcus tumor in a 52-year-old smoker
                                                                             who presented with right shoulder pain.
                                                                             Transthoracic needle aspiration revealed
                                                                             squamous cell carcinoma.


metastasis, which must be further proven by CT or             types of lung cancer to cause brain metastases. Although
endoscopic ultrasound-guided needle biopsy before             occasionally asymptomatic, brain metastases usually cause
withholding potentially curative resection.                   either non-focal symptoms, such as headache (most com-
                                                              mon), nausea, and vomiting, or focal abnormalities,
Liver                                                         including seizures, hemi-sensorimotor changes, and cra-
Metastatic involvement of the liver is common and             nial nerve deficits. Neurologic symptoms precede lung
usually clinically silent early in the course of disease.     cancer symptoms in most patients with concurrent dis-
Liver metastases are particularly common with SCLC.           ease. Metastases develop more commonly in the cerebral
History and physical exam do not dependably detect            hemispheres, particularly in the parietal and frontal lobes,
liver metastases. Liver involvement may be suggested          than in the cerebellum.41 Metastatic lesions are detected
by abnormalities on the initial staging CT or by elevated     by CT or MRI. Central nervous system metastases signal
liver test values. Advanced liver involvement may be          stage IV disease and generally herald an ominous progno-
associated with systemic symptoms, such as anorexia,          sis, but neuro- and radiosurgical advances have resulted
weight loss, and jaundice.                                    in successful treatment of brain metastases leading to
                                                              improvements in neurologic status and survival.41,42 In
Central nervous system                                        SCLC the brain is a common site of relapse and prophy-
Lung cancer is the most common cause for brain metas-         lactic cranial irradiation is shown to confer a significant
tases, accounting for approximately 70% of cases.40 Clin-     3-year survival benefit to those patients who experience a
ical and autopsy data indicate that approximately 40% of      complete initial response.43
lung cancer patients will develop brain metastases.17 Small      Other forms of central nervous involvement by meta-
cell and adenocarcinoma are the most common histologic        static lung cancer include spinal cord metastases and
80 Textbook of Lung Cancer

leptomeningeal carcinomatosis. Intraspinal lesions             dromes, the course of most paraneoplastic syndromes
usually cause back pain that is worsened by movement,          is analogous to that of the underlying lung cancer.
straining, and supine positioning. Neurologic deficits         Table 8.2 lists the paraneoplastic syndromes associated
from spinal cord compression, such as sensory defects          with lung cancer. The most common paraneoplastic
at or below the level of the lesion, paraparesis or para-      syndromes are discussed below.
plegia, and bowel/bladder incontinence tend to develop
quickly, progress rapidly, and be irreversible. In this        Hypercalcemia
event, spinal metastases become a medical emergency            Hypercalcemia is the most frequently encountered para-
for which steroids should be starting pending definitive       neoplastic syndrome, occurring in up to 12.5% of patients
therapy. Leptomeningeal carcinomatosis is uncommon             with lung cancer.47 Lung cancer is the most commonly
and uniformly predicts a short survival time. Neuro-           responsible malignancy, with squamous cell the usual
logic symptoms may also result from a number of para-          histologic type. Hypercalcemia generally results from
neoplastic syndromes, which are discussed below.               tumor production of parathyroid hormone-related pep-
                                                               tide (PTHrP).48 Rarely, hypercalcemia is due to osteolytic
                                                               bony metastases or aberrant elaboration of other cyto-
                                                               kines. PTHrP mimics the actions of endogenous para-
Skeletal metastases occur in approximately 25–30% of
                                                               thyroid hormone (PTH), so hypercalcemia results from
lung cancer patients and are typically found as oste-
                                                               heightened osteoclastic bone breakdown, decreased bone
olytic lesions in the vertebral bodies, ribs, and long
                                                               formation, and decreased renal calcium excretion. The
bones of the arms and legs.17 These lesions usually pro-
                                                               manifestations of hypercalcemia are malaise, weakness,
duce pain or elevations of calcium or alkaline phos-
                                                               fatigue, abdominal pain, constipation, anorexia, polydip-
phatase.37 Twenty percent of SCLC patients may also
                                                               sia, polyuria, confusion, hyporeflexia, and shortened QT
have bone marrow involvement, which may not initially
                                                               interval on electrocardiogram. Coma and death are late
be accompanied by clinical or laboratory abnormalities.
                                                               manifestations. Diagnosis is made by demonstrating a
Bony metastases may be detectable on plain radiographs.
                                                               combination of increased serum ionized calcium level
If these are negative or non-diagnostic, a planar bone scan,
                                                               (or disproportionate increase in total serum calcium
single photon emission computed tomogram (SPECT),
                                                               relative to the serum albumin), normal or low PTH level
or 18F-FDG-PET scan should be obtained. Of these
                                                               by immunoassay (to rule out primary hyperparathyroid-
three, 18F-FDG-PET is the most sensitive, but is associ-
                                                               ism), and exclusion of other causes of hypercalcemia
ated with greatest expense and is not universally
                                                               (granulomatous disorders such as sarcoidosis, hyper-
available.44,45 Directed MRI of the culprit region remains
                                                               thyroidism, adrenal insufficiency, acute renal failure,
an alternative as MRI is highly sensitive and specific for
                                                               Paget’s disease, and medications such as thiazide diuret-
bony metastasis, although it has not yet been system-
                                                               ics and vitamin D). It is also very important to rule out
atically compared to 18F-FDG-PET in this regard.
                                                               bony metastases. PTHrP is detectable by radioimmuno-
                                                               assay. Treatment strategies are volume repletion with nor-
Paraneoplastic effects                                         mal saline, increased urinary calcium excretion with a
Bronchogenic carcinomas are associated with paraneo-           loop diuretic such as furosemide, decreased bony resorp-
plastic syndromes more than any other tumor. Ten to            tion with bisphosphanates, calcitonin, or gallium, and
twenty percent of lung cancer patients will develop            treatment of the underlying malignancy. A novel thera-
paraneoplastic syndromes.46 These diverse phenomena,           peutic approach inhibiting osteoclast activity through
most of which are more common with SCLC, result                the use of an immunologically mediated tumor necrosis
from effects of lung cancer on other organ systems             factor receptor blockade has effectively inhibited hyper-
beyond those related to the physical presence of the           calcemia in a murine model.49 This therapeutic approach
primary or metastatic lesions. The clinical manifesta-         has yet to be fully investigated. Hypercalcemia in the set-
tions are frequently non-specific and are mediated by          ting of lung cancer is generally a late complication occur-
the ectopic production of biologically active peptides,        ring in the setting of advanced disease. The median survival
cytokines, and antibodies. An awareness of the para-           after onset of hypercalcemia is two to three months.
neoplastic syndromes is important since they may be
the presenting feature of an otherwise difficult to detect     Syndrome of inappropriate antidiuretic hormone
lung cancer in its earlier or recurrent stages. With the       The cardinal manifestation of the syndrome of inappro-
clinically frustrating exception of the neurologic syn-        priate antidiuretic hormone (SIADH) is hyponatremia
                                                                                    Clinical diagnosis and basic evaluation 81

Table 8.2 Paraneoplastic syndromes associated with lung      Table 8.2 Continued
  Syndrome of inappropriate antidiuretic hormone
                                                               Hypercoagulable state
  Cushing’s syndrome
                                                                 Migratory thrombophlebitis
                                                                 Disseminated intravascular coagulation
                                                                 Non-bacterial thrombotic endocarditis
                                                               Leukocytosis/leukemoid reaction
  Carcinoid syndrome
                                                               Thrombocytopenia purpura
  Hypoglycemia                                               Renal
  Hypouricemia                                                 Glomerulonephritis
  Cachexia/anorexia                                            Tubulointerstitial disorders
                                                               Nephrotic syndrome
  Clubbing/hypertrophic osteoarthropathy                     Modified from references 37 and 46.

  Acanthosis nigricans                                      due to the inappropriately sustained ectopic produc-
  Erythema gyratum repens                                   tion of arginine vasopressin (AVP; antidiuretic hor-
  Hyperpigmentation                                         mone), which acts on the distal renal tubule to promote
  Urticaria                                                 free-water conservation. Small cell is almost always the
  Vasculitis                                                underlying lung cancer histologic type.50 SIADH can
  Pruritis                                                  occur with equal frequency in limited and extensive
  Basex’s syndrome (acrokeratosis)                          SCLC and may produce symptoms in 5% of patients.46
  Tylosis                                                   What, if any, prognostic significance SIADH may have
  Erythroderma                                              is unclear, although a recent study suggested a slightly
  Acquired ichthyosis                                       worse survival in those patients with limited stage SCLC
  Erythema annulare centrifugum                             and SIADH when compared with those without SIADH.51
  Sign of Leser–Trelat                                      This is in contrast to earlier studies that found no dif-
                                                            ference in responsiveness to chemotherapy or survival
Musculoskeletal                                             in patients with SCLC and SIADH in comparison to
 Polymyositis                                               those without SIADH.50,52 Clinical manifestations of
 Myopathy                                                   hyponatremia are due to cerebral edema and occur
Neurologic                                                  more in relation to the rate of fall of the serum sodium
  Lambert–Eaton myasthenic syndrome                         rather than to the absolute serum sodium level. Because
  Peripheral neuropathy                                     the hyponatremia usually develops slowly in SIADH,
  Cerebellar degeneration                                   many patients are asymptomatic at presentation. Early
  Limbic encephalitis                                       symptoms include fatigue, weakness, nausea, and
  Polyradiculopathy                                         anorexia. The diagnostic criteria for SIADH are hypona-
  Myelopathy                                                tremia, serum hypoosmolality (<275 mosm/kg), inap-
  Opsoclonus/myoclonus                                      propriately increased urine osmolality (>200 mosm/kg),
  Dysautonomia                                              natriuresis (urine sodium >20 mEq/l), clinical euvolemia,
  Retinopathy                                               and the absence of renal, adrenal, and thyroid dysfunc-
                                                            tion. Central nervous system disorders, other pulmo-
                                              (Continued)   nary lesions (notably pneumonia), and drugs (including
                                                            cyclophosphamide, tricyclic antidepressants, thiazide
                                                            diuretics, morphine, and vincristine) can also cause
82 Textbook of Lung Cancer

   Asymptomatic or mildly symptomatic patients may           may in the future replace urinary free cortisol or low-
be treated with restriction of water intake to less than 1   dose dexamethasone suppression as a first-line screen-
liter per day (although sustained compliance is diffi-       ing test.54 The diagnosis is at times problematic as
cult) and demeclocycline (which gradually blocks the         tumors responsible for Cushing’s syndrome may have
action of AVP on the kidney). More serious symptoms,         variable secretory activity and, especially pulmonary
such as seizures, cognitive decline, and mental status       carcinoids, may be suppressible with low-dose dexa-
changes, or more profound hyponatremia (serum                methasone. Treatment options include resection (carci-
sodium <120 mEq/l), should be treated with normal            noidtumors),chemotherapy(SCLC),bilateraladrenalectomy,
(0.9%) saline and a loop diuretic. Use of normal saline      or medical suppression of adrenal glucocorticoid pro-
alone may actually decrease the serum sodium concen-         duction with ketoconazole, aminoglutethimide, etomi-
tration so a loop diuretic must be added. The use of         date, or metyrapone.
hypertonic (3%) saline is rarely indicated. The goal
                                                             Neurologic syndromes
should be to raise the serum sodium at a maximum rate
                                                             There are several stereotypic neurodegenerative syn-
of 2 mEq/l/hour (maximum 20 mEq/l/day) to a target of
                                                             dromes that occur primarily in SCLC patients. These
120–125 mEq/l. More aggressive sodium correction
                                                             paraneoplastic syndromes are distinct from the non-
may theoretically result in central pontine myelinolysis,
                                                             focal neurologic dysfunction induced by systemic effects
a devastating central neurologic insult usually resulting
                                                             of cancer. They are felt to be sequelae of autoimmune
in death.
                                                             phenomena that can involve any level(s) of the nervous
                                                             sytem (brain, cranial nerves, spinal cord, peripheral
Ectopic adrenocorticotropic hormone syndrome
                                                             nerves, neuromuscular junction, and muscle). The pro-
Cushing’s syndrome describes a constellation of
                                                             posed pathogenetic sequence begins with the ectopic
findings due to excess glucocorticoid production.
                                                             expression by tumor cells of antigens similar to those
Approximately 80% of adrenocorticotropic hormone
                                                             normally expressed in the nervous system. The shared
(ACTH)-dependent cases of Cushing’s syndrome are
                                                             antigen is sensed as foreign and an immune response
due to Cushing’s disease – an ACTH-secreting tumor of
                                                             ensues, causing nervous system injury and clinical
pituitary origin. The remaining cases are due primarily
                                                             deficits.55,56 In support of this mechanism are the obser-
to ectopic ACTH or corticotropin-releasing hormone
                                                             vations that these syndromes are associated with spe-
(CRH) production, usually by bronchial carcinoid
                                                             cific detectable antibodies, nervous system injuries are
tumors, but also occurring as a result of thymic carci-
                                                             strikingly limited to specific cell types, deposits of
noid, gastrinoma, pheochromocytoma, and small cell
                                                             immunoglobulin have been demonstrated in areas of
carcinoma.53 Ectopically produced ACTH directly stim-
                                                             neuronal cell loss, and the characteristic antibodies are
ulates adrenal glucocorticoid release, while CRH trig-
                                                             made in the central nervous system by autoreactive
gers ACTH release from the pituitary. Slowly growing
                                                             lymphocytes. The prototypic process of the autoanti-
carcinoid tumors may be accompanied by the classic
                                                             body pathogenetic mechanism is the Lambert–Eaton
features of Cushing’s syndrome, including truncal
                                                             myasthenic syndrome (LEMS). However, not all patients
weight gain, moon facies, hypertension, purplish cuta-
                                                             with clinically similar syndromes have detectable
neous striae, hirsutism, glucose intolerance, and proxi-
                                                             autoantibodies, attempts to induce similar syndromes
mal muscle weakness. Cushing’s manifestations in more
                                                             in animals with passive immunoglobulin transfer or
rapidly growing SCLC are usually limited to weight
                                                             immunization with the culprit antigen have been largely
loss, hypertension, edema, weakness, poor skin integ-
                                                             unsuccessful, and immunosuppressants are not usually
rity, hypokalemic alkalosis, and glucose intolerance.
                                                             effective treatments. Our understanding of these syn-
Overall, less than 5% of SCLC patients develop Cush-
                                                             dromes continues to evolve.
ing’s syndrome46 and its occurrence predicts a shorter
survival time, perhaps due to the co-morbidities induced     Lambert–Eaton myasthenic syndrome
by glucocorticoid excess. An elevated 24-hour urinary        Proximal muscle weakness, hyporeflexia, and auto-
free cortisol level (four or more times the upper limit of   nomic dysfunction (dry mouth, erectile dysfunction,
normal) and failure to suppress cortisol during low-         constipation, blurred vision) characterize LEMS. The
dose dexamethasone challenge generally confirm the           pathognomonic electromyographic finding is a marked
presence of Cushing’s syndrome. Late-night salivary          increase of the compound muscle action potential fol-
cortisol levels have been shown to have high diagnostic      lowing high rates of nerve stimulation. Similarly, aug-
sensitivity and specificity for Cushing’s syndrome and       mented strength and reflexes can be demonstrated on
                                                                                Clinical diagnosis and basic evaluation 83

physical exam after maximal contraction of the involved     neurologic improvement. Somewhat ironically, ANNA-1
muscle groups. Clinical manifestations are due to anti-     seropositivity is associated with more limited stage
bodies to P/Q type voltage-gated calcium channels           SCLC at presentation, higher complete tumor response
expressed on the presynaptic cholinergic synapses of        to chemotherapy, and longer survival.60 Patients with
peripheral nerves that interfere with the release of ace-   unexplained neurologic findings, ANNA-I positivity,
tylcholine.57 These voltage-gated calcium channels          and a history of smoking should undergo a thorough
also appear on SCLC cells. Treatments of potential          search for SCLC, including a chest CT with contrast. If
benefit include 3,4-diaminopyridine (increases presyn-      evidence of SCLC is not clearly identified by CT the
aptic calcium influx), pyridostigmine (inhibits acetyl-     addition of an 18F-FDG-PET scan should be consid-
cholinesterase), oral immunosuppressive agents such as      ered as the combination of CT and 18F-FDG-PET has
corticosteroids, plasma exchange, intravenous immu-         been shown in one small series to be 100% sensitive for
noglobulin, and treatment of the underlying tumor.          tumor detection.61 Five to fifteen percent of SCLC patients
Approximately one-third to one-half of LEMS patients        may be ANNA-1 seropositive without neurologic
will improve with treatment of the underlying SCLC.         findings.
However, not all patients with LEMS have an identifi-
able underlying malignancy.                                 Other neurologic paraneoplastic syndromes
                                                            Type 2 antineuronal nuclear autoantibodies (ANNA-2),
Antineuronal nuclear autoantibodies-1-associated            also known as anti-Ri antibodies, are linked with
(ANNA-1) syndromes                                          opsoclonus/myoclonus (opsoclonus are involuntary,
ANNA-1, also known as anti-Hu antibodies, are IgG           conjugate, arrhythmic high-amplitude, saccadic eye
antibodies that recognize a family of nuclear mRNA          movements) in breast cancer. Paraneoplastic cerebellar
binding proteins expressed in SCLC cells and neurons        degeneration is associated with a specific anti-Purkinje
of the central and peripheral nervous systems. These        cell antibody called anti-Yo (PCA 1) in females with
antibodies are distinct from the autoantibodies of sys-     breast and gynecologic malignancies. Similar syndromes
temic lupus erythematosis, and whether ANNA-1 anti-         can occur in SCLC and NSCLC, but lung cancer patients
bodies have a pathogenetic role in the neurologic           are typically, although not always, ANNA-2 or anti-Yo
manifestations remains unclear. Seropositivity for          seronegative. Cancer-associated retinopathy is a rare
ANNA-1 is associated with a diverse set of neurologic       complication of SCLC, felt to be due to detectable anti-
disorders that can occur in varying combinations.58         bodies directed at the retinal photoreceptor layer or
Lucchinetti and colleagues59 reported on the wide spec-     ganglion cells. SCLC is also strongly associated with
trum of neurologic and oncologic findings in 162            other antineuronal autoantibodies such as collapsing
ANNA-1 seropositive patients. Twice as many women           response-mediating protein-5 (CRMP-5), which has yet
were afflicted as men. By the end of follow-up, a malig-    to be directly associated with a discrete clinical syn-
nancy had been detected in 142 patients (88%), with         drome. It has been suggested that abnormalities identi-
81% having SCLC. Of the patients with SCLC, 17              fied on autoantibody paraneoplastic panels may serve
developed at least one other malignancy. Neurologic         best to predict the underlying neoplasm rather than a
signs associated with ANNA-1, in decreasing frequency,      specific neurologic syndrome.62
were neuropathy (sensory > mixed somatic > autonomic
> motor), cerebellar ataxia, limbic encephalitis (neu-      Other paraneoplastic syndromes
rocognitive and neurobehavioral deficits), polyradicul-     Clubbing of the fingers and toes is characterized by loss
opathy, LEMS, myopathy, myelopathy, opsoclonus/             of the angle between the base of the nail bed and cuti-
myoclonus, motor neuronopathy, brachial plexopathy,         cle, rounded nails, and enlargement of the digit tips.
and aphasia. Gastrointestinal dysmotility occurred          Hypertrophic osteoarthropathy (HPO) is a painful, pro-
in 38 (28%) patients, as manifested primarily by gastro-    liferative periostitis that classically involves long bones
paresis and intestinal pseudoobstruction due to             of the arms and legs. The affected bones reveal periosteal
involvement of the myenteric plexus. The neurologic         new bone formation on plain radiographs and increased,
manifestations preceded the cancer diagnosis in 96% of      symmetric uptake on radionuclide studies. Clubbing
patients, and usually progressed in a subacute manner.      and HPO are rare entities that can occur together or as
None of the 49 patients who received immunosuppres-         isolated findings. The cause(s) remains unknown; how-
sant therapy (steroids, plasma exchange, intravenous        ever recent data suggest that platelet microthrombi with
immunoglobulin, or cyclophosphamide) experienced            subsequent release of platelet-derived and vascular
84 Textbook of Lung Cancer

endothelial growth factors may play a role in the devel-     tamponade from metastatic disease. Pain may cause the
opment of clubbing.63 Clubbing and HPO can occur in          patient to favor the upper extremity ipsilateral to a
conjunction with bronchogenic carcinoma, as well as a        superior sulcus tumor. Neck palpation may yield evi-
variety of cardiopulmonary suppurative processes             dence of spread to supraclavicular lymph nodes. Focal
(bronchiectasis, cystic fibrosis, empyema, subacute          rib tenderness implies metastases. Direct extension of
bacterial endocarditis), usual interstitial pneumonitis/     lung cancer to the chest wall is rarely palpable. The
idiopathic pulmonary fibrosis, pulmonary arteriovenous       combination of percussible dullness, diminished breath
malformations, congential cyanotic heart disease,            sounds, and reduced fremitus suggests pleural effusion,
inflammatory bowel disease, and cirrhosis. The poten-        hemidiaphragm dysfunction due to phrenic nerve
tial association between the inflammatory myopathies         entrapment, or postobstructive pneumonitis/atelectasis.
and lung cancer remains to be fully defined.64 Similarly,    Bronchial breath sounds and increased fremitus indi-
it is unclear how thoroughly the physician should            cate consolidation with patent proximal airways. Focal
search for malignancy in patients with unexplained           wheezing is detected with central airway compromise
venous thromboembolism. A prospective randomized             by an endobronchial tumor or extrinsic compression,
trial of 201 patients with idiopathic venous throm-          generalized wheezing with COPD. Concurrent intersti-
boembolism65 identified a 10% incidence of occult            tial lung diseases, such as asbestosis, may be heralded
malignancy in the extensively screened cohort. Over a        by characteristic Velcro-type inspiratory crackles.
two-year follow-up, 9.8% of patients in the control          Depending on their distribution, rubs may be due to
group subsequently developed symptomatic malig-              venous thromboembolic events or metastatic pericar-
nancy. Overall malignancies were detected earlier and at     dial or pleural involvement.
an earlier stage in the extensively screened group,             The remainder of the exam is equally important. Per-
although a significant survival benefit could not be         tinent skin findings include cutaneous metastases, typi-
demonstrated. Currently no professional organization         cally over the torso and scalp, and Basex’s syndrome,
recommends extensive screening for malignancy in the         which is hyperkeratosis of the acral regions. Acanthosis
setting of idiopathic venous thromboembolism. A pru-         nigricans, brown velvety plaques of the groin, back of
dent strategy may be to maintain a low threshold of          neck and axillae, may be paraneoplastic phenomena,
suspicion for malignancy when venous thromboembo-            but are more commonly seen with obesity and diabetes.
lism develops without conventional risk factors, and to      The differential diagnosis for bony pain in the cancer
proceed with additional testing as directed by history,      setting includes skeletal metastases and HPO. Liver
physical exam, and routine initial investigation.            metastases may be palpable. A thorough nervous sys-
                                                             tem examination is crucial, especially in patients with
                                                             headache, sensorimotor complaints, and back pain.
PHYSICAL EXAMINATION                                         Unilateral lower extremity swelling, tenderness, and
                                                             erythema may accompany deep venous thromboses.
A careful physical exam is a vital component of the lung        The history and physical exam findings can be com-
cancer evaluation as it may provide important diagnos-       bined to estimate general health status, such as by the
tic, prognostic, and staging clues. General appearance       Karnofsky (Table 8.3) or Eastern Cooperative Oncology
may be normal or may reveal debilitation, cachexia,          Group (ECOG, Table 8.4) performance scores.66,67
lethargy, pallor, jaundice, fever, or significant co-        These clinical indices provide a convenient framework
morbidities. Blood pressure irregularities can be seen in    to rate the impact of the lung cancer and co-
conjunction with neurologic or adrenal paraneoplastic        morbidities on the patient. Performance status has been
phenomena. Hoarseness suggests recurrent laryngeal           reproducibly shown to be an important prognostic vari-
nerve compromise.                                            able in NSCLC and SCLC, and usually influences treat-
   Respiratory system examination should be conducted        ment decision-making.
in an orderly manner. On inspection, tachypnea may
signal painful rib metastases, pleural effusions, or post-
obstructive pneumonia, while expiratory prolongation         IMAGING
is consistent with underlying COPD. Signs of venous
hypertension limited to the head, neck, and arms are         Standard chest radiograph
seen with SVC syndrome, while jugular venous hyper-          The standard posteroanterior and lateral chest radio-
tension and pulsus paradoxus are signs of pericardial        graph is usually the first test to suggest bronchogenic
                                                                                      Clinical diagnosis and basic evaluation 85

 Table 8.3 Karnofsky Performance Scale (modified from Mor et al66)

 Definition                              Percent      Criteria

 Able to carry on normal activity         100         Normal; no complaints; no evidence of disease
 and to work; no special care             90          Able to carry on normal activity; minor signs or symptoms of
 needed                                               disease
                                            80        Normal activity with effort; some signs or symptoms of disease
 Unable to work; able to live at            70        Cares for self; unable to carry on normal activity
 home; cares for most personal                        or to do active work
 needs; a varying amount of                 60        Requires occasional assistance but is able to care for most of
 assistance is needed                                 needs
                                            50        Requires considerable assistance and frequent medical care
 Unable to care for self; requires          40        Disabled; requires special care and assistance
 equivalent of institutional or             30        Severely disabled; hospitalization is indicated, although death
 hospital care; disease may be                        may not be imminent
 progressing rapidly                        20        Very sick; hospitalization necessary; active supportive
                                                      treatment necessary
                                            10        Moribund; fatal processes progressing rapidly

 Table 8.4 Eastern Cooperative Oncology Group Performance Scale (from Oken et al67)

 Performance status        Definition

 0                         Fully active; no performance restrictions
 1                         Strenuous physical activity restricted; fully ambulatory and able to carry out light
 2                         Capable of all selfcare but unable to carry out any work activities.
                           Up and about >50% of waking hours
 3                         Capable of only limited selfcare; confined to bed or chair >50% of waking hours
 4                         Completely disabled; cannot carry out any selfcare; totally confined to bed or chair

carcinoma, and it helps to assess the intrathoracic extent       peripherally as a solitary nodule or mass. Large cell car-
of cancer, guides subsequent work-up, and identifies             cinoma is characteristically a large peripheral mass. BAC
simultaneous thoracic disease.68 The spectrum of pos-            may appear as a nodule or an alveolar infiltrate that can
sible findings is broad, but the most common are a               be diffuse. The drawbacks of plain chest radiography
localized opacity (nodule or mass), pleural effusion,            include lack of specificity and resolution limitations.
infiltrate, atelectasis, and adenopathy. Certain radio-          Lesions smaller than 2–3 mm are not reliably detectable
graphic appearances may suggest histologic types of              and the miss rate for lesions less than 2 cm may exceed
lung cancer, but these generalizations are not absolute.         50%.70 Regions obscured by the heart, clavicles, and
Squamous cell carcinoma usually presents as a large              diaphragm may be particularly difficult to interpret.
mass centered at or near the hilum, that may cavitate.           Estimates are that chest radiography is 70–80% accu-
Due to the central airway origin, up to 50% of patients          rate in the overall detection of lung cancer, 50–60%
with squamous cell carcinoma will present with endo-             sensitive in the detection of hilar adenopathy, and less
bronchial obstruction with postobstructive pneumonia             than 50% sensitive in the detection of mediastinal ade-
or atelectasis.69 SCLC may also present as a rapidly             nopathy.71 Studies using commercially available comput-
enlarging central mass with contiguous hilar and medi-           er-aided diagnostic software to improve the sensitivity of
astinal involvement. Only 5–10% of SCLCs present as              digital chest radiographs show modest improvements
peripheral lung lesions. Adenocarcinoma typically arises         in nodule detection.72
86 Textbook of Lung Cancer

Computed tomography                                          Table 8.5 Causes of solitary pulmonary nodules (from
CT greatly enhances the imaging of bronchogenic car-         Midthun et al74)
cinoma by providing further definition of the primary
lesion’s appearance, detecting concurrent parenchymal        Infectious granuloma
or pleural disease missed by plain chest radiography,           Tuberculosis
demonstrating lymphangitic spread of malignancy,                Histoplasmosis
guiding diagnostic maneuvers, and evaluating hilar and          Coccidiomycosis
mediastinal lymph node metastases. CT also helps in          Bronchogenic carcinoma
the evaluation of distant metastases by the routine prac-    Metastatic cancer
tice of extending the examination to include the liver          Breast
and adrenals. The delineation by CT of the relation of          Head and neck
bronchogenic carcinoma to surrounding structures is             Colon
particularly important since these findings significantly       Renal cell
influence prognosis and, in the case of NSCLC, surgical         Sarcoma
options. However, the resolution limitations of CT in           Germ cell
this regard must be acknowledged. Consensus calls for        Bronchial carcinoid
intrathoracic lymph nodes larger than 1 cm in the short      Hamartoma
axis dimension to be considered abnormal by CT; how-         Organizing pneumonia/abscess
ever, using this criterion CT is only 57% sensitive and      Wegener’s granulomatosis
82% specific in identifying hilar and mediastinal lymph      Rheumatoid nodule
metastases.73 The sensitivity of CT suffers from micro-      Arteriovenous malformation
scopic lymph node metastases, while the specificity is       Pulmonary infarction
influenced by benign causes for lymphadenopathy,             Bronchogenic cyst
such as reactive hyperplasia, granulomatous inflamma-        Lipoma
tion, and anthracosis. CT also has difficulties in accu-     Amyloidoma
rately diagnosing chest wall or mediastinal structure
invasion, detecting endobronchial lesions, and differ-
entiating tumor from adjacent atelectasis or pneumo-
nia. Hence, CT is not a substitute for histologic           comparison studies are insufficient, the next step is to
information and patients must not be denied surgery         assess for calcification in the nodule with CT. Central,
for NSCLC simply on CT findings without tissue con-         concentric, or popcorn calcification patterns are reli-
firmation.                                                  able indicators of their benign nature. Eccentric calcifi-
                                                            cation does not rule out malignancy. Thin-section CT
Solitary pulmonary nodule                                   images may also detect fat within the nodule, indicative
Solitary pulmonary nodule (SPN) is a common clinical        of a hamartoma, which is always benign. Taking advan-
radiologic dilemma. Defined as a singular rounded           tage of the differences in vascular supply between
lesion entirely surrounded by normal lung parenchyma        benign and malignant nodules, Swensen and col-
and without associated lymphadenopathy, an SPN may          leagues75 demonstrated that the level of nodule enhance-
be caused by malignant and benign processes                 ment detected by thin-section CT after injection of
(Table 8.5).74 The majority of SPNs are benign. Most        intravenous contrast reliably differentiated benign ver-
malignant SPNs are clinical stage I bronchogenic carci-     sus malignant lesions (Figure 8.3). Using 15 Hounsfield
nomas. SPNs are usually incidental findings on plain        units as the threshold for enhancement, sensitivity of
chest radiographs or CTs obtained for other purposes.       this technique for malignancy was 98%. Specificity was
The questions become whether the SPN is benign or           just 58%, since some inflammatory and infectious
malignant, and whether it should be observed, biop-         lesions may enhance. The negative predictive value was
sied, or removed. The evaluation begins, if possible,       96% – if a nodule does not enhance, it is almost always
with review of previous chest radiographs. A nodule         benign. Recently 18F-FDG-PET was compared to nod-
that has been radiographically stable for at least two      ule enhancement CT and found to have similar sensi-
years is by definition benign, and no further maneuvers     tivity and superior specificity in differentiating malignant
are necessary. A steadily growing nodule is considered      from benign pulmonary nodules, although nodule-
malignant and should be immediately resected. When          enhancement demonstrated a negative predictive value
                                                                                   Clinical diagnosis and basic evaluation 87

(a)                                       (b)                                        Figure 8.3
                                                                                     CT images demonstrating enhancement
                                                                                     of 87 Hounsfield units (HU) of a left lung
                                                                                     nodule after injection of iodinated
                                                                                     contrast (31 HU on the precontrast image
                                                                                     versus 118 HU on the postcontrast
                                                                                     image). The circle within the nodule
                                                                                     circumscribes the region used to
                                                                                     measure enhancement.
                     HU= 31                                   HU= 118

of 100%.76 The authors concluded that 18F-FDG-PET             Ground-glass opacities
is preferable to nodule-enhancement CT in evaluating          Recent advances in CT screening for lung cancer (dis-
indeterminate pulmonary nodules; however nodule-              cussed below) have led to increased detection of focal
enhancement CT remains a useful tool due to its very          ground-glass opacities (GGOs). A GGO is defined as a
high negative predictive value, convenience, and lower        hazy area of increased lung attenuation with preserved
cost. If radiologic studies are inconclusive, clinical fac-   bronchial and vascular margins (Figure 8.4).81 These
tors which predict a higher risk of malignancy include        features may be the result of interstitial thickening, air
advanced age of the patient, smoking history, prior           space filling or partial collapse, or increased capillary
malignancies, and larger nodule size. The patient’s           blood flow; alternatively they may be seen as a feature
wishes must be considered in the decision-making pro-         of normal exhalation. As such, GGO is a non-specific
cess. Lesions ≥3 cm in size are malignant in over 90%         finding which may be caused by a variety of infectious,
of cases and should not be observed. If a lesion is not       inflammatory, and neoplastic processes.82,83 A recent
removed and is indeterminate, then it must be observed.       series84 demonstrated that GGOs with no concomitant
Observation typically involves obtaining serial chest CT      solid component will represent malignancy approxi-
scans every three months for the first six months, and        mately 20% of the time; however with serial follow-up
then every six months for the remainder of two years.77       almost 40% will regress or disappear spontaneously. In
Serial plain chest radiographs do not reliably detect         the same series, GGOs with a concomitant solid compo-
enlargement of small nodules. If the nodule grows, it         nent represented malignancy approximately 30% of the
must be resected. If the nodule is stable for two years,      time; however up to 50% regressed or disappeared spon-
it is safe to assume that it is benign.                       taneously. Regression, when present, occurred within
    With the introduction of helical and multi-detector       the first 90 days of follow-up in the vast majority of cases.
row CTs the detection of nodules as small as 1–2 mm           Malignant and premalignant lesions are most commonly
is becoming common. The Mayo Clinic CT Screening              BAC, adenocarcinoma, and atypical adenomatous hyper-
Trial demonstrated that less than 1% of nodules <5 mm         plasia.85 Female gender, spiculated border, a concomi-
in size in patients without a history of cancer proved to     tant solid component, and size greater than 1 cm appear
be malignant.78 Henschke and colleagues79 further dem-        to be risk factors for malignancy, whereas an elevated
onstrated that the follow-up interval for nodules <5          serum eosinophil count may predict a benign etiology.
mm in size at initial detection could safely be extended      When malignant, tumor doubling times vary widely and
to 12 months. The likelihood that an incidentally             may be as long as 1486 days for some BACs.86 Frequent
detected nodule is malignant also depends on known            spontaneous regression, relatively high malignancy rates,
risk factors such as cigarette smoking, as well as radio-     and long doubling times all make management decisions
graphic characteristics such as density. With this in         for GGOs problematic, and currently no specific guide-
mind the Fleischner Society80 has endorsed a statement        lines exist for the follow-up or management of GGOs.
recommending variable follow-up of small nodules              Based on available data it may be reasonable to biopsy
(<8 mm) identified incidentally based on patient risk         GGOs that persist beyond 90 days and are greater than
factors and nodule size at the time of detection. Included    1 cm in size or have other concerning characteristics.
in this is a provision for no follow-up of incidentally       Serial follow-up, if elected, should continue beyond five
detected nodules less than or equal to 4 mm in size in        years before determining that an identified GGO does
low-risk patients.                                            not represent malignancy.
88 Textbook of Lung Cancer

                                                                      F-fluoro-2-deoxy-D-glucose positron emission
                                                                    Accurate staging of NSCLC is essential to determine
                                                                    appropriate therapy and estimate prognosis. Evaluation
                                                                    of mediastinal nodal disease and extrathoracic metasta-
                                                                    sis is crucial in this regard due to their impact on oper-
                                                                    ative candidacy and potential surgical cure. As discussed
                                                                    above, the accuracy of CT for predicting mediastinal
                                                                    nodal metastasis is not ideal. 18F-FDG-PET is a radio-
                                                                    nuclide test that involves injection of the radioisotope
                                                                       F-fluorodeoxyglucose (18F-FDG). Tissues with high
                                                                    metabolic activity, such as high-grade neoplasms,
                                                                    demonstrate increased glucose uptake relative to nor-
                                                                    mal tissues and will show increased isotope deposition.
Figure 8.4                                                          A meta-analysis of 18 studies found 18F-FDG-PET
Chest CT demonstrating a ground-glass opacity measuring             to have a sensitivity of 84% and specificity of 89%
12 × 7 mm (circled). Note the preservation of underlying vascular
                                                                    when investigating the mediastinum for metastases
and interstitial structures.
                                                                    (Figure 8.5).73 In lymph nodes smaller than 1 cm spec-
                                                                    ificity may be as high as 95%, although sensitivity is
                                                                    lower.92 18F-FDG-PET also increases detection of extra-
CT lung cancer screening                                            thoracic metastases (Figure 8.6), identifying unsus-
Five-year survival for stage I lung cancer approaches               pected distant metastases in as many as 28% of patients
70%; however <20% of lung cancers are detected at                   with stage III disease in one series,93 and reducing by
this early stage. That the vast majority of these early             20% non-therapeutic thoracotomies in a series enrolling
stage lung cancers are asymptomatic and identified                  patients with stages IA–IIIA NSCLC.94 18F-FDG-PET
incidentally on a radiograph or CT obtained for other               imaging has been shown to be superior to conventional
purposes has raised tremendous interest in devising a               imaging for identifying tumor recurrence.95 False-posi-
rational method to screen for lung cancer radiographi-              tive results may be seen with various inflammatory and
cally, similar to the way a mammogram is used to screen             infectious processes such as sarcoidosis, pulmonary
for breast cancer. Early screening trials conducted in              Langerhans cell histiocytosis, and mycobacterial and
the 1970s using chest radiography and sputum cytol-                 fungal diseases. False-negative results may occur
ogy demonstrated a higher incidence rate, resectability,            with low-grade neoplastic processes such as BAC and
and survivorship among the intensively screened group,              bronchial carcinoid tumors. Because of the occasional
but failed to show a mortality benefit (summarized in               false-positive findings potentially metastatic sites should
reference 87). A number of more recent studies inves-               be proven by biopsy when clinically and technically
tigating the use of low-dose CT have shown an ability               feasible.96
to detect earlier stage cancers; however, they have also
shown high false-positive rates with indeterminate nod-             Magnetic resonance imaging
ules identified in up to 70% of participants.88,89 Recent           MRI does not have a routine role in the evaluation of
five-year prospective data collected on over 1500 high-             lung cancer. However, its superiority over CT in distin-
risk participants suggest that overdiagnosis rather than            guishing tumor abutment versus invasion of chest wall,
earlier diagnosis may be playing a role in the use of CT            vertebral, and mediastinal structures makes MRI a use-
screening, and did not demonstrate a mortality bene-                ful adjunct in situations such as superior sulcus tumors
fit.90 Conversely, a recently reported multicenter study91          and possible neuroforaminal encroachment. The mag-
enrolling over 31 000 patients over ten years identified            netic resonance angiogram (MRA) is the study of choice
484 lung cancers, 85% of which were stage I. For those              to investigate vascular invasion.
patients diagnosed at stage I, the estimated ten-year
survival rate was 88%, and 92% for those who under-                 Other nuclear medicine studies
went surgical resection within one month of diagnosis.              In NSCLC patients with marginal pulmonary function,
At this time no professional organization recommends                quantitative ventilation-perfusion (V/Q) lung scans
screening for lung cancer.                                          can be used to assess candidacy for lung resection.
                                                                               Clinical diagnosis and basic evaluation 89

(a)                                                (c)                           Figure 8.5
                                                                                 18F-FDG-PET scan with CT fusion
                                                                                 demonstrating a primary adenocarci-
                                                                                 noma in the left upper lobe (a), with
                                                                                 contralateral hilar metastasis (b).
                                                                                 (c) Coronal 18F-FDG-PET without CT
                                                                                 fusion, demonstrating no extrathoracic
                                                                                 involvement. Transbronchial needle
                                                                                 aspirate of the right hilar lymph node
                                                                                 confirmed metastatic adenocarcinoma
                                                                                 with stage IIIB NSCLC assigned. (See color
                                                                                 plate section, page xiii)


The fraction of total ventilation or perfusion from the    evaluation by plain radiography or MRI, and, under
contralateral lung is multiplied by the preoperative       appropriate clinical circumstances, biopsy.
forced expiratory volume in 1 second (FEV1) to predict
postoperative FEV1 for patients undergoing pneumo-
nectomy. A postoperative FEV1 of 40% of predicted          DIAGNOSTIC TECHNIQUES
suggests the patient should tolerate resection from a
pulmonary perspective.97 Bone scan and 18F-FDG-PET         An accurate tissue diagnosis is an essential early step in
are useful in investigating bony metastases in patients    the management of lung cancer because of its therapeutic
with bone pain, hypercalcemia, increased alkaline          and prognostic import. Biopsy procedures are not always
phosphatase, and/or pathologic fractures. Of these three   required before surgical therapy, but are conducted in
techniques, 18F-FDG-PET is the most sensitive and          most patients suspected of lung cancer since clinical and
has the additional advantage of identifying other areas    radiographic findings are not uniquely assigned to SCLC
of intra- and extrathoracic metastases. Abnormalities      or NSCLC. Various techniques are available to obtain
identified with these techniques will require further      tissue for cytologic and histopathologic analysis.
90 Textbook of Lung Cancer

(a)                                                 (c)                          Figure 8.6
                                                                                 18F-FDG-PET scan with CT fusion
                                                                                 demonstrating a primary adenocarci-
                                                                                 noma involving the left upper lobe with
                                                                                 ipsilateral mediastinal lymph node
                                                                                 metastasis (a), and left adrenal mestasta-
                                                                                 sis (b). (c) Coronal 18F-FDG-PET without
                                                                                 CT fusion demonstrating mediastinal and
                                                                                 extrathoracic (left adrenal) involvement.
                                                                                 CT-guided biopsy of the left adrenal
                                                                                 confirmed metastatic adenocarcinoma
                                                                                 with stage IV NSCLC assigned. (See color
                                                                                 plate section, page xiv)


Sputum examination                                          consecutive early morning samples or a three-day pooled
                                                            sputum specimen are generally recommended.100 A spu-
Sputum cytology
                                                            tum sample can be obtained spontaneously or induced,
Sputum cytology is a non-invasive method to obtain a
                                                            and is considered representative if bronchial epithelial
diagnosis in appropriate situations.98 The yield depends
                                                            cells or alveolar macrophages are present. Overall diag-
on the ability of the patient to produce acceptable spu-
                                                            nostic yield appears highest with specimens collected
tum, tumor size, location of the tumor in relation to
                                                            spontaneously, except in the setting of peripherally
major central airways, and the skills of the cytopatholo-
                                                            based cancers where induced specimens appear more
gist. The average sensitivity is approximately 65%, with
                                                            informative.101,102 Abnormal findings may also result
sensitivities ranging from 22 to 98% reported.99 Most
                                                            from concurrent pulmonary infections (false-positives)
studies, although not all, show decreased sensitivity for
                                                            or unsuspected head and neck cancers.
the diagnosis of peripherally based nodules and masses,
with an overall sensitivity of 71% for central and 49%      Sputum cytometry
for peripheral lesions.99 The appropriate number of         Recent data suggest that the yield of sputum cytology
specimens to collect remains unclear, but one to three      may be improved through the use of molecular, genetic,
                                                                                 Clinical diagnosis and basic evaluation 91

and immunocytochemical markers of malignancy.                specimens. TBNA should be obtained before sampling
Studies evaluating archived sputum specimens collected       other endoscopically visible lesions to avoid false-positive
as part of lung cancer screening programs have shown         results. Bleeding is a very infrequent complication of
that abnormal cells may be identified as early as twenty     TBNA. Autofluorescence bronchoscopy exploits the
months prior to the diagnosis of lung cancer using these     difference in fluorescence properties between normal
techniques. Xing and colleagues103 further demon-            bronchial mucosa and that of invasive and pre-invasive
strated a twenty-fold improvement in sensitivity over        disease. The best-known device uses a helium-cadmium
sputum cytology alone using automated cytometric             laser (442-nm wavelength) and an optical multichannel
techniques. They were able as well to detect severe dys-     analyzer in place of the standard white light source,
plasia/carcinoma in situ lesions and correctly identified    with normal mucosal surfaces having a green coloration
over 70% of peripherally based cancers. A sensitivity of     whereas premalignant and malignant lesions appear
75% and specificity of 98% has been shown for semi-          reddish in color. A prospective, multicenter trial dem-
automated sputum cytometry in the diagnosis of lung          onstrated an increase in the detection of preinvasive
cancer in a multinational study.104 These results have       disease with the use of autofluorescence by a factor of
sparked interest in the implementation of this tech-         2.1 when compared to white light bronchoscopy
nique as part of a co-ordinated lung cancer screening        alone.110 Bronchoscopy in COPD patients confers only
process.                                                     a slightly increased risk if obstruction is severe.

Flexible fiberoptic bronchoscopy                             Transthoracic needle aspiration
Flexible fiberoptic bronchoscopy is commonly used for        Peripheral lesions or those with extension to the medi-
diagnostic and staging purposes. Endoscopically visible      astinum, chest wall, or pleura may also be sampled by
abnormalities are approached with traditional biopsy         fluoroscopically or CT-guided transthoracic needle
forceps, brushings, and washings. Transbronchial nee-        aspiration (TTNA). Suspicious peripheral lesions are
dle aspirations (TBNAs) may also be performed on sub-        sometimes directly resected for diagnosis and treatment
mucosal tumors or those causing extrinsic bronchial          if surgery would be the anticipated maneuver regard-
compression. The yield from an endoscopically visible        less of TTNA results. However, TTNA may be applied
lesion should be in excess of 80%. Peripheral lesions        when a tissue diagnosis is needed but the patient can-
are sampled with fluoroscopically guided transbron-          not or will not undergo surgery, the patient is
chial biopsies, brushings, and washings. Lesion size is      undecided about surgery pending tissue confirmation
the primary determinant of outcome, with yields of           of cancer, or fiberoptic bronchoscopy was non-diagnostic.
25% reported for malignant lesions under 2 cm, 60–70%        Yields above 90% have been reported.111,112 Pneumotho-
for lesions >2cm, and 80% for lesions >4 cm.105              rax is the main complication, occurring in up to 30% of
Yield, particularly for lesions <2 cm, may be increased      cases, yet less than 15% typically require a chest tube.
with the use of electromagnetic navigation bronchos-         Tumor seeding of the biopsy tract is a very rare compli-
copy, with a recent study demonstrating 74% diagnos-         cation. Increased risk situations for TTNA include
tic yield for peripheral lesions in this size range.106      bullous emphysema in the region to be biopsied, lesions
Transbronchial lung biopsies should detect lymphan-          located away from the pleural surface, a poorly coop-
gitic spread of malignancy. For staging purposes, bron-      erative patient, and underlying lung disease whose
choscopy may occasionally detect synchronous lesions,        impact would significantly increase if pneumothorax
assess proximal extent of tumor, and facilitate sampling     developed. There is a substantial false-negative rate
of paratracheal, subcarinal, and hilar lymph nodes by        (20–30% of patients with a negative TTNA may have a
TBNA.                                                        malignant lesion)37 so indeterminate or negative TTNA
   Traditional TBNA sensitivity is 50%, with a specificity   results must not be interpreted as a diagnostic end-
of 90% for mediastinal staging.107 However, guidance         point. A repeat TTNA is diagnostic in 35–65% of cas-
using endobronchial ultrasound (EBUS) increased the          es.37 Percutaneous radiologic-guided needle aspiration
sensitivity to 94% in one study of 500 patients.108 EBUS     is used to confirm metastases to liver, bone, and
also appears superior to CT in differentiating airway        adrenals.
tumor infiltration from extrinsic compression.109 Chest
CT should be obtained before TBNA to help guide the          Endoscopic ultrasound
attempts. Use of 19-gauge needles improves sensitivity       The linear array echoendoscope was introduced in the
by allowing procurement of cytologic and histologic          mid-1990s and is gaining popularity due to its ability to
92 Textbook of Lung Cancer

permit fine-needle aspiration of mediastinal abnormali-     OVERVIEW OF BASIC EVALUATION
ties from a transesophageal approach that are not easily
accessed by bronchoscopy or mediastinoscopy. Endo-          The purpose of the basic evaluation is to efficiently and
scopic ultrasound (EUS) easily identifies vascular struc-   accurately establish the diagnosis and initial extent of
tures and is useful in sampling tissue from inferior and    lung cancer. Aspects of this process are influenced by
posterior mediastinal (station 8, 9), aortopulmonary        local practice biases. The core elements include a careful
window (station 5, 6), and subcarinal (station 7) lymph     history and physical exam, posteroanterior and lateral
nodes. Lobar (station 12), interlobar (station 11), and     chest radiographs, and basic blood tests, including com-
anterior tracheal nodes (station 3) are not well evalu-     plete blood count and chemistry profile (especially elec-
ated by EUS. In a study of 26 patients undergoing           trolytes, serum calcium, alkaline phosphatase,
transesophageal biopsy performed with EUS and fine-         glutamic-oxaloacetic transaminase, albumin, total biliru-
needle aspiration the overall sensitivity for the diagno-   bin, and creatinine).36 While the cost-effectiveness of the
sis of malignancy was 89% and the specificity was 83%,      blood tests can be debated, they may suggest metastatic
with a positive predictive value of 100% and a negative     disease, paraneoplastic phenomena, or co-morbidities.
predictive value of 75%.113 Recent studies further sug-     Chest CT with extension to upper abdominal CT is rou-
gest that EUS may be superior to CT and PET in estab-       tinely obtained to define the primary lesion and locore-
lishing mediastinal staging of NSCLC,114,115 and may be     gional extent of disease. 18F-FDG-PET scanning plays an
superior to mediastinoscopy in sampling paratracheal        additive role in addressing the solitary pulmonary nod-
and subcarinal nodes.116                                    ule and should be included when investigating mediasti-
                                                            nal and extrathoracic metastases from a known NSCLC.
Thoracic surgery techniques                                 Testing for extrathoracic metastases is pursued as directed
Cervical mediastinoscopy and anterior mediastino-           by the initial information. Biopsy of suspected metastases
tomy have been the traditional routes by which histo-       may allow simultaneous diagnosis and staging. For
logic verification of mediastinal metastases has been       peripheral chest lesions the diagnostic options are TTNA,
obtained. These are safe procedures whose findings          bronchoscopy, VATS, or thoracotomy. It is unclear
may obviate the need for further surgery in NSCLC           whether TTNA or bronchoscopy is the better initial
patients. Cervical mediastinoscopy allows sampling of       choice. TTNA may enjoy a higher yield for smaller
the right paratracheal and subcarinal nodes, while          lesions, but also a higher complication rate. Bronchos-
anterior mediastinotomy accesses the left paratracheal,     copy allows for endobronchial visualization and would
supra-aortic, and aortopulmonary window nodes.37 It         still be performed at the time of thoracotomy if TTNA
remains controversial whether mediastinal sampling          were positive. For central lesions or hemoptysis with
should be routinely performed before all surgery for        negative chest film, sputum cytology is also an option,
NSCLC. Many surgeons may forego mediastinoscopy             and bronchoscopy is usually favored over TTNA.
in patients with radiographic T1N0 disease due the             Additional pulmonary testing may be necessary if
relatively low prevalence (5–15%) of nodal metastases       surgical resection is considered. Given the common
in this group. 18F-FDG-PET may have a role in these         etiologic thread of smoking, it is not surprising that
patients, allowing those without evidence of mediasti-      80–90% of lung cancer patients also have COPD,
nal involvement to avoid mediastinal lymph node             20–30% with severe disease.118 Lung resection, inci-
sampling, although PET combined with CT may still           sional pain, medical appliances, and postoperative use
miss up to 5% of mediastinal micrometastases.117 Vid-       of sedatives and analgesics impact negatively on lung
eo-assisted thoracoscopic surgery (VATS) is a more          function and defense. Preoperative spirometry and dif-
recent, less invasive technique for sampling of indeter-    fusing capacity (DLCO) should be obtained. Patients with
minate peripheral nodules, pleural thickening and           FEV1 >1.5–2 l, maximal voluntary ventilation (MVV)
effusions, and mediastinal/hilar lymph nodes. Scalene       >50% predicted, and DLCO >60% predicted can proceed
or supraclavicular lymph node biopsy is an appropri-        to thoracotomy. Patients below these values may need
ate diagnostic and staging procedure in the setting of      to undergo a more thorough examination that includes
clinically significant enlargement. The patient with a      quantitative V/Q lung scanning and/or exercise testing
suspicious lesion (enlarging or spiculated nodule)          with evaluation of maximum oxygen uptake. Although
without evidence of metastatic disease may go               no value categorically precludes surgery, predicted
directly to thoracotomy for definitive diagnosis and        postoperative FEV1 <40% of predicted, hypercapnia
treatment.                                                  (PCO2 >45), or maximal oxygen consumption <10 ml/
                                                                                           Clinical diagnosis and basic evaluation 93

kg/min during exercise testing predicts significant post-            2. Thun MJ, Jemal A. How much of the decrease in
operative problems.119 The use of VATS and limited                      cancer death in the United States is attributable to reductions
                                                                        in tobacco smoking? Tobacco Control 2006; 15: 345–7.
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survival versus those enjoyed with resectable stage I                6. Tockman MS, Anthonisen NR, Wright EC et al. Airways
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earlier lung cancer detection and more accurate staging.                1987; 106: 512–18.
The recent use of spiral CT scanners allows for extremely            7. Lee DJ, Fleming LE, Leblanc WG et al. Occupation and lung
                                                                        cancer mortality in a nationally representative U.S. Cohort:
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extent whether CT screening is adopted as a viable                      evidence-based clinical practice guidelines. Chest 2006; 129:
standard screening modality. Sputum cytometry and                       147–53S.
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                                                                        chest roentgenogram. Chest 1988; 93: 70–5.
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    9         Staging, classification, and prognosis
              Michael Dusmet, Peter Goldstraw

              Contents Introduction • The staging system • The staging process • The staging tests • Restaging after
              induction chemotherapy • Other prognostic indicators • Prognosis

INTRODUCTION                                                  first step at thoracotomy using rapid, ‘frozen section’
                                                              histology prior to proceeding with treatment by pulmo-
It is logical that this chapter should fall between the       nary resection.
preceding one on diagnosis and evaluation and those              Thus staging has several objectives, some patient
that follow on the treatment modalities for non-small         orientated and some disease centered. Precise staging
cell lung cancer (NSCLC) and small cell lung cancer           will allow the clinician to offer the individual patient
(SCLC). At its most simplistic, ‘staging’ is the process by   the best treatment, on the basis of the understanding
which the clinician examines and describes the local,         of prognosis that derives from the stage. Staging
regional, and distant extent of the cancer. This precise      allows clinicians to evaluate the results of different
information is then used to determine the appropriate         treatment regimens and to exchange and compare them
therapy for a patient diagnosed to have lung cancer.          between different centers. This also allows new treat-
However, staging should not be thought of as a set of         ment strategies to be assessed. Finally it allows us to
investigations that are performed between diagnosis           evaluate in an on-going manner the results of staging
and treatment. Many of the tests that are undertaken to       modalities.
establish the diagnosis, such as chest radiography,              We will consider the separate aspects of staging: the
bronchoscopy, and pleural aspiration cytology, provide        ‘staging system’, the ‘staging process’, and the ‘staging
valuable information as to stage. Often the choice of         tests’.
test by which to establish the diagnosis will be made on
the basis of the clinician’s assessment of the probable
stage of the disease. In this context, obviously taking       THE STAGING SYSTEM
into account the financial cost and the potential mor-
bidity of every procedure, it is desirable to undertake       The International Staging System (ISS) for lung cancer
first the test that will prove the highest stage. For exam-   is the TNM Classification of Malignant Tumors, admin-
ple, if a patient has a lung lesion and a probable adrenal    istered by the International Union Against Cancer
metastasis, biopsy of the adrenal will, if positive, pro-     (UICC).1 This provides a recognized shorthand to
vide both a tissue diagnosis of cancer and the stage          describe the extent of the disease, in which the
(M1).Tests undertaken to decide stage proceed in par-         T descriptor indicates the extent of the primary tumor,
allel with those required to establish the diagnosis and      the N descriptor the extent of lymph node involvement,
others to assess patient fitness for possible treatment       and the M descriptor the presence or absence of distant
options, often interweaving and providing information         metastases. For each descriptor, advancing numeric
across these categories. Tests may have to be repeated        subscripts are allocated for progressively advancing
if undertaken without sufficient foresight to look            disease. The latest revision of the ISS was published in
beyond the diagnosis and consider the consequential           1997,2,3 and integrated into the sixth edition of the
issues of treatment. Sometimes treatment may be rec-          UICC TNM Classification of Malignant Tumors manual
ommended after staging and before a firm diagnosis. A         in 2002.4 The next revision of the staging system is
surgeon may ‘stage’ a patient and recommend thoraco-          due to be published early in 2009. The descriptors as
tomy with only the strong clinical–radiographic suspi-        presently defined are listed in Table 9.1. A more precise
cion of lung cancer and without pursuing the diagnosis        definition of the boundaries and definitions can be found
to a cytologic or histologic conclusion. In such circum-      in another article by Dr Mountain.5 The definition
stances the surgeon will establish the diagnosis as the       of the great vessels includes the aorta, the vena cava,
98 Textbook of Lung Cancer

 Table 9.1 TNM descriptorsa

 Primary tumor (T)
 TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or
     bronchial washings but not visualized by imaging or bronchoscopy
 T0 No evidence of primary tumor
 Tis Carcinoma in situ
 T1 Tumour ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence
     of invasion more proximal than the lobar bronchusb (i.e. not in the main bronchus)
 T2 Tumor with any of the following features of size or extent:
     • >3 cm in greatest dimension
     • involves main bronchus, ≥2 cm distal to the carina
     • invades the visceral pleura
     • associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve
         the entire lung.
 T3 Tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors),
     diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main bronchus <2 cm distal to the
     carina, but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the
     entire lung
 T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus,
     vertebral body, carina; or tumor with a malignant pleural or pericardial effusion,c or with satellite tumor
     nodule(s) within the ipsilateral primary-tumor lobe of the lung
 Regional lymph nodes (N)
 NX Regional lymph nodes cannot be assessed
 N0 No regional lymph node metastasis
 N1 Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes
      involved by direct extension of the primary tumor
 N2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
 N3 Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular
      lymph node(s)
 Distant metastasis (M)
 MX Presence of distant metastasis cannot be assessed
 M0 No distant metastasis
 M1 Distant metastasis presentd
   Reproduced with kind permission of Dr CF Mountain and the Editor of Chest.2
   The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also
 classified T1.
   Most pleural effusions associated with lung cancer are due to tumor. However, there are a few patients in whom multiple cytopathologic examinations of pleural
 fluid show no tumor. In these cases, the fluid is non-bloody and is not an exudate. When these elements and clinical judgement dictate that the effusion is not
 related to the tumor, the effusion should be excluded as a staging element and the patient’s disease should be staged T1, T2, or T3. Pericardial effusion is classified
 according to the same rules.
   Separate metastatic tumor nodule(s) in the ipsilateral non-primary-tumor lobe(s) of the lung are also classified M1.

and their main intrathoracic branches and tributaries.                                     For convenience, TNM subsets with similar survival
The point at which the pulmonary vessels become great                                   prospects and for which treatment options would be
vessels (a T4 descriptor) is the pericardium: the intra-                                similar are combined into stage groups (Table 9.2)
pericardial portions of these vessels are considered to                                 and the example given above would be assigned to
be great vessels. As an example, a tumor of 5 cm in diam-                               stage IV.
eter, involving the ipsilateral mediastinal lymph glands                                   Staging is done at various time points during the
and with an additional pulmonary nodule, believed to                                    patient’s journey through preliminary investigations
be malignant, in the contralateral lung would be                                        and then treatment. It is important to know when
described as T2N2M1.                                                                    staging is done so as to compare like with like when
                                                                                               Staging, classification, and prognosis 99

 Table 9.2    Stage grouping: TNM subsetsa,b
                                                                         Malignant Tumors brought to the staging system for
                                                                         lung cancer in 1997 as many studies on induction/
 Stage                                         TNM subset                neo-adjuvant therapy were designed and/or imple-
 0                                        Carcinoma in situ              mented before that year. The four main differences are:
 IA                                           T1N0M0
                                                                         (1) that stages I and II were subdivided, respectively,
 IB                                           T2N0M0
                                                                             into stages IA, IB and IIA, IIB; these reflect the
 IIA                                          T1N1M0
                                                                             increase in size of the tumor from T1 to T2 (i.e. ≤
 IIB                                          T2N1M0
                                                                             or >3cm in diameter);
                                                                         (2) stage T3N0M0 was moved from stage IIIA to IIB as
 IIIA                                         T3N1M0
                                                                             the five-year survival is more akin to this latter
                                                                         (3) separate nodules within the same lobe were assigned
                                                                             to the T4 category; and
 IIIB                                         T4N0M0
                                                                         (4) separate nodules in other, ipsilateral lobes and the
                                                                             contralateral lung were included in M1 disease.
                                              T2N3M0                        Many clinicians feel that such detailed staging is
                                              T3N3M0                     irrelevant for SCLC, and consider that a cruder division
                                              T4N3M0                     into ‘limited’ and ‘extensive’ disease allows clinical deci-
 IV                                       Any T Any N M1                 sions to be made on treatment.6 There are two defini-
                                                                         tions: from the Veterans Administration Lung Study
  Staging is not relevant for occult carcinoma, designated TXN0M0.
                                                                         Group (VALG) and from the International Association
  Reproduced with the kind permission of Dr CF Mountain and the Editor
 of Chest.2
                                                                         for the Study of Lung Cancer (IASLC). In the former,
                                                                         limited disease (LD) is defined as tumor which is
                                                                         restricted to one hemithorax, often including the ipsi-
                                                                         lateral supraclavicular fossa, basically a single radio-
evaluating different treatment regimens. The initial, pre-               therapy field, whilst any wider-spread disease, including
treatment, stage is the clinical/evaluative stage, or                    distant metastases, is considered as extensive disease.
cTNM. This may integrate the information obtained                        In the IASLC staging system all patients without distant
from imaging and bronchoscopy as well as, for exam-                      metastases are considered to have LD, including those
ple, the histopathology from a fine needle aspiration                    with a malignant pleural effusion and all patients
biopsy (FNAB) of a distant metastasis. Obviously, with                   with contralateral mediastinal and/or supraclavicular
the addition of information obtained at surgery and the                  lymph node metastases to be included in the LD cate-
pathologic examination of the resection specimen, the                    gory. It has been shown that the IASLC staging system
postsurgical/pathologic stage known as the pTNM will                     is a better discriminator of survival.7 Whilst this dis-
be more accurate. (See comments later on ‘stage migra-                   tinction is certainly sufficient for the vast majority of
tion’.) The ‘y’ prefix is used when the patient is restaged              sufferers with this cell type the TNM stage remains rel-
after induction or neo-adjuvant therapy (induction                       evant for the fortunate patient with unusually localized
therapy being a treatment modality aimed at rendering                    disease (stage I essentially, possibly stage IIA) for whom
an inoperable stage tumor operable; the goal of neo-                     surgical therapy or multimodality therapy should be
adjuvant therapy is to improve the survival rate of an                   considered.5,8
operable tumor). This can be used in conjunction with
the ‘c’ and ‘p’ prefixes. Thus ycTNM would reflect the
clinical restaging after induction or neo-adjuvant ther-                 THE STAGING PROCESS
apy and ypTNM the pathologic (i.e. postsurgical) stage
after similar presurgical chemo- and/or radiotherapy.                    The clinician is confronted with a bewildering array of
The ‘r’ prefix is used for the staging of recurrent tumors               tests which may, when used appropriately, provide
and the ‘a’ prefix for autopsy findings.4                                information as to the extent of disease and therefore
   It is important to understand the principle differ-                   permit one to stage the patient and advise on therapy.
ences the fifth edition of the TNM Classification of                     The value and place of each test will be discussed in the
100 Textbook of Lung Cancer

next section. The clinician may utilize any and all such     Manual for Staging of Cancer, produced by the American
tests to construct a clinical/evaluative TNM stage           Joint Committee on Cancer Staging and End Results
(cTNM). Such tests may include surgical exploration          Reporting.15 This is most usually done after surgical
such as mediastinoscopy and video-assisted thoracos-         resection. The designation R is used to define this. RX
copy (VATS) undertaken prior to a decision to recom-         indicates that it is not possible to evaluate the presence
mend treatment. It is as well to remember that as one        of residual disease. R0 indicates that no residual disease
proceeds with this information-gathering exercise, the       remains, i.e. that there was a complete resection with all
tests become increasingly costly and more invasive.          resection margins through normal, non-tumoral tis-
Once sufficient information has been collected as to         sues. R1 indicates that microscopic residual tumor
permit a decision regarding treatment, then further          remains and R2 signifies that there is macroscopic
tests become obtrusive and unwarranted. The difficulty       residual tumor after what must be considered an incom-
for the clinician is to know where to draw the line and      plete resection. Most workers interpret the R1 status as
to decide that the evidence is sufficiently reliable as to   applying to the case where the resection margins are
make the case for a particular treatment.                    unexpectedly positive on subsequent histologic exami-
   There can be no rigid protocol for staging and the        nation of the resection specimen. Honest surgeons will
clinician will decide the next step based upon the over-     also use this descriptor when tumor tissue has been
all picture as it emerges as each step provides additional   cleaved off remaining structures. This classification is
information. For most clinicians the critical point in the   not part of the staging system but represents good prac-
staging process is reached once the patient’s disease has    tice. The 2005 IASLC guidelines define the requirements
been shown to be too extensive to permit surgical treat-     of complete resection.16 These require histologically
ment. The oncologist or radiotherapist might still con-      proven free resection margins, complete lymph node
sider other staging tests to be important in defining the    clearance (vide infra) with no extracapsular spread in
most appropriate regimen. If the patient comes through       the nodes, and disease-free highest mediastinal node.
the assessment of the clinician and is still considered      We believe that at least six lymph node stations (three
operable, the surgeon may wish to define the stage           N1 and three N2) need to be completely resected (as
more precisely before making a final decision to oper-       opposed to sampled) to qualify as lymph node clear-
ate. As this frequently involves a decision as to the        ance, as specified in the European Society of Thoracic
probable extent of resection, and the use of surgical        Surgeons (ESTS) guidelines for intraoperative staging.17
investigations such as mediastinoscopy, this step should     When the resection margins are free but all of these
be left to the surgeon.                                      criteria are not met, or if there is carcinoma in situ at
   The issue as to which tests are considered the mini-      the bronchial resection margin, or if the pleural lavage
mum necessary to establish cTNM has been considered          cytology is positive, then the term ‘uncertain resection’
by the IASLC, and is one that is regularly updated at        should be used.
their workshops.9,10 The American Thoracic Society and          As time passes the disease may recur or progress and
the European Respiratory Society have accepted similar       additional tests may be indicated to establish a retreat-
recommendations.11 More recent guidelines have been          ment or rTNM. Some would consider that our ultimate
published by the American College of Chest Physicians        insight into the extent of disease is realized at autopsy,
(ACCP) in 2003,12 and by the National Institute for          when a TNM can be created. However, time is the ulti-
Health and Clinical Excellence (NICE) in the UK in           mate test and our understanding of disease progression
2005.13 A summary of these recommendations is shown          is curtailed by death, preventing the development of
in Table 9.3.                                                clinically relevant disease that could be overlooked at
   Once a decision has been made as to treatment, the        autopsy.
cTNM assigned to that patient should not be changed             In summary, the first step in the evaluation of a
in the records. As alluded to above, additional informa-     patient with suspected lung cancer is to take a very
tion will accumulate if the patient proceeds to thoraco-     careful history and perform a thorough physical exami-
tomy and pulmonary resection. This will allow the            nation. Chest radiographs and computerized tomo-
pTNM to be established. This should be recorded sepa-        graphic (CT) scans (chest and abdomen to include the
rately, and does not replace the cTNM.                       entire liver and both adrenals) are then obtained. Bron-
   The UICC4 allows and recommends that a record             choscopy will usually be performed at this time, espe-
be made of the assessment of residual disease after          cially if the tumor is centrally located. If there is a
treatment. This is also the recommendation in the            suspicion of brain metastases appropriate imaging will
                                                                                 Staging, classification, and prognosis 101

Table 9.3 Pretreatment minimal staging6,9,11,12

Step 1
Investigation                                     Patient group     Confirmatory tests
Clinical history           Weight loss and        All patients      As appropriate
                           performance status
Clinical examination                             All patients       As appropriate
Chest radiographs         PA                     All patients       Aspiration of any effusion
                          Lateral                                   (considered positive if cytology malignant)
Blood tests               Hb                     All patients       As for high-risk patients in
                          Alk phosphatase                           Step II
                          Lactate dehydrogenase
If still thought suitable for curative therapy proceed to Step II

Step II
Investigation                  Patient group               Confirmatory tests
Bronchoscopy                   All patients with central   The features of proximal, extrinsic
                               tumors or those in whom     compression are unreliable and require
                               central extension is        further evaluation of the mediastinum by
                               suspected                   CT and/or mediastinal exploration
CT chest and upper             All patients if available   Dubious findings confirmed (not
abdomen (to lower                                          necessarily histologic)
pole of kidneys with
iv contrast enhancement
of mediastinal vessels)
Liver ultrasound              High risk groupa if CT
                              of abdomen not available
Brain assessment by           Advisable in high risk groupa
MRI (or CT if MRI not
  High risk patients are those having non-specific features identified by Hooper et al.14
• Unexplained anaemia (Hb <11%)
• Unexplained weight loss (>8 lb (3 kg) in 6 months)
• Abnormal alk phosphatase, or transaminase
• Where any clinical suspicion of metastatic disease exists
• Patients with stage III disease
If still thought suitable for curative treatment proceed to Step III

Step III
Investigation                                       Patient group
(a) PET-CT                                          All patients
(b) Bone scan only if PET not available             Skeletal X-rays ± CT/MRI of bone if dubious positive result
(c) Bronchoscopy if not previously                  All patients
(d) Thoracoscopy (video-assisted)                   If pleural effusion present and cytology negative but clinical
                                                    suspicion remains, do a pleural biopsy

102 Textbook of Lung Cancer

 Table 9.3 Continued

 (e) Mediastinal exploration
   • It is recommended that this
     is performed pre-operatively by:
     • Transtracheal or transesophageal         Patients in whom CT suggests mediastinal
          aspiration                            invasion or if CT shows aspiration nodes >1.0 cm in Short
                                                axis diameter
     • Cervical mediastinoscopy                 Same
     • Additional evaluation of the             The above groups with tumors of the left upper
         subaortic fossa by left anterior       lobe or left main bronchus if suspicion of station
         mediastinotomy or VATS                 5 or 6 metastases on CT or PET
   • This must be performed                     All patients – including those whose
     intra-operatively                          mediastinum has been assessed preoperatively
                                                • Palpation insufficient
                                                • Careful and extensive mediastinal
                                                    dissection (‘systematic nodal
                                                • Separate labeling as per Naruke
                                                    or ATS of excised nodes for
                                                    subsequent histologic examination
                                                    (only N1 nodes on resection
                                                • Re-evaluation of T stage:
                                                    completion of intra-operative
                                                    staging of tumor and pleural
     Proceed with definitive therapy, which will be surgical resection in all but the most unusual

be obtained (preferably magnetic resonance imaging            remind ourselves of the importance of good clinical
(MRI) – vide infra). If the patient is a candidate for rad-   acumen. All of our elaborate scans have to be directed
ical (i.e. ‘curative’) therapy then a positron emission       by clinical assessment and interpreted in the light of
tomography (PET)-CT should be obtained.13 While this          this.
staging process is being undertaken the functional eval-
                                                              Clinical history and examination
uation of the patient can be carried out so that at the
                                                              These remain the most basic and most cost-effective
end of this process a treatment decision can be made. If
                                                              assessments of disease extent. The clinician, whilst
the treatment decision is to give the patient induction
                                                              enquiring as to symptoms of the primary tumor, will be
therapy this process will need to be repeated at the term
                                                              looking to assess performance status and co-morbid
of the induction therapy so as to determine the logical
                                                              conditions. Watching the patient come into the consul-
next step.
                                                              tation room and careful enquiry into his/her functional
                                                              status and exercise tolerance will determine the patient’s
THE STAGING TESTS                                             ability to undergo aggressive treatment, be it surgery,
                                                              chemotherapy, or radiotherapy. Investigations may be
Lung cancer is dealt with nowadays by teams which             curtailed in a very unfit patient because their results
comprise pulmonary physicians, surgeons, oncologists,         will not influence treatment choices. The performance
radiotherapists, palliative care physicians, radiologists,    status (Table 9.4) of every patient should be recorded
pathologists, and numerous support staff. In the UK           at the first clinical visit.
this is known as the multidisciplinary team (MDT). In            A few questions are critical to assess stage. The pres-
an age of technologic progress it is often necessary to       ence of chest wall pain is more accurate at determining
                                                                                 Staging, classification, and prognosis 103

 Table 9.4 ECOG performance status142
                                                             the inclusion criteria for the study (patients with ‘oper-
                                                             able’ NSCLC vs all patients with suspected or proven
 Grade    ECOG performance status                            NSCLC vs patients with suspected N2 disease) as this
 0        Fully active, able to carry on all predisease      has an obvious impact on the incidence of N3 disease
          performance without restriction                    detected by this investigation. Thus in one study of
 1        Restricted in physically strenuous activity        ‘operable’ patients with NSCLC this technique proved
          but ambulatory and able to carry out work          N3 disease by virtue of supra-clavicular lymph node
          of a light or sedentary nature, e.g. light         metastases in 8% of patients, but this led to upstaging
          house work, office work                            of only 4%.19 In a study of patients with lung cancer at
 2        Ambulatory and capable of all self-care but        any stage, 31% were found to have supra-clavicular
          unable to carry out any work activities; up        lymph node metastases in non-palpable nodes.20 This
          and about more than 50% of waking hours            was the same frequency as probable or proven adrenal
 3        Capable of only limited self-care, confined        metastases and the supra-clavicular lymph node metas-
          to bed or chair more than 50% of waking            tases were often associated with mediastinal lymphade-
          hours                                              nopathy and/or other distant metastatic disease. This
 4        Completely disabled; cannot carry out any          study also showed that US was superior to CT in detect-
          self-care; totally confined to bed or chair        ing non-palpable supra-clavicular lymph node metasta-
 5        Dead                                               ses. Finally, the yield was again very low in otherwise
                                                             apparently operable patients with NSCLC. In one study
                                                             of patients with NSCLC and probable stage N2 disease,
                                                             46% of patients were found to have supra-clavicular
chest wall invasion than a CT scan. The presence of          lymph node metastases, and this obviated the need for
unexplained weight loss should alert the clinician to        other staging procedures in 42%.21 These results have
the increased possibility of disseminated disease in such    two implications. First it means that US-guided FNAB
patients. A patient may well dismiss weight loss as          of supra-clavicular lymph nodes will obviate the need
attributable to changes in diet and a deliberate attempt     for more invasive staging procedures in a significant
at weight reduction. Further enquiry may show that           number of patients, sparing them the risks of the pro-
repeated previous attempts at weight reduction have          cedure and making considerable cost savings for the
failed without the assistance of disseminated malig-         health-care economy. Second, it will upstage a signifi-
nancy! The patient coming to see a chest specialist will     cant number of patients, and this can have considerable
not volunteer the recent onset of bone pain, assuming        therapeutic consequences as in many cases this will
it to be degenerative or traumatic in nature, and may        mean a shift from so-called curative treatment modali-
assume that hoarseness is due to the trauma of cough-        ties to a more palliative approach. However, the yield
ing. Similarly, patients and their relatives may rational-   and benefit are greatest in patients who are already sus-
ize the change in personality as due to anxiety after        pected of having at least stage IIIA disease, and the
hearing the diagnosis and dismiss neurologic symptoms        yield in patients with stage I and II disease is much more
as due to minor nerve damage.                                limited, making its routine application for this subset of
   A careful examination should focus upon any ques-         patients much more debatable. This finding was con-
tions raised in the history and also routinely examine       firmed in another study in which only 3/117 patients
for cervical lymphadenopathy and hepatomegaly. One’s         were upstaged by supra-clavicular US-guided biopsy of
ability to detect enlarged neck nodes improves with          non-palpable lymph nodes.22
practice and this important examination should not be
designated to the most junior member of the team.            Chest radiography
   Examination of the supra-clavicular fossa with ultra-     This is usually the starting point in further evaluation.
sound (US)-guided FNAB is becoming increasingly              Whilst it usually provides clues as to the diagnosis, it
popular and does detect a number of otherwise unsus-         also gives valuable staging information as to tumor size
pected lymph node metastases, which are very impor-          and possible local invasion.23 It is as well to check the
tant as they are an N3 determinant (stage IIIB). When        radiograph for rib erosion, elevation of the hemidia-
reading the literature on routine US screening of the        phragm, the presence of other lung nodules, or evi-
supra-clavicular fossa it is important to determine          dence of an effusion (Figure 9.1). The presence of such
the prevalence of nodal disease, which will be related to    features may allow one to cut short the process of
104 Textbook of Lung Cancer

                                                                        the surgeon will wish to examine the airway with respi-
                                                                        ration suspended under general anesthesia, often using
                                                                        the rigid bronchoscope with its wider field of view and
                                                                        facility for larger biopsies. Bronchoscopy also allows
                                                                        the clinician to rule out other small endobronchial
                                                                        tumors and demonstrates anatomic variants of bron-
                                                                        chial anatomy to the surgeon.

                                                                        Computerized tomography
                                                                        CT has greatly aided the staging of lung cancer and the
                                                                        proliferation of CT scanning facilities attests to the
                                                                        enormous value of this investigation. However, much
                                                                        depends upon technical aspects of the scanner, the pro-
                                                                        tocol used for the study, and the experience of the radi-
                                                                        ologist.25 CT scans of the chest provide an enormous
                                                                        amount of three-dimensional information as to disease
                                                                        extent. One can analyze the individual components of
Figure 9.1                                                              the scan, assessing the accuracy with which CT can
The chest radiograph of a patient with a mass in the right upper
lobe (arrow). The film also shows gross widening of the superior
                                                                        detect mediastinal gland involvement, mediastinal inva-
mediastinum (arrow head), strongly suggestive of mediastinal            sion, chest wall invasion, the presence of additional
nodal disease, but there is also a right pleural effusion. Aspiration   pulmonary nodules, or deposits in the abdominal
cytology of the effusion gave the diagnosis of adenocarcinoma,          organs or brain. However, in reality the value of the
allowed staging of the disease as T4 (stage IIIB), and also showed
                                                                        information provided by CT scanning is far greater than
the patient to be inoperable.
                                                                        the sum of its component parts. The three-dimensional
                                                                        construct helps the surgeon anticipate the possible
                                                                        extent of resection, the technical problems that may be
assessment by establishing the diagnosis and staging                    encountered, and the areas to inspect for possible tumor
the patient with a single investigation, such as pleural                extension. The surgeon can use such information in
aspiration cytology. The posteroanterior and lateral                    evaluating the patient’s fitness for such extended sur-
films can also be useful for tumor localization in rela-                gery, to guide intraoperative assessment, and to plan
tion to the fissures.                                                   the operative strategy to deal with likely areas of exten-
                                                                        sion or concern. It does not matter to the surgeon that
Hematologic parameters                                                  such areas of concern may prove to be fallacious, it is
Parameters such as anemia, disturbance of liver enzymes,                better to be prepared, but for the clinician the lack of
or elevation of serum alkaline phosphatase are reliable                 specificity must be an ever-present concern in evaluat-
indicators, suggesting a greater probability of distant dis-            ing the true extent of disease. One would not want to
ease.24 Such tests are inexpensive and widely available,                deny the patient potentially curative surgery on the
and should be a routine part of the staging process.                    basis of a radiographic feature that lacks accuracy. Con-
                                                                        firmatory tests are often necessary, particularly if the
Bronchoscopy                                                            decision hinges upon a single, adverse CT feature.
For the patient who remains operable at this point a                       The significance of additional pulmonary nodules will
wide vista of additional tests may be appropriate. The                  depend upon geographic factors such as the local prev-
diagnosis may be established by sputum cytology, an                     alence of benign granulomatous disease. In one study,
underutilized investigation, but for all patients except                two-thirds of such nodules were shown to be definitely
those with extensive disease, bronchoscopy will be                      benign, and only 11% were definitely malignant.26 Medi-
undertaken. This provides an opportunity for more                       astinal lymph nodes can be seen more easily on CT than
accurate determination of cell type by histologic exam-                 with conventional radiology.27 As the size of such nodes
ination and allows one to assess the proximal extent of                 increases, so does the probability that they contain
the disease within the tracheobronchial tree. The                       metastases. However, there is no size criterion below
fiberoptic bronchoscope is an excellent screening tool                  which deposits are excluded with certainty, nor above
for the respiratory physician, but in borderline cases                  which deposits are certain to be present (Figure 9.2).
                                                                                           Staging, classification, and prognosis 105

Figure 9.2                                                           Figure 9.3
A CT scan of the chest with contrast enhancement of the mediasti-    A CT scan of a patient with a left upper lobe tumor.
nal vessels. An enlarged node is visible in the right paratracheal   The CT shows unequivocal evidence of irresectable involvement of
area (arrow). Although this node was larger than 1 cm, it was        the mediastinum with tumor encircling the main pulmonary
shown at mediastinoscopy to be benign, and this was confirmed        artery to its origin. A left anterior mediastinotomy would be
at subsequent thoracotomy.                                           unnecessary unless tissue diagnosis was required.

As one increases the size limit permitted for normality,             discussed below). These are: large tumors, central
those nodes deemed ‘abnormal’ are more likely to con-                tumors, PET-positive hilar nodes, and cell type of ade-
tain metastases, and the evaluation gains greater speci-             nocarcinoma or large cell poorly differentiated carcino-
ficity, but at the cost of declining sensitivity. If one             ma.35 This should be taken into account when deciding
applies a lower cut-off the reverse applies, sensitivity             whether invasive mediastinal staging is indicated. Also,
rises at the expense of falling specificity, and one is              many surgeons will be more cautious (i.e. more exten-
more likely to designate nodes as ‘abnormal’ when they               sive in their preoperative staging) when faced with a
do not contain metastases.28 This is the dilemma for the             higher risk resection (right pneumonectomy, for exam-
radiologist. The commonest compromise is to report                   ple) or a high-risk patient, or both together.
nodes as abnormal if their short-axis diameter is greater               Mediastinal invasion may be suggested on CT, but this
than 1.0 cm.29 The accuracy of this assessment depends               assessment is unreliable36 unless there is gross involve-
upon many factors: the speed of the scanner, the use of              ment (Figure 9.3). More frequently the CT scan of the
contrast to enhance the mediastinal vessels, and the                 chest will show that the tumor, and the associated
rigor with which lymph node deposits are sought at                   atelectasis or consolidation, is contiguous with the medi-
thoracotomy. The reported sensitivity and specificity                astinal outline (Figure 9.4). If CT does not demonstrate
fall from 70–80% to 60% when the CT assessment is                    a fat line separating these two opacities the radiologist
subjected to detailed intrathoracic staging.30–32 Abnor-             will warn that invasion may be present.37 This judge-
mal nodes, larger than this, should be examined by                   ment carries a sensitivity and specificity of around
mediastinal exploration to gain histologic confirmation              60%,38 but is imperfect and dependent upon the expe-
of their involvement. Such enlarged nodes within the                 rience of the radiologist. Such a worry can often be
superior mediastinum are accessible to cervical medias-              resolved by mediastinoscopy (Figure 9.5), with the
tinoscopy and anterior mediastinotomy (see later).                   addition of mediastinotomy in appropriate cases. A
Enlarged nodes beyond the reach of these techniques                  suggestion of mediastinal invasion beyond the reach of
can be accessible to video-assisted thoracoscopy (VATS),33           these techniques can be inspected using VATS, but is
but such nodes have less impact on the results of surgi-             usually deferred until thoracotomy when a more deter-
cal treatment and their accurate designation can usually             mined assessment of resectability can be made without
be left until thoracotomy.                                           the danger of massive bleeding. The CT evaluation of
   If the CT scan of the chest shows the mediastinal                 chest wall invasion is similarly imperfect unless rib ero-
nodes are within this size limit the surgeon may pro-                sion or extension outside the chest wall can be demon-
ceed to thoracotomy without mediastinal exploration.34               strated.39 Fortunately, such invasion does not preclude
However, there are four classic risk factors for false neg-          successful resection with good survival results.40,41
ative mediastinal imaging studies (including position                   Most clinicians when requesting a CT scan will ask
emission tomography (PET) scanning, which will be                    for the chest study to extend into the abdomen to the
106 Textbook of Lung Cancer

                                                                                        Figure 9.4
                                                                                        A chest radiograph (a) and CT scan (b) of
                                                                                        a patient with a tumor in the right
                                                                                        middle lobe. This was initially deemed
                                                                                        inoperable by another clinician based
                                                                                        on his interpretation of the CT scan. The
                                                                                        appearances are not unequivocal and at
                                                                                        thoracotomy resection of a T2N0 tumor
                                                                                        was possible by bilobectomy. The chest
                                                                                        radiograph (c) was taken 3 years later
                                                                                        and the patient is still well and disease-
                                                                                        free 12 years later.

Figure 9.5
The CT scan of a patient with a tumor in the right upper lobe
encroaching upon the mediastinum and the right main bronchus.   Figure 9.6
This was evaluated by mediastinoscopy and found to be resect-   The CT of the abdomen suggested a liver metastasis. The
able. The patient underwent right upper lobectomy and sleeve    appearances were not clarified by ultrasound and a needle biopsy
resection for a T2N1 tumor.                                     showed a benign hemangioma.

lower pole of the kidneys in a search for distant metas-        found this to be a useful role for PET, if this is available
tases in the liver, abdominal nodes, adrenals, and kid-         (see later). The addition of CT of the brain is debated.
neys. Whilst this is a useful addition to the CT protocol,      Undoubtedly the number of unsuspected metastases
an isolated abnormality should not be taken as proof            discovered is small, around 5%,12,43 but as this has a
unless there is confirmatory evidence that such an              profound effect on the advisability of thoracotomy we
abnormality is metastatic (Figure 9.6).42 This may              routinely undertake CT of the brain, chest, and
require CT-guided needle biopsy (Figure 9.7). We have           abdomen prior to surgery.44 If there is any suspicion of
                                                                                       Staging, classification, and prognosis 107

                                                                  Mediastinal exploration
                                                                  This is a fundamental tool to select patients for surgery
                                                                  because of the strong negative prognostic implication
                                                                  of N2 and N3 disease. The ESTS has recently published
                                                                  guidelines on both the pre-operative and the intra-op-
                                                                  erative lymph node staging.17,35 If it is felt that the
                                                                  patient would be a candidate for induction (also called
                                                                  neo-adjuvant) therapy, then it may be desirable to avoid
                                                                  surgical staging of the mediastinum so that the most
                                                                  definitive procedure can be carried out in an unoper-
                                                                  ated and unscarred mediastinum at the end of the
                                                                  induction therapy (see section below on restaging of
Figure 9.7
A CT-guided needle biopsy of an indeterminate mass in the right   the mediastinum after induction therapy). It can also be
adrenal gland. It showed the presence of an adenoma.              desirable to avoid surgical staging in more frail patients.
                                                                  Unfortunately, the reliability (the combined sensitivity
                                                                  and specificity) of all techniques increases with inva-
                                                                  siveness. The true gold standard of mediastinal staging
                                                                  is the systematic nodal dissection done at the time of
                                                                  thoracotomy. Mediastinoscopy has a false-negative rate
brain metastases, and indeed for screening purposes,              of less than 10%,56 whereas all endoscopic techniques
MRI should always be the preferred brain imaging                  with FNAB have a false-negative rate of around 15% in
modality unless local availability is an issue.45,46              the best of hands. So the decision as to how to proceed
                                                                  will depend on the clinical indices of suspicion for
Scintigraphic scans                                               mediastinal lymph node involvement as well as the
These are largely obsolete, with the possible exception           patient and the planned resection, as it is clearly
of bone scintigraphy.47 This has retained a place in stag-        desirable to avoid the discovery of false-negative stag-
ing if and only if PET is not available. Most clinicians          ing at thoracotomy in a high-risk situation. So in most
use bone scans selectively in ‘high-risk’ individuals in          centers mediastinoscopy is now used selectively to
whom distant metastases have been suggested clinically            evaluate the mediastinum when CT has suggested the
by symptoms, or the presence of non-specific features             presence of enlarged mediastinal nodes or mediastinal
such as weight loss or disturbed blood parameters.48,49           invasion,57 if there are PET-positive nodes in the
As false-positive bone scans can occur with trauma and            mediastinum, or if there are other clinical indices lead-
degenerative conditions it is as well to follow up any            ing to heightened suspicion of mediastinal lymph node
abnormality with skeletal radiology, and in doubtful              involvement.
cases a local CT or MRI of the area.50 However, if a                 Cervical mediastinoscopy58 is undertaken under gen-
whole body PET scan is obtained then the bone scan is             eral anesthesia through a short cervical incision. It
redundant. PET has both higher sensitivity and higher             allows inspection and biopsy of lymph nodes in the
specificity than scintigraphic bone scans.51–53 However,          paratracheal region to both sides of the trachea, in the
despite this higher accuracy confirmatory studies                 pretracheal area, and below the carina, excluding gross,
should be performed if there is any doubt about the               often irresectable, nodal metastases. When the nodes
diagnosis of metastatic disease.12                                are of a normal size and metastases are small and intra-
                                                                  nodal there is obviously a risk of sampling error, and
Abdominal ultrasound                                              this is the most common cause of false-negative medi-
This is widely available and, in experienced hands, is as         astinoscopy. The one area where more overt mediasti-
good as CT at detecting metastases in the liver54 or              nal nodal deposits can be missed is classically the
adrenals.55 If CT is not available, US should be per-             inferior part of station 7 (the subcarinal nodes) as well
formed in high-risk cases. US is helpful to obtain                as its most posterior aspect. This risk can be minimized
additional information to characterize any abdominal              by dissecting station 7 off both left and right main
abnormality on CT, and may obviate the need for nee-              bronchi, as well as off the pericardium posteriorly prior
dle biopsy. It is also a useful guiding technique for the         to taking biopsies. There are several reports of false-
biopsy, if required.                                              negative rates of well over 10%. We feel that using a
108 Textbook of Lung Cancer

video mediastinoscope, with its greatly enhanced vision,      performed prior to surgery when video-assisted resec-
this is unacceptable and, if this is the case, the surgeon    tion is planned.
should consider taking more care to identify all possi-          Mediastinoscopy can also be very useful to assess
ble nodes, to dissect them out more so that larger biop-      direct mediastinal invasion by right upper lobe tumors,
sies can be taken safely, and to prepare the subcarinal       so in some cases it can also be useful to assess T stage
fossa as described above so that it can be extensively        and thus resectability. When wishing to inspect the
biopsied. When the tumor is a left-sided tumor it is the      area around the aortic arch and subaortic fossa, as in
practice of the authors to do this part of the mediasti-      patients with tumors arising in the left upper lobe or
noscopy quite aggressively because it then becomes            reaching the left main bronchus, cervical mediastinos-
part of the systematic nodal dissection. Likewise, as it      copy should be supplemented by left anterior mediasti-
is extremely difficult to reach L4 and L2 effectively         notomy.58 This allows digital examination and, if necessary,
through a left thoracotomy, it is the practice of the         cautious biopsy of disease in this area (Figure 9.8). It is
authors to resect as many nodes as possible at medias-        applied selectively depending upon the CT appearances
tinoscopy, again with the view that mediastinoscopy, if       in this area of the mediastinum.62 Some surgeons prefer
negative, will then become a seamless part of the oper-       to use VATS to biopsy stations 5 and 6. Such tech-
ative management of the tumor, fulfilling the philoso-        niques do not exclude more subtle mediastinal disease
phy of intraoperative staging as described in the ESTS        but, with experience, ensure that complete resection is
guidelines.17                                                 possible in 95% of negative cases.63,64 The surgeon will
   Two more radical methods of mediastinal staging have       often be encouraged to proceed with thoracotomy and
been described. These are VAMLA (video-assisted media-        resection when other, less accurate techniques such as
stinoscopic lymphadenectomy) and TEMLA (transcer-             CT have raised doubts. When the lung cancer is in the
vical extended mediastinal lymphadenectomy).59–61 As          left upper lobe and the CT shows only small-volume
the names imply, both techniques aim to perform               nodes, completely surrounded by fat, in the para- or
a radical mediastinal lymphadenectomy removing all the        subaortic area on CT, some surgeons do not routinely
para-tracheal nodes as well as emptying out in a radical      explore this area preoperatively because the five-year
manner the subcarinal fossa (and therefore more than          survival in patients with this pattern of nodal disease
just station 7). TEMLA also aims to remove stations 5,        may be equivalent to that of patients with N1 (i.e. stage
6, and 8. In experienced hands these techniques can be        II) disease, and not that of patients with N2 (i.e. stage
performed safely with entirely acceptable morbidity.          IIIA disease).65,66
However, at the moment experience is limited and they
are only performed in a few centers. Furthermore their        Mediastinal needle biopsy
exact place in mediastinal staging remains to be estab-       This can be undertaken through the bronchoscope.67
lished. First, do we truly want a perfect method to stage     Suitable target nodes should be identified in the main
the mediastinum? Patients with true minimal N2 dis-
ease (single-station, intracapsular involvement) have a
25–40% five-year survival with surgery alone. It is
uncertain whether it is in these patients’ best interest to
be denied surgery because they are found to have N2
disease. Second, at the end of this chapter we shall
explore the issue of restaging the mediastinum after
induction chemotherapy. It is when the N2 disease has
been eradicated that there is an indication for surgery.
This would be impossible after VAMLA or TEMLA,
making the decision whether to proceed with surgery
more difficult because all that would be left would be
to assess the decrease in the maximal standardized
uptake value (SUV max) of the primary tumor as a              Figure 9.8
measure of the response to induction chemotherapy.            This patient has a tumor in the left upper lobe and the surgeon is
                                                              undertaking evaluation by cervical mediastinoscopy and left
The major advantage for such techniques at present            anterior mediastinotomy. After all biopsies have been taken,
would appear to be in allowing the mediastinal compo-         bi-digital palpation of the subaortic fossa will exclude invasion or
nent of systematic nodal dissection (see later) to be         gross mediastinal gland enlargement in this critical area.
                                                                                    Staging, classification, and prognosis 109

carina or the paratracheal area, usually on CT. This           thus a useful tool to detect and characterize the primary
technique may obtain tissue diagnosis and confirm              tumor as well as loco-regional and distant metastases.73
irresectability, but there is a small risk of false-positive   It can characterize the lung lesion reliably in many
samples.68,69 It cannot be considered to be a reliable         cases,74 failing only to detect very small deposits and
alternative to staging the mediastinum by surgical explo-      more indolent tumors such as broncho-alveolar carci-
ration prior to thoracotomy, even with US-guided biop-         noma.75 False-positive cases can occur with chronic
sies. Overall, bronchoscopic FNAB techniques have a            inflammatory conditions, most notably tuberculosis
false-negative rate of around 15%, so the main value of        and histoplasmosis. PET may thus have a role in diag-
these techniques is when this minimally invasive tech-         nosis and its place relative to bronchoscopy or needle
nique proves mediastinal lymph node involvement.               aspiration is under discussion.76 PET is reliable for
                                                               lesions that are over 8–10 mm in diameter, and should
Transesophageal fine needle aspiration (with                   probably not be performed for smaller lesions.12 Inter-
ultrasound guidence)                                           est, however, has focused on the possibility that PET
EUS-FNA has been used to assess the presence of                could aid the non-invasive search for metastatic disease
mediastinal node enlargement, but is limited by the            in the mediastinum and at distant sites.77 Initially it was
same size criteria as CT.70 The transesophageal route is       said that PET is more accurate in the detection of medi-
attractive as a conduit to examine the mediastinum             astinal nodal disease than CT and even mediastinal
below the carina, beyond the reach of the mediastino-          exploration, with a reported sensitivity of 80–100%
scope, as well as the left para-tracheal area, checking        and specificity of 70–100%.78 However, the images
areas where CT has suggested mediastinal lymph node            produced by FDG-PET scanners are indistinct and lack
involvement or tumor invasion. The results have proven         anatomic precision (Figure 9.9). It is difficult to accu-
unreliable,71 being of a similar order of magnitude as         rately define the margins of hilum and mediastinum. In
with trans-tracheal biopsies. The same caveats therefore       many centers this problem has been addressed by con-
apply to this technique, even with US guidance. How-           comitant PET and CT scanning in a dedicated PET-CT
ever, it has been shown that EUS-FNA can be used to            scanner. Two studies have shown the superiority of
improve the yield of mediastinoscopy.69 In this study          integrated PET-CT as compared to the combination of
there were 36/100 patients who were ultimately proven          a PET study and a CT with correlation of the images by
to have N2/N3 disease. These were located within reach         the examining physician.79,80 This superiority was found
of EUS-FNA in 29 patients, and were positive at EUS-           to be significant for the determination of T stage,
FNA in 22. Mediastinoscopy detected N2 (17%) or N3             N stage, and M stage. A final caveat regarding PET is that
(2%) lymph node metastases in 19 of the 100 patients.          one study has shown it to be significantly less reliable
These were located within reach of mediastinoscopy in          in smokers (or recent quitters) than in non-smokers.81
29 patients and were confirmed in 19 of these patients.        The maximal SUV was also higher in never-smokers,
Lymph node metastases were confirmed in 31 (86%) of            both in the primary tumor and in mediastinal metasta-
36 patients by either EUS-FNA or mediastinoscopy.              ses. This could be due to the fact that the background
The five lymph node metastases that were missed by             FDG uptake is higher in smokers than in never-smok-
both techniques were located at station 4L in one              ers. Most centers having access to PET continue to rely
patient, 5 in one patient, 7 in two patients, and 8 in one     upon CT and confirm positive PET findings by medi-
patient. This study also showed that T4 status can be          astinal exploration, thus adding to the expense of stag-
correctly assessed by this technique in a number of            ing.82 There is also the philosophical problem as to
cases. Similar results with this combined technique            whether one wishes to detect all mediastinal nodal
have been reported by others.72                                deposits. There are many reports of five-year survival of
                                                               20–30% after complete resection in the presence of
Positron emission tomography                                   truly minimal N2 disease.64,83–85 Mediastinal explora-
PET using the 18F-labeled glucose analog fluoro-2-de-          tion will miss such subtle N2 disease, perhaps to the
oxy-D-glucose (FDG-PET) has emerged as an exciting             patient’s benefit, encouraging one to proceed with sur-
addition to the staging tests. It is expensive, and in         gery with complete resection in 85% of cases.64 It is
many areas is still not widely available, and we are still     unknown to what extent detection of this minimal N2
assessing its cost-effectiveness. It provides an alterna-      burden and induction chemotherapy would alter the
tive, metabolic search for malignant disease that is inde-     natural history of this entire very small subset of
pendent of the anatomic features of the deposits and is        patients (because induction therapy does not eradicate
110 Textbook of Lung Cancer

                                                                                  Figure 9.9
                                                                                  The chest radiograph (a) of a patient who
                                                                                  presented with a tumor in the left lower
                                                                                  lobe; there is an additional lesion at the
                                                                                  right apex (arrow). The CT scan (b) did
                                                                                  not suggest this additional lesion was a
                                                                                  tumor. An FDG-PET study (c) showed high
                                                                                  uptake in both lesions, and the right-
                                                                                  sided lesion was confirmed histologically
                                                                                  to be malignant.

N2 disease in the majority of patients with more bulky       value was 36%.90 This underscores the value of the rec-
N2 disease). Furthermore, we do not know if the results      ommendation in the current ACCP12 and NICE13 guide-
of induction chemotherapy would be better, worse, or         lines for histologic verification of apparent solitary
the same as adjuvant chemotherapy, which would now           metastases detected by PET.
be offered to these patients unless contraindicated.            Similarly our experience with PET as a staging tool
   PET will detect otherwise unsuspected distant metas-      for the mediastinum has grown and some of the initial
tases in 11–29% of patients otherwise thought suitable       enthusiasm has been tempered by this experience.
for thoracotomy.86–88 However, the specificity of this       There have been many recent studies and all essentially
evaluation is not 100%. With regard to distant staging,      show similar results to the three published reports.90–92
the initial enthusiasm for PET needs to be tempered. A       These studies included between 202 and 400 patients.
recent study with much larger numbers (350 patients)         The sensitivity of PET ranged from 64 to 71%, the spec-
demonstrated solitary extrathoracic lesions in 72 patients   ificity from 77 to 84%, the positive predictive value
(21%). A diagnosis was obtained in 69: 37 were true          from 44 to 56%, and the negative predictive value from
metastases, 32 were not. These 32 lesions proved to be       87 to 91% (Table 9.5). An editorial by Kernstine
unrelated malignancies in 6 and benign tumors or             explains why these values are the best one can expect
inflammatory lesions in 26.89 Similarly, in the study by     with the current technology.93 What these results mean
Reed et al otherwise unsuspected metastatic disease was      is that, if one relies exclusively on PET to rule out N2/
identified in 15/287 (5.2%), as well as three second         N3 disease, between 9 and 13% of patients will be found
primary tumors. However, PET also identified 19              at thoracotomy to have unexpected N2 disease which
potential areas of M1 disease that were proven not to be     might have precluded surgery. Putting together what we
metastases (6.6%). Thus the sensitivity of PET for M1        know from the CT era and this knowledge it seems rea-
disease was 83%, the specificity was 90%, the negative       sonable to proceed with thoracotomy for small, periph-
predictive value was 99%, and the positive predictive        eral tumors (unless known to be an adenocarcinoma or
                                                                                        Staging, classification, and prognosis 111

 Table 9.5 Accuracy of PET-CT for mediastinal staging

 Reference                  Number of        Sensitivity (%)   Specificity (%)     Positive predictive      Negative predictive
                            patients                                               value (%)                value (%)

 Reed et al90               303              61                84                  56                       87
 Gonzalez-Stawinski         202              64                77                  45                       88
 et al91
 Cerfolio et al92           400              71                67                  44                       91

poorly differentiated large cell carcinoma) on the basis
of the PET scan alone, provided that the surgeon is pre-
pared to resect unexpected minimal N2 disease if found,
on the basis that surgery alone offers a 20–35% chance
of cure in this situation.35 This might be improved with
adjuvant chemotherapy if the patient is fit for this treat-
ment modality. Otherwise, invasive staging of the medi-
astinum should be carried out. This does not make PET
useless. First, in the apparent stage I (and possibly II)
patients with peripheral lesions it can allow lung resec-
tion to be carried out without surgical staging of the
mediastinum. Second, because it is precisely the patients
                                                               Figure 9.10
with the highest risk of unsuspected mediastinal dis-
                                                               An MRI scan of a patient with a right-sided Pancoast tumor. The
ease who are also at highest risk of distant metastatic        scan gives coronal reconstruction of this difficult area, but also
disease that PET has the highest chance of detecting           suggested nodes at the main carina, which were confirmed to
otherwise occult stage IV disease.                             contain metastatic disease at mediastinoscopy.
   Integrated PET-CT has been shown to be more accu-
rate than PET alone with correlation to a previously           in difficult areas such as the lung apex and lower medi-
performed CT;79,80 however not to a degree that funda-         astinum.98 Most would recommend MRI when evaluat-
mentally changes this discussion about the indications         ing Pancoast tumor (Figure 9.10).99 With modern, fast,
for surgical staging of the mediastinum.                       multislice CT scanners and the software to do multipla-
   Despite all our improvements in non-invasive staging,       nar reconstructions many of the advantages of MRI
invasive staging remains the closest we have to a pre-         have been obviated. If appropriately thin cuts are
thoracotomy gold standard for the detection of N2 dis-         obtained, modern CT scanners have higher spatial res-
ease. The risk factors for unsuspected N2 disease that         olution than MRI. However, MRI remains of value as a
we knew from the CT era of staging are still pertinent         problem-solving tool looking at the central nervous
in the PET age. They are tumor size, location, and his-        system. MRI is more accurate than CT at detecting and
tology and PET-positive hilar nodes.35 Large tumors,           characterizing brain lesions.45,46,100 If there is a clinical
central tumors and adenocarcinoma/poorly differenti-           suspicion of brain metastases then MRI should be
ated large cell carcinomas present the greatest risk of        obtained unless there are local availability issues. We
false-negative non-invasive staging. The true gold stan-       would also recommend its use if CT of the brain shows
dard for the precise diagnosis and assessment of N2            an abnormality (to rule out multifocal disease) or when
disease remains the intra-operative systematic nodal           clinical suspicion remains after a negative CT. The rou-
dissection.17 This is not only a staging tool but could        tine use of MRI as a screening tool for asymptomatic
also have a beneficial effect on outcome.94–97                 brain metastases has not been shown to be of value.
                                                               Similarly, if the CT raises doubts as to tumor extension
Magnetic resonance imaging                                     around the spine and into the spinal canal, MRI will
MRI is little or no more accurate than CT in routine           give clearer definition and valuable information. When-
staging. Some authorities consider that the ability to visu-   ever a neurosurgical opinion is to be sought, MRI
alize in planes other than axial gives MRI an advantage        should be obtained beforehand.
112 Textbook of Lung Cancer

   The tests described above should allow one to deter-          tools such as PET-CT will improve this. It is clearly
mine cTNM and, in appropriate cases, recommend tho-              important that the surgeon obtains such valuable insight
racotomy. For the surgeon, however, the staging process          into the extent of disease before making a decision
does not end there. We have come to appreciate that a            whether to proceed with resection, and when judging
detailed re-evaluation at thoracotomy is a valuable step         the extent of pulmonary resection necessary to achieve
prior to proceeding with resection. Intrathoracic staging        complete resection.
will evaluate areas of concern remaining after CT and               Systematic nodal dissection (SND) begins with the
subsequent mediastinal evaluation, search for addi-              excision of all mediastinal fat and the lymph nodes con-
tional pulmonary nodules and pleural deposits not seen           tained therein (Figure 9.11). It is recommended that
on CT,101 and permit a thorough evaluation of nodal              the nodes be labeled in accordance with an internation-
extent by systematic nodal dissection.102                        ally recognized chart such as that proposed by Naruke
   There is debate as to the value of pleural lavage             (Figure 9.12)107 or that of Mountain and Dressler
cytology as a routine step immediately after opening             (Figure 9.13).3 It is our routine to slice these nodes at
the chest. Kondo and his colleagues found positive               the operating table and examine the internal architec-
pleural cytology in 9% of cases and showed it to be a            ture before deciding whether rapid histologic confirma-
strong indicator of poor prognosis.103 Other workers             tion is necessary by frozen section analysis. If resection
have confirmed the incidence of positive cytology but            is deemed possible we proceed to examine the N1
did not find a statistically significant influence on prog-      nodes similarly, in a centrifugal fashion, until the extent
nosis after resection.104 We have reviewed our experi-           of resection has been determined. The only nodes
ence with pleural lavage cytology. We found malignant            remaining in the resection specimen can be assumed to
cells in the lavage in 4.5% of the 292 patients studied.         be N1. In such a way the surgeon will ensure complete
Positive pleural lavage had a statistically highly signifi-      resection with the minimum resection of lung paren-
cant and independent impact on survival: patients with           chyma.
positive pleural lavage had a median survival of only 13            We have shown that SND will disclose N2 disease in
months, as compared to 49 months for those with a                18% of patients coming to thoracotomy without histo-
negative lavage.105                                              logic evidence preoperatively, and only 60% of patients
   Despite rigorous preoperative staging with CT and,            will be shown to be node negative.108 This study con-
where appropriate, mediastinal exploration, cTNM has             firmed that SND could not be omitted on the basis of
been shown to be inaccurate in over half of the patients         cell type, tumor size, tumor origin, lobe of origin, or by
coming to thoracotomy.106 Whilst occasionally cTNM               preoperative mediastinal exploration. As ‘skip’ lesions
will overestimate the extent of disease, in most cases the       to the mediastinal nodes without hilar node involve-
disease will be shown to be more extensive. As yet we            ment were found in 6% of cases, the assessment of the
do not know precisely how the integration of newer               mediastinum is important irrespective of the findings in

(a)             STEP 1                     (b)                STEP 2                  Figure 9.11
                                                                                      An operative specimen showing fat and
                                                                                      lymph node stations removed during the
                                                                                      first step in SND (a). These can be
                                                                                      correlated with the Naruke chart to show
                                                                                      that a complete circumnavigation of the
                                                                                      right side of the mediastinum has been
                                                                                      accomplished. Step 2 of the nodal
                                                                                      dissection (b) removes the nodes from the
                                                                                      fissure and the hila of the individual
                                                                                                                                     Staging, classification, and prognosis 113

                                                                                                                    Subsequent histologic examination of lymph node
                                                                          1                                      stations removed at surgery will show metastases that
                                                                                                                 the surgeon had not appreciated in up to 9% of cases.109
                                                           2           2
                                                                                                                 The pathologist will also study the specimen and
                                                                3 6
                                                       4              4
                                                                          5                                      attached lymph nodes, looking for the presence of
                                   14             10                          10
                                             10                 7
                                                                                                                 pleural invasion and satellite lesions that may have
                                  13 12                    10         10                      14
                                                   10                         10
                                                                                             13                  eluded the surgeon. Some authors have suggested that
                             14         11                                                  12 13

                                                                                             11        13
                                                                                                                 the use of monoclonal antibody stains will detect nodal

                                                       8              8                     12
                                                                                                                 deposits not seen with conventional stains in up to 6%
                                                                                                  13 14          of lymph nodes in 22% of patients.110 Others have sug-

                                                                                                                 gested that this is the result of taking additional slices
                                                                                                                 of the nodes and that the majority of such micrometas-
                                                   9                               9
                                                                                                                 tases will be found with conventional stains by more
                                                                                                                 thorough histologic examination.111
                                                                                                                    To establish the pTNM the clinician will thus have to
                                         1 Superior mediastinal or highest mediastinal
                                                                                                                 scrutinize the operative findings and study the detailed
                                         2 Paratracheal                                                          pathology report. The accuracy of pTNM will depend
                                         3 Pretracheal
            1                             3a anterior mediastinal
                                                                                                                 heavily on the detailed nature of such reports.
                                          3p retrotracheal or               3a     2
            2 3        3a
    3p                                        posterior mediastinal          6
                                         4 Tracheobronchial                      5 4
                                         5 Subaoratic or Botallo’s
                                         6 Paraaortic (ascending aorta)
                                                                                                                 RESTAGING AFTER INDUCTION CHEMOTHERAPY
                                         7 Subcarinal                                  8
                                         8 Paraesophageal
                                            (below carina)                                                       A full discussion of the place of induction chemother-
                                         9 Pulmonary ligament
                                                                                                                 apy in the management of NSCLC is outside the remit
                                         10 Hilar
                                         11 Interlobar                                                           of this chapter. However, if multimodality therapy is
                                         12 Lobar … upper lobe
                                                      middle lobe and
                                                                                                                 considered, restaging of the patient prior to surgery is
                                                      lower lobe                                                 of paramount importance.
                                         13 Segmental
                                         14 Subsegmental                                                            Recently there have been studies that have challenged
Figure 9.12                                                                                                      the role of surgery in all but true minimal N2 disease
The nodal chart devised by Naruke. The lymph node stations are                                                   (i.e. intracapsular, single node N2 disease found at
numbered: 1–9 indicate mediastinal nodal stations. (Reproduced                                                   the time of thoracotomy), showing apparently similar
with permission of Dr T Naruke and Mosby Inc from J Thorac                                                       results with radical radiotherapy after induction
Cardiovasc Surg 1978; 76: 832–9.107)
                                                                                                                 chemotherapy.112–114 However, in one of these studies114
                                                                                                                 there was a significantly improved progression-free sur-
the hilum. If mediastinal node deposits are discovered                                                           vival with surgery and a trend towards increased overall
at thoracotomy and yet complete resection has been                                                               survival, and the authors concluded that surgery can be
confirmed to be feasible, the surgeon must decide                                                                considered in fit patients, especially if a pneumonec-
whether to proceed with resection, balancing the                                                                 tomy will not be required. In another,112 the number of
reduced prospects of survival after complete resection                                                           complete responses (only 4% overall) was far less than
and the added morbidity and mortality of pulmonary                                                               usually found and the pneumonectomy rate (50%) was
resection. The surgeon will be aware that the patient                                                            unusually high, so it does seem fair to consider the
has already necessarily incurred the morbidity and                                                               results of the experience to date as inconclusive. The
mortality of thoracotomy (annual returns, The Society                                                            authors of this European trial112 themselves point out
of Cardiothoracic Surgeons of Great Britain and Ire-                                                             that we do not know what the outcome would be in the
land), and will base the decision to resect upon the                                                             patients who are now considered to be the appropriate
patient’s fitness, the extent of resection necessary, the                                                        candidates for surgery, i.e. those who have been down-
cell type, and the number and position of positive                                                               staged from N2 to N1 or N0. It is interesting to note
nodes. Complete resection will be deemed appropriate                                                             that in this same study the locoregional recurrence rate
in 85% of cases, although the perioperative mortality is                                                         was much lower in the surgery arm (55% vs 32% in the
higher and the five-year survival reduced to around                                                              radiotherapy arm). Finally, RTOG 89-01 was closed
20–30%.64,83–85                                                                                                  prematurely to give priority to another trial, which will
114 Textbook of Lung Cancer

                                                                    Figure 9.13
                                                                    The nodal chart established by the American
                                                                    Joint Committee on Cancer (AJCC) and the Union
                                                                    Internationale Contre le Cancer (UICC) in 1997.3
                                                                    (See color plate section, page xv)

weaken the conclusions that can be drawn from this              Repeat mediastinoscopy has been used to restage the
trial.113                                                    mediastinum. The best results have been published
   With induction chemotherapy, typically 30–50% of          (and recently updated) by the Antwerp group.119 Over
patients will have the N2 nodes cleared of cancer by the     10 years they had 32 patients who underwent repeat
induction therapy. It is interesting to note that, when      mediastinoscopy after induction therapy. They were
there was sequential induction therapy comprising che-       able to perform the procedure in all patients and had
motherapy followed by chemoradiation therapy, and            only five false-negative repeat mediastinoscopies, yield-
when PET was performed at the outset, after the              ing a sensitivity of 71%, a specificity of 100% and an
chemotherapy and at the end of the induction process         accuracy of 84%. De Leyn et al reported the Leuven
it was the postchemotherapy PET (and not the PET             experience of 30 prospectively studied patients and, in
post-total induction therapy) that was the better predic-    their hands, there were only five positive repeat medi-
tor of survival.115                                          astinoscopies. In 18 cases the node which had been
   If the N2 nodes have been cleared of cancer, the five-    positive at the first mediastinoscopy could not be ade-
year survival ranges from 29 to 44%,35,116,117 and if a      quately assessed because of extensive scarring and
pathologic complete response is observed the five-year       fibrosis. All patients underwent thoracotomy and the
survival is estimated to be 54% (median survival not         systematic nodal dissection revealed persistent N2 dis-
reached).118 If, on the other hand, this is not the case     ease in 17. Therefore the sensitivity of repeat mediasti-
then the five-year survival is 7–24%, usually below the      noscopy was 29%, its specificity was 100%, and its
10–15% range in most studies. This is why it is consid-      accuracy only 60%.120 A Dutch group reported their
ered essential to restage the mediastinum after induc-       experience with repeat mediastinoscopy in 15 patients.
tion therapy to avoid futile and potentially dangerous       In 6 patients the procedure was considered to be inad-
thoracotomies and resections if there is persistent N2       equate; there were 9 adequate procedures – 2 were true
disease. Unfortunately there is no perfect tool to restage   positives and 2 were false negatives.121 The conclusion
the mediastinum.35                                           must be that in the real world repeat mediastinoscopy
                                                                                     Staging, classification, and prognosis 115

is a challenging operation with insufficiently robust            chemotherapy.124 These patients underwent induction
results to recommend its routine use for restaging of the        chemotherapy followed by chemo-radiation therapy
mediastinum after induction therapy.                             then surgery. A PET-CT was performed at time 0, after
   CT scanning is even more inaccurate for restaging             the chemotherapy (t1), and at the end of the induction
than it is for primary staging.35 PET, when used for             process (t2). Patients with either a complete response
restaging the mediastinum after induction therapy, is            or less than 10% viable tumor cells in the tumor had a
less accurate than when used for primary staging, with           drop in SUV max of 67% at t1 and 73% at t2. Follow-up
a sensitivity of 50–60% and a specificity of 85–90%.35           was short so the survival data are difficult to interpret.
Fused PET-CT is better that PET alone in this situation          Another group used PET to study the metabolic rate of
and in one study (with by far the best results) the sen-         glucose.125 The multivariate analysis showed that the
sitivity was 77%, the specificity was 92%, and the accu-         absence of N2/N3 disease at PET had a survival hazard
racy was 83%.120 However the results of fused PET-CT             ratio of 2.33 (95% CI 1.04–5.22; p <0.04). Reading
are not usually as good as this.35 Again, a variety of           from the graphs, this translates into a three-year sur-
FNAB techniques have been described, with essentially            vival of a little under 0.6 for N2/N3 negative patients vs
the same sensitivity and specificity as when used in the         around 0.25 for those with N2/N3 disease. The hazard
chemo-naïve setting. Thus restaging of the mediastinum           ratio for each 10% drop in the metabolic rate of glucose
after induction therapy in N2 disease remains a fraught          was 0.99 (95% CI 0.98–0.99; p <0.01). A residual met-
subject, often requiring a complex step-wise approach            abolic rate of glucose after induction of ≤0.13 had a
with CT, PET-CT, trans-tracheal or esophageal FNAB,              hazard ratio of 1.95 (95% CI 1.28–2.97; p <0.002).
and repeat mediastinoscopy, and still with a risk of             Again, looking at the graphs this translates into a three-
false-negative assessment of the mediastinum.35                  year survival of around 0.6 vs 0 for a value >0.013.
   As we have seen, tissue diagnosis is the ideal restaging         Restaging with PET may also reveal previously unde-
tool, but it is difficult and, even in the best hands, it will   tected metastases after induction chemotherapy. This
always have a finite false-negative rate; it also requires       was seen in 9/47 patients in one study,126 and in 10/56
heavy use of time and resources, and can submit the              in another.127
patient to multiple procedures. PET has been shown to               The only alternative would be to try to stage the
be an alternative, or surrogate way to restage the medi-         mediastinum with any of the variety of FNAB tech-
astinum after induction therapy. Cerfolio et al have             niques, and, if that fails but there is a high index of
published two papers on an overlapping patient popu-             clinical suspicion of N2 disease, administer induction
lation, looking at the change in the SUV max on PET              chemotherapy to the patient. This would allow medias-
before and after induction chemotherapy.122,123 In the           tinoscopy to be performed in an unscarred mediasti-
first study122 they demonstrated that a drop in SUV max          num, hopefully with a much higher sensitivity. However
of 80% in the primary tumor predicted a pathologic               this approach is unvalidated at present.
complete response with a sensitivity of 90%, a specific-            There is one important pitfall with the whole concept
ity of 100%, and an accuracy of 96%. These results are           of offering patients induction chemotherapy. The harsh
roughly as accurate as the best combined invasive                reality is that only 30–50% of patients will be down-
restaging strategies. In the second study123 they showed         staged and offered surgery, the rest going on to radical
that a drop in SUV max of 75% predicted complete                 radiotherapy. This means that their chemo-radiation
response. If the SUV max in the mediastinal nodes                therapy will be sequential instead of concurrent, and
decreased by 55% there was a very high chance of being           there is a consensus now that concurrent chemo-
a partial responder. The median decrease in SUV max              radiotherapy is the standard of care in stage IIIA and
was 100% (range 75–100%) in complete responders,                 IIIB disease. The patient needs to be aware of this when
58% (range 2–100%) in patients who had a complete                consent is sought for induction therapy.
response in the N2 nodes but residual viable tumor in
the primary tumor, and 32% (range 5–82%) in patients
with residual N2 disease. In terms of N2 disease,                OTHER PROGNOSTIC INDICATORS
PET-CT was less reliable. A decrease of SUV max of
>55% had a likelihood ratio of 9.1 in predicting clear-          Table 9.6 summarizes known or supposed prognostic
ance of the N2 nodes, but in reality residual N2 disease         factors in surgically resected NSCLC. Cell type is not per
was missed by PET-CT in 13/65 patients (20%). One                se a prognostic indicator,128 but as we have discussed
group studied the SUV max before and after induction             previously certain cell types (adenocarcinoma and large
116 Textbook of Lung Cancer

 Table 9.6 Prognostic factors in surgically resected NSCLC

 Prognostic factors               Tumor related                   Host related               Environment related

 Essential                        T category                      Weight loss                Resection margins
                                  N category                      Performance status         Adequacy of mediastinal
                                  Extracapsular nodal                                        dissection
                                  Superior sulcus location
 Additional                       Histologic type                 Gender                     Radiotherapy dose
                                  Grade                           Age                        Adjuvant radiotherapy
                                  Vessel invasion
                                  Tumor size
 New and                          Molecular/biologic              Quality of life
 promising                        markers                         Marital status
 Published with kind permission of the editors and the UICC.129

cell poorly differentiated carcinoma) represent a risk              successful management of NSCLC is 1% per patient-
factor for presenting at a higher stage of disease. The             year, and this is doubled if the patient continues to
failure of screening to improve survival in a screened              smoke. It is now starting to emerge that smoking can
population129 is in part due to so so-called overdiagno-            interfere with the effectiveness of radiotherapy.134 Simi-
sis of indolent disease, proving that the term indolent             larly, smoking can reduce the effectiveness of chemo-
adenocarcinoma is not an oxymoron. Only performance                 therapy upregulation of the pathways targeted by
status equals stage in its impact on survival after all             chemotherapy, thus inhibiting chemotherapy-induced
treatment modalities. Others factors such as weight loss            apoptosis.135 Smoking has a particularly strong inhibi-
and the presence of systemic symptoms are accepted as               tory effect on tyrosine-kinase inhibitors (TKIs). The
important. Cell type, degree of differentiation, and vascu-         BR.21 study on erlotinib in NSCLC showed that plasma
lar invasion may be significant, but reports vary depend-           concentrations of the drug were around twice as high in
ing upon stage and whether surgery was possible.130 Sex             non-smokers and ex-smokers compared to current
is a prognostic indicator – females have better survival            smokers. This is attributed to a lack of induction of cyto-
independently of TNM stage and histology.131–133 Age                chrome P450 1 A isoforms by cigarette smoke as well as
has an impact on treatment but is not an independent                a higher incidence of K-ras mutations in smokers result-
variable. Certainly information on these factors should             ing in faster plasma clearance of erlotinib in smokers.136
be recorded and data presented in any report of results.               Genomics are starting to show promise in identifying
There is great interest in biologic markers in lung cancer,         patients at high risk of recurrence.137 It remains to be
and the hope that a panel of markers, including onco-               proven whether these patients will benefit from more
genes and tumor suppresser genes, can provide an                    aggressive postoperative chemotherapy. Similarly,
independent, biologic method of anticipating outcome.               ERCC1 is an enzyme that can repair the DNA damage
At present our knowledge of these markers is imperfect,             induced by cisplatin. When cisplatin-based adjuvant
and there are still no markers that have translated into            chemotherapy was given to patients, those with tumors
the clinical setting because they do not discriminate in            that were ERCC1-negative had a significantly longer
a sufficiently robust way to allow therapeutic decisions            survival than those with ERCC1-positive tumors.138
to be made.130 It is recommended that, where possible,                 The SUV max also seems to indicate prognosis.139
cryopreserved tissue from well-staged, surgical speci-              When the SUV max is higher than 10, tumors tend to
mens should be stored for future studies.                           be more likely to be poorly differentiated and to present
   On-going smoking is increasingly found to have an                at a higher stage. For each stage, if the SUV max is
effect on prognosis. All textbooks cite that the risk of            greater than the median value seen for that stage this
developing a second primary lung cancer following                   also tends to indicate a poorer prognosis – for example
                                                                                    Staging, classification, and prognosis 117

in stage IB NSCLC the four-year survival was 80% for a       than the original patients do in that group, defined by
SUV max lower than median, and only 66% when it              cruder staging techniques, and the prognosis of the
was higher than the median (p = 0.048). These values         group is thus improved. The shifting populations are
were, respectively, 64% vs 32% (p = 0.028) for stage II      evident in any study giving details of the results of
and 64% vs 16% (p = 0.012) for stage IIIA.                   surgery based upon cTNM and pTNM. In one study,142
                                                             the number of patients who fell into the T1N0 category
                                                             fell from 349 to 264 when shifting from cTNM to pTNM
                                                             and, conversely, the number of patients with T3N0
PROGNOSIS                                                    disease rose from 109 to 147. This demonstrates the
                                                             improved staging achieved by thoracotomy. The five-
The survival of patients with each stage of disease is       year survival of patients based upon pTNM will always
discussed in detail in the chapters on treatment in this     be superior to that based upon cTNM, and this effect is
book, but a few comments are pertinent when consid-          more pronounced in higher stage groups. In another
ering staging. When reading the literature on the results    study,2 the five-year survival of T1N0 patients rose from
of treatment of lung cancer, especially surgical series,     61% to 67%, a 10% improvement, when moving from
the reader is reminded of two phenomena: what Shields        cTNM to pTNM, whilst survival of T3N0 patients rose
has termed ‘the diminishing denominator’,140 and the         from 22% to 38%, an improvement of 87% in the sur-
impact of ‘stage migration’ or the Will Rogers effect.141    vival of this group. These statistical realities are legiti-
   The diminishing denominator can give a false impres-      mate, but one must resist the temptation to attribute
sion of the value of surgery in an advanced stage of lung    the improved survival to the staging evaluation itself.
cancer by reporting only the results on patients found          The prognosis of NSCLC is very variable in different
to be within this stage at thoracotomy and surviving         series. This is often a reflection of the rigor of both
complete resection. Other patients are ‘censored’ from       the pre- and intra-operative staging of the cancer. If
the analysis if found at thoracotomy not to fall into the    pre-operative staging is not completely thorough there
study population, if resection is not possible, if incom-    will be 10–20% undetected N2 disease at thoracotomy,
plete resection has been performed, and even if dying        provided that intra-operative staging has been done as
after operation. The reported survival of patients in this   it should. However, there are still many centers that
stage who survive complete resection gives little guid-      do not routinely perform systematic nodal dissection
ance to the clinician armed only with cTNM, and results      (which in itself is a term which is often abused). A tell-
are further inflated by the use of actuarial survival sta-   tale sign is the five-year survival of stage I NSCLC.
tistics. Thus 300 patients with a presumptive advanced       In properly staged patients this will be around 80%,
stage (IIIA for example) may proceed to thoracotomy.         down to around 65% when staging is less rigorous.
Eighty will be found to be in a lesser stage at thoraco-     Stage migration will then deploy its effects as stage
tomy, 60 will be technically irresectable (so-called open    progresses.
and close thoracotomy), 95 will undergo an incomplete           When evaluating the benefits of any treatment for
resection (R1 or R2, as described in a previous section),    lung cancer it is important to study each paper care-
and 15 will die after surgery. The analysis is thus          fully, to determine the true denominator, and to note
restricted to the 50 patients who survived a complete        all the tests used to define the population under study.
resection for the designated advanced stage. Therefore       Thus the reader may be better able to place into context
the actuarial survival of the 10 who survive to five years   the results reported in the following chapters.
after complete resection is computed to be 20%. Whilst
this may impress the unwary, closer study reveals that
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     study comparing chemotherapy and radiotherapy with preop-                 vance of response evaluation using [18F]-2-fluoro-2-deoxy
     erative chemotherapy and surgical resection in patients with              D-glucose positron emission tomography in patients with
     non-small-cell lung cancer with spread to mediastinal lymph               locally advanced non-small-cell lung cancer. J Clin Oncol
     nodes (N2); final report of RTOG 89-01. Radiation Therapy                 2005; 23: 8362–70.
     Oncology Group. Int J Radiat Oncol Biol Phys 2002; 54:             126.   Hellwig D, Graeter TP, Ukena D et al. Value of F-18-fluorode-
     365–9.                                                                    oxyglucose positron emission tomography after induction
114. Albain KS, Swann RS, Rusch V et al. North American Lung                   therapy of locally advanced bronchogenic carcinoma. J Tho-
     Cancer Group. Phase III study of concurrent chemotherapy                  rac Cardivasc Surg 2004; 128: 892–9.
     and radiotherapy (CT/RT) vs CT/RT followed by surgical             127.   Akhurst T, Downey RJ, Ginsgerg MS et al. An initial experi-
     resection for stage IIIA (PN2) non-small cell lung cancer                 ence with FDG-PET in the imaging of residual disease after
     (NSCLC): outcomes update of North American Intergroup                     induction therapy for lung cancer. Ann Thorac Surg 2002; 73:
     0139 (RTOG 9309). J Clin Oncol 2005; 23(16S, part I of II):               259–66.
     7014.                                                              128.   Brundage MD, Mackillop WJ. Lung cancer. In: Gospodarow-
115. Eschmann SM, Friedel G, Paulsen F et al. Repeat 18F-FDG                   icz MK, O’Sullivan B, Sobin LH, eds. Prognostic Factors in
     PET for monitoring neoadjuvant chemotherapy in patients                   Cancer, 3rd edn. Hoboken, New Jersey: John Wiley & Sons,
     with stage III non-small cell lung cancer. Lung Cancer 2007;              2006: Chapter 19.
     55: 165–71.                                                        129.   Bach P, Jett JR, Pastorino U et al. Computed tomography screen-
116. Port JL, Korst RJ, Lee PC et al. Surgical resection for residual          ing and lung cancer outcomes. JAMA 2007; 297: 953–61.
     N2 disease after induction chemotherapy. Ann Thorac Surg           130.   Graziano SL. Non-small cell lung cancer: clinical value of
     2005; 79: 1686–90.                                                        new biological predictors. Lung Cancer 1997; 17 (Suppl 1):
117. Voltolini L, Luzzi L, Ghiribelli C et al. Results of induction            s37–58.
     chemotherapy followed by surgical resection in patients with       131.   Visbal AL, Williams BA, Nichols FC 3rd et al. Gender differ-
     stage IIIA (N2) non-small cell lung cancer: the importance of             ences in non-small-cell lung cancer survival: an analysis of
     nodal downstaging after chemotherapy. Eur J Cardiothorac                  4,618 patients diagnosed between 1997 and 2002. Ann Tho-
     Surg 2001; 20: 1106–12.                                                   rac Surg 2004; 78: 209–15.
118. Pisters KMW, Kris MG, Gralla RJ et al. Pathological complete       132.   de Perrot M, Licker M, Bouchardy C et al. Sex differences in
     response in advanced non-small-cell lung cancer following                 presentation, management, and prognosis of patients with
     preoperative chemotherapy: implications for the design of                 non-small cell lung carcinoma. J Thorac Cardiovasc Surg
     future non-small-cell lung cancer combined modality trials.               2000; 119: 21–6.
     J Clin Oncol 1993; 11: 1757–62.                                    133.   Cerfolio RJ, Bryant AS, Scott E et al. Women with pathological
119. De Waele M, Hendriuks J, Lauwers P et al. Nodal status                    stage I, II and III non-small cell lung cancer have a better
     at repeat mediastinoscopy determines survival in non-small                survival than men. Chest 2006; 130: 1796–802.
     cell lung cancer with mediastinal nodal involvement, treated       134.   Browman GP, Wong G, Hodson I et al. Influence of cigarette
     by induction therapy. Eur J Cardiothorac Surg 2006; 29:                   smoking on the efficacy of radiation therapy in head and neck
     240–3.                                                                    cancer. N Engl J Med 1993; 328: 159–63.
120. De Leyn P, Stroobants S, De Wever W et al. Prospective com-        135.   Dasgupta P, Kinkade R, Joshi B et al. Nicotine inhibits apop-
     parative study of integrated positron emission tomography-                tosis induced by chemotherapeutic drugs by up-regulating
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     in the assessment of residual mediastinal lymph node disease       136.   Comis RL. The current situation: erlotinib (tarceva) and gefi-
     after induction chemotherapy for mediastinoscopy – proven                 tinib (iressa) in non-small cell lung cancer. Oncologist 2005;
     stage IIIA – N2 non-small-cell lung cancer: a Leuven Lung                 10: 467–70.
     Cancer Group Study. J Clin Oncol 2006; 24: 3333–9.                 137.   Potti A, Mukherjee S, Petersen R et al. A genomic strategy
121. Maas KW, Schramel FMNH. Repeat mediastinoscopy after                      to refine prognosis in early-stage non-small cell lung cancer.
     neoadjuvant therapy for non-small cell lung cancer. Lung                  N Engl J Med 2006; 355: 570–80.
     Cancer 2003; 39: 347.                                              138.   Olaussen KA, Dunant A, Fouret P et al. DNA repair by ERCC1
122. Cerfolio RJ, Bryant AS, Winokur TS et al. Repeat FDG-PET                  in non-small-cell lung cancer and cisplatin-based adjuvant
     after neoadjuvant therapy is a predictor of pathologic response           chemotherapy. N Engl J Med 2006; 355: 983–91.
122 Textbook of Lung Cancer

139. Cerfolio RJ, Bryant AS, Ohja B, Bartolucci AA. The maximum         141. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenom-
     standardized uptake values on positron emission tomography              enon: stage migration and new diagnostic techniques as a
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     survival. J Thorac Cardiovasc Surg 2005; 130: 151–9.                    J Med 1985; 312: 1604–8.
140. Shields TW. The significance of ipsilateral mediastinal lymph      142. Naruke T, Goya T, Tsuchiya R, Suemasu K. Prognosis and
     node metastasis (N2 disease) in non-small cell carcinoma of             survival in resected lung carcinoma based on the new interna-
     the lung. A Commentary. J Thorac Cardiovasc Surg 1990; 99:              tional staging system. J Thorac Cardiovasc Surg 1988; 96:
     48–53.                                                                  440–7.


Rami-Porta R, Ball D, Crowley J et al. on behalf of the International       forthcoming (seventh) edition of the TNM classification for
    Staging Committee. The IASLC Lung Cancer Staging Project:               lung cancer. J Thorac Oncol 2007; 2: 686–93.
    proposals for the revision of the T Descriptors in the forthcom-    Groome PA, Bolejack V, Crowley JJ et al. on behalf of the International
    ing (seventh) edition of the TNM classification for lung cancer.        Staging Committee, Cancer Research and Biostatistics. The IASLC
    J Thorac Oncol 2007; 2: 593–602.                                        Lung Cancer Staging Project: validation of the proposals for revi-
Rusch VW, Crowley J, Giroux DJ et al. on behalf of the International        sion of the T, N, and M Descriptors and consequent stage group-
    Staging Committee on Cancer Research and Biostatistics. The             ings in the forthcoming (seventh) edition of the TNM classification
    IASLC Lung Cancer Staging Project: proposals for the revision           of malignant tumors. J Thorac Oncol 2007; 2: 694–705.
    of the N Descriptors in the forthcoming (seventh) edition of the    Groome PA, Bolejack V, Crowley JJ et al. on behalf of the Interna-
    TNM classification for lung cancer. J Thorac Oncol 2007; 2:             tional Staging Committee, Cancer Research and Biostatistics.
    603–12.                                                                 The IASLC Lung Cancer Staging Project: proposals for the revi-
Postmus PE, Brambilla E, Chansky K et al. on behalf of the Interna-         sion of the TNM stage groupings in the forthcoming (seventh)
    tional Staging Committee. The IASLC Lung Cancer Staging                 edition of the TNM classification of malignant tumors. J Thorac
    Project: proposals for revision of the M Descriptors in the             Oncol 2007; 2: 706–14.
  10 Treatment of non-small cell lung cancer

10.1 Treatment of NSCLC: surgery
               Robert J Korst

               Contents Introduction • Historical summary • Stage I disease (T1–2N0) • Stage II disease (T1–2N1 and T3N0)
                • Stage III disease • Stage IV disease • Special considerations • Palliative surgery • Summary

INTRODUCTION                                                    lobectomy was performed by Davies in 1912. It was not
                                                                until the advent of an effective underwater drainage
Lung cancer is one of the leading causes of cancer death        system, however, that pulmonary resection could safely
worldwide. Approximately 80% of cases of newly diag-            be performed on more of a routine basis. Following a
nosed lung cancer are of the non-small cell type (NSCLC).       report by Graham of the first pneumonectomy in 1933,
Unfortunately, a large percentage of these patients will        surgical resection became the treatment of choice for
have inoperable disease on the basis of distant metasta-        lung cancer. Over the next several decades, various types
ses (stage IV) or locally advanced disease (stage IIIB).        of anatomic lung resections continued to be described,
For the remaining patients with early stage disease (stage      including segmentectomy, sleeve lobectomy, and pneu-
I and II), as well as selected patients with locally advanced   monectomy, as well as resection for superior sulcus
disease (stage IIIA), complete surgical resection remains       tumors.
the best hope for cure, provided that the operative risk           Through the 1970s and 1980s, it became recognized
is tolerable.                                                   that despite radical resection with negative margins,
   Over the past four decades, several points regarding         many patients with resected NSCLC ultimately died of
the conduct of resection have become accepted as the            their disease, with the majority of recurrences being dis-
surgical management of NSCLC has evolved. First,                tant metastases. This fact was especially true for patients
incomplete resections leaving either gross or micro-            found to have disease metastatic to the lymph nodes
scopic disease behind will fail to cure the disease and         (locally advanced disease) at the time of resection. As a
are rarely indicated in a palliative setting. Intraoperative    result of this observation, strategies which combine
frozen section analysis should be employed frequently           treatment modalities (surgery, chemotherapy, and radi-
to ensure negative margins. Second, general oncologic           ation) are becoming more popular and are the subject
principles should be followed, including the resection          of active investigation for nearly all stages of NSCLC. In
of the tumor and surrounding normal lung (lobectomy             addition, recent breakthroughs in the use of adjuvant
or pneumonectomy) with draining lymphatics and lymph            chemotherapy following complete resection of NSCLC
nodes. Third, the mediastinal lymph nodes should be             are changing the postoperative management of patients
dissected to accurately stage the patient, and fourth, en       with this deadly disease.
bloc resection of the tumor and surrounding structures
is desirable whenever technically possible.
                                                                STAGE I DISEASE (T1–2N0)
   Survival following surgical resection for NSCLC is
stage-dependent (Table 10.1.1). Despite the develop-
                                                                Patients with this early stage of NSCLC typically present
ment of the principles mentioned above, less than 15%
                                                                without symptoms and most are cured with primary
of all patients can presently be expected to be cured of
                                                                surgical excision. These tumors are usually peripheral in
their disease. This dismal figure underscores the need
                                                                location and are discovered on a routine chest radiograph.
for prevention as well as continued investigation into
                                                                These peripheral ‘coin lesions’ are mainly adenocarcino-
better treatment options for patients with NSCLC.
                                                                mas, or bronchioloalveolar carcinomas. Uncommonly,
                                                                a radiographically ‘occult’ tumor may be discovered.
HISTORICAL SUMMARY                                              Unlike the peripheral lesions, occult tumors are mainly
                                                                squamous in histology and patients may present with
Although non-anatomic pulmonary resection for lung              hemoptysis. Not infrequently, occult tumors are detected
cancer had been reported in 1895, the first anatomic            during screening bronchoscopy after a previous lung
124 Textbook of Lung Cancer

                                                                 pulmonary reserve, this practice should be avoided
 Table 10.1.1 Survival following resection for NSCLC by stage    whenever possible due to the higher rate of local recur-
 (see text for references)                                       rence and trend toward decreased long-term survival
 Stage                                  Five-year survival (%)   when these lesser resections are performed, a standard
                                                                 set by the results of The Lung Cancer Study Group
 Stage I                                                         (LCSG) trial 821.4 In this study, patients with T1N0
 Overall                                        76               NSCLC were randomized to undergo either lobectomy or
 T1N0M0                                         84               limited resection (wedge resection or segmentectomy).
 T2N0M0                                         68               Patients who underwent limited resection had a signifi-
 Stage II                                                        cantly higher rate of local recurrence than those in the
 T1–2N1M0                                       47               lobectomy group, with a survival difference approach-
 T3N0M0                                                          ing statistical significance. However, in the modern era
   Chest wall invasion                          56               of lung cancer screening using computed tomography
   Mediastinal invasion                         29               (CT), many tumors are detected while still very small
   Proximal bronchus                            36               (<1–2 cm). This observation, combined with the emer-
 Stage III                                                       gence of retrospective studies reporting excellent sur-
 N2                                                              vival rates following limited resection for small, T1 lung
   Clinically negative                          34               cancers,5,6 suggests that a trial similar to LCSG 821
   mediastinum                                                   should be initiated to reset the standard for these very
   Clinically positive                            9              small, screen-detected tumors.
   mediastinum                                                       Most anatomic pulmonary resections for stage I NSCLC
                                                                 have traditionally been performed using a posterolat-
                                                                 eral thoracotomy, during which a rib-spreading retrac-
cancer resection,1 or in patients who have undergone             tor is utilized. However, many surgeons now undertake
bronchoscopy as part of the work-up for another pro-             these resections using a complete, videothoracoscopic
cess, such as head and neck or esophageal cancer.                (VATS) approach. The most commonly performed type
   Complete surgical excision is the treatment of choice         of VATS resection involves the creation of two thora-
for stage I NSCLC, provided the operative risk is accept-        coscopy ports as well as a 6–8 cm ‘utility’ incision, the
able. Patients should undergo preoperative pulmonary             latter used for dissection of the hilum as well as specimen
function testing to assess lung reserve, as well as cardiac      retrieval. Multiple published reports have suggested that
evaluation if indicated from the patient’s history. The          anatomic pulmonary resections can be performed safely,
operation of choice is anatomic lobectomy. Occasion-             and are oncologically sound when performed via VATS
ally, a more extensive resection needs to be performed           for early-stage lung cancer.7,8 Additional benefits include
when the location of the tumor is such that removal of           less postoperative discomfort as well as decreased length
a single lobe is not adequate. When the tumor pro-               of hospital stay with the VATS approach compared to
trudes into the mainstem bronchus, sleeve lobectomy is           open thoracotomy. As a result, VATS lobectomy has
the procedure of choice to obtain negative bronchial             replaced its open counterpart for the management of
margins; however, a tumor involving the bronchus                 stage I lung cancer in many centers.
intermedius usually requires a bilobectomy, while a                  Although it has been suggested that mediastinal
lesion more extensively involving the mainstem bron-             lymph node dissection is unnecessary in patients with
chus requires pneumonectomy. Pneumonectomy may                   very small T1 tumors, the vast majority of patients
also be indicated in the rare circumstance when the              undergoing resection for NSCLC should have this pro-
tumor is closely associated with the proximal, extra-            cedure routinely performed. Although this approach
pericardial pulmonary artery. For upper lobe lesions that        has never definitively been shown to improve survival,
invade the pulmonary artery to the lower lobe a vascular         it is the only way to accurately stage a patient’s disease,
sleeve resection can be performed, sparing the lower             and adds very little time and morbidity to the operation.
lobe. Multiple series now suggest that sleeve resection for      In addition, approximately 16% of patients with periph-
central tumors produces results similar to that seen with        eral T1N0 tumors where the primary tumor is less than
pneumonectomy from an oncologic standpoint.2,3                   3 cm in size will have mediastinal node metastases.9
   Although limited resections (wedge resection or seg-          When resecting a right-sided tumor, the right paratra-
mentectomy) remain an option for patients with poor              cheal, pretracheal, subcarinal, and inferior pulmonary
                                                                                          Treatment of NSCLC: surgery 125

ligament nodes should be dissected. On the left, the          344 patients with stage IB NSCLC to either surgery
preaortic, aortopulmonary window, subcarinal and              alone or surgery followed by four cycles of paclitaxel/
inferior pulmonary ligament nodes are accessible. Given       carboplatin chemotherapy.14 No statistically significant
the uncertain survival benefit of complete mediastinal        difference in survival was noted between groups. As a
lymph node dissection for early-stage NSCLC, a ran-           result, the role of adjuvant chemotherapy in the man-
domized trial conducted by The American College of            agement of patients with completely resected stage IB
Surgeons Oncology Group is currently underway to              NSCLC remains controversial. Many clinicians will rec-
investigate this question.                                    ommend adjuvant chemotherapy to these patients if their
   Operative mortality following pulmonary lobectomy          tumors appear to possess characteristics associated with
for all stages of disease should not surpass 2%, but should   a poor prognosis (e.g. tumors greater than 5 centimeters,
be considerably less for patients with stage I disease.       vascular/lymphatic invasion). Adjuvant radiotherapy is
Morbidity and mortality increase with higher stages of        currently not recommended for patients with com-
disease and extended resections. Operative mortality          pletely resected stage I NSCLC, in light of the results of
following pneumonectomy is near 6% in most series,            a meta-analysis showing that postoperative radiother-
with some being even lower.10 The five-year survival for      apy may increase mortality in these patients.15
patients with completely resected T1N0 lesions sur-              Most clinicians would agree that patients require fol-
passes 80% in some reports, while this figure is reduced      low-up after resection for NSCLC; however, the nature
to approximately 65% for T2N0 tumors. The overall             of the follow-up regimen remains controversial. Given
five-year survival for patients with completely resected      the poor prognosis associated with recurrent metastatic
stage I NSCLC is approximately 75%.11 Recurrences             disease in patients who have undergone resection of
following complete resection for stage I NSCLC are            NSCLC, follow-up regimens should probably be geared
mainly in the form of distant metastases, as displayed        toward the detection of second primary lung cancer
in Table 10.1.2.                                              (SPLC), which occurs with an annual cumulative inci-
   No form of adjuvant therapy has traditionally been         dence of 2% per patient/year of follow-up.16 Recent pub-
recommended for patients undergoing resection of              lished data suggest that serial computed tomography
stage I NSCLC. Recent randomized trials, however,             (CT) of the chest has the ability to detect SPLC while still
have suggested a small survival benefit for patients with     in its early stages;17 however, the cost-effectiveness of
completely resected stage IB-III NSCLC. One of these,         this approach has not yet been substantiated.
the National Cancer Institute of Canada Clinical Trials
Group (NCIC) trial JBR.10, randomized 482 patients
with stage IB or II NSCLC to either surgery alone or          STAGE II DISEASE (T1–2N1 AND T3N0)
platinum-based adjuvant chemotherapy.13 Patients in
the adjuvant therapy arm enjoyed significantly longer         N1 disease
overall survival (69% vs 54% at five years) compared to       Patients with T1–2N1 NSCLC represent a small subset
those who underwent surgery alone. Despite this, mature       in the spectrum of this disease, usually comprising less
results of the Cancer and Leukemia Group B (CALGB)            than 10% of patients coming to surgery. As with stage
9633 trial, performed exclusively in stage IB patients, did   I, the majority of patients can be effectively treated with
not support these findings. CALGB 9633 randomized             lobectomy, although about a third will require pneu-
                                                              monectomy, mainly due to involved hilar lymph nodes
                                                              adherent to the pulmonary artery or major bronchi.
 Table 10.1.2 Sites of first distant recurrence following         Similar to stage I disease, it is important to perform
 resection in 159 patients with stage I NSCLC lung cancer12   a thorough mediastinal lymph node dissection in this
                                                              group of patients, especially since there is a higher inci-
 Site                                            Number       dence of occult N2 disease. Recurrence following com-
 Brain                                             51         plete resection for T1–2N1 NSCLC is common, with
 Lung                                              20         five-year survival rates approaching only 45%.18 As
 Liver                                             14         with stage I, the most common form of recurrence is
 Bone                                              11         distant metastatic disease, especially if the tumor is an
 Other                                              8         adenocarcinoma. Patients enjoying a better prognosis
 Disseminated                                       5         tend to be those with small primary tumors, squamous
                                                              histology, and only one involved lymph node.
126 Textbook of Lung Cancer

T3N0 disease
Chest wall involvement
T3 tumors invading the chest wall are readily amenable
to surgical resection. As a general guideline, one rib
above and one below the gross margin of the tumor
should be taken to ensure negative margins. Although
en bloc resection is desirable and should be achieved
whenever possible, discontinuous resection can be done
when absolutely necessary as long as meticulous atten-
tion is paid toward documenting margins. It currently
remains controversial whether a complete chest wall
resection, including ribs, is necessary for tumors invad-
ing only the parietal pleura. A parietal pleurectomy with
negative deep margins may be sufficient, but should be
used with extreme caution.
   Following resection, the issue of chest wall reconstruc-
tion needs to be addressed. The first question regarding
this is whether the chest wall reconstruction is really
necessary, and this usually depends on the assessment
of chest wall stability. After resection of short segments
of one or two ribs, or up to three posterior segments
under the paraspinous muscles or scapula, reconstruc-
tion is not usually necessary. When reconstruction is
undertaken, the marlex/methylmethacrylate sandwich
technique readily restores stability and prevents the flail
chest phenomenon during breathing (Figure 10.1.1). A          Figure 10.1.1
Gore-Tex patch, stretched tightly, has also been used         Stage IIB NSCLC (T3N0M0) invading the chest wall. (a) Chest CT
                                                              revealing a large lung mass invading the chest wall. Cervical
with acceptable results. Mortality following chest wall
                                                              mediastinoscopy was negative, while transthoracic needle
resection is low, but is related to the size and location     aspiration revealed large cell carcinoma.(b) Chest radiograph
of the defect in the chest wall, the amount of lung           following right upper lobectomy, mediastinal lymph node
resected, and the technique of reconstruction.                dissection, and resection of the involved chest wall. Stable
   Factors which affect long-term survival following resec-   reconstruction was achieved using a marlex mesh and methyl-
                                                              methacrylate prosthesis.
tion of these tumors are the extent of chest wall involve-
ment, the ability to completely resect the tumor, and
the presence or absence of lymph node involvement.
                                                              attained when the mediastinum is invaded. Addition-
The overall five-year survival of patients with T3N0M0
                                                              ally, even when these tumors are completely resected and
tumors invading the chest wall undergoing complete en
                                                              the mediastinal nodes are negative, patients with T3
bloc surgical resection is approximately 50–60%.19
                                                              disease invading the mediastinum have a worse prog-
Patients with a T3N0M0 tumor that involves only the
                                                              nosis when compared to other types of T3 tumors.20
parietal pleura have a better prognosis than those where
                                                                 Due to the high frequency of N2 disease, patients
the tumor invades into muscle and ribs.
                                                              with evidence of mediastinal invasion on CT scan should
                                                              undergo cervical mediastinoscopy to rule out nodal
Tumors invading the mediastinum                               involvement or T4 disease. If N2 disease is detected,
Tumors invading the mediastinal pleura, fat, nerves,          induction (neo-adjuvant) therapy may offer these
and pericardium, but not the major mediastinal vessels        patients a better chance at long-term survival, if surgi-
or organs, represent another subset of the T3 classifica-     cal resection is being considered. If there is no N2, N3,
tion. These patients have a notoriously poor five-year        or T4 disease found at mediastinoscopy, these patients
survival following surgical resection alone. In part, this    can undergo primary surgical resection with five-year
poor survival is due to the high likelihood of mediastinal    survival rates of 30% if complete resection can be
node metastases and the low rate of complete resection        performed.20
                                                                                         Treatment of NSCLC: surgery 127

Tumors in proximity to the carina                            sues or associated N2 disease have been reported to have
Tumors within 2 cm but not involving the main carina         a five-year survival of 80% in one series.22 Patients with
comprise another subset of T3 tumors. As with the            T3 tumors approaching the carina associated with N2
other T3 tumors, patients with these proximal bron-          nodal metastases separate from the primary tumor (‘true’
chial lesions are candidates for surgical resection. Tech-   N2) have a negligible five-year survival. Patients with
nical considerations when resecting tumors involving         N2 disease which is present by virtue of direct spread
the main bronchi pertain to the extent of resection,         from the primary tumor, however, remain surgical can-
intraoperative airway management, and techniques of          didates. Therefore, it is mandatory to perform cervical
sleeve resection. Small, solitary squamous cell lesions      mediastinoscopy prior to an attempted resection to iden-
confined to the left main bronchus with no invasion          tify those patients with ‘true’ mediastinal nodal disease
through the bronchial wall can very occasionally be          who would receive no benefit from primary surgical
handled with excision of the main bronchus alone, with       resection. If N2 nodes are identified at cervical medias-
total lung preservation and primary anastomosis. How-        tinoscopy, induction therapy may be of value, but this
ever, frequently these lesions are multiple and are best     awaits clinical trials.
treated with endobronchial laser or radiation (brachyther-      The role of adjuvant therapy for stage II NSCLC has
apy). If resection is being considered for a solitary,       evolved similar to that for stage I disease. The previ-
proximal lesion on the right, however, usually a pneu-       ously mentioned Canadian trial13 demonstrated a small,
monectomy or right upper lobe sleeve resection is            but significant survival benefit of adjuvant, platinum-
required due to the close proximity of the right upper       based chemotherapy for patients with stage II NSCLC
lobe orifice to the main bronchus. Sleeve lobectomy (vs      who have undergone complete surgical resection.
pneumonectomy) is the preferred resection when pos-          Although no clear survival benefit has been noted,
sible for tumors extending into the orifice of the lobar     patients with incompletely resected tumors or those
or mainstem bronchus.                                        with mediastinal nodal metastases should receive post-
   When invasion into peribronchial tissues or N1 disease    operative radiation therapy to decrease the incidence of
is present, sleeve lobectomy can be attempted if the dis-    local recurrence.15 Intraoperative implantation of radio-
ease is limited, but pneumonectomy is usually required       isotopes may potentially be of some benefit for those
for extranodal spread. If the tumor extends very close       patients who undergo an incomplete resection. The role
to the carina, resection of the main bronchus flush with     of induction chemoradiotherapy in poor prognostic T3
the trachea may be required to encompass the tumor           tumors (N2 disease, full thickness chest wall invasion)
with negative margins. In this case, stapling of the bron-   is now being investigated.
chial stump may not be possible and a hand-sewn closure
may be required. If not, tracheal sleeve pneumonectomy
is the procedure of choice.                                  STAGE III DISEASE
   Airway management and ventilation are of paramount
importance when the proximal bronchi are resected.           Stage IIIA (T3N1) disease
Standard double lumen endobronchial tubes or endo-           T3 tumors with associated ipsilateral bronchopulmo-
bronchial blockers with single lung ventilation can be       nary or hilar lymph node involvement comprise the first
utilized for sleeve resections of the main bronchi. Tra-     category of stage IIIA disease. The preferred treatment
cheal sleeve pneumonectomy requires ventilation of the       is, again, complete resection via lobectomy with medi-
distal remaining lung. This problem can be handled in        astinal lymph node dissection. The previously men-
several ways, including passage of a thin, single lumen      tioned issues concerning N1 disease apply in this setting
endotracheal tube past the anastomotic site, jet ventila-    as well.
tion into the distal lung, or in-field ventilation through
the open bronchus using sterile ventilator tubing.           Stage IIIA (N2) disease
   Factors which adversely affect long-term survival fol-    The decision to perform primary surgical resection for
lowing resection include peribronchial extension of the      patients with N2 disease requires careful preoperative
tumor and the presence of N2 nodal metastases. Over-         selection, since the overall five-year survival for patients
all five-year survival following complete resection for      with N2 disease undergoing surgical resection alone is
tumors within 2 cm of the carina is currently reported       a mere 5–15%. Those with only single station, intracap-
to be 36%;21 however, patients with tumor confined to        sular nodal disease, T1 primary tumors, and ‘clinically’
the main bronchi with no invasion of peribronchial tis-      negative mediastinums by mediastinoscopy or CT
128 Textbook of Lung Cancer

scanning are reported to enjoy a five-year survival of          Multimodality therapy
approximately 30% following complete surgical resec-            Induction chemotherapy emerged as an option for
tion, compared to less than 10% for those with ‘bulky’          patients with N2 disease after it became clear that only
N2 disease identified preoperatively and those with             a minority of these patients benefit from surgical resec-
associated T3 primary tumors.23 Patients with left upper        tion alone and that preoperative radiation therapy has
lobe tumors and N2 disease confined to level 5 or 6             no effect on survival. To date, many phase II trials of
have the best prognosis of all, with five-year survival         induction chemotherapy or chemoradiation therapy
rates as high as 42% when completely resected.24 Unfor-         both with and without postoperative adjuvant therapy
tunately, patients with ‘minimal’ N2 involvement for            have been reported. Preoperative chemotherapy, such
whom primary surgery is beneficial represent a small            as the MVP regimen utilized at The Memorial Sloan
fraction of all patients with N2 disease, and clearly fur-      Kettering Cancer Center and The University of Toronto,
ther therapeutic advances need to be made for those             has shown survival benefit in this group of patients
patients with bulky, ‘clinical’ N2 disease.                     when compared to historical controls.28,29 The majority
   Although adjuvant radiotherapy provides no survival          of reports, however, deal with preoperative chemora-
benefit compared to surgery alone, a reduction in local         diation and essentially mirror the results of the previ-
recurrence is seen.15 Unfortunately, 80% of patients            ously mentioned induction chemotherapy trials.
undergoing surgical resection for NSCLC with N2 nodal           Although hundreds of patients have been enrolled in
disease recur at distant metastatic sites (especially brain),   such phase II studies, no real effect of the treatment can
suggesting that further systemic therapy is needed to           be assessed for two reasons. First, the chemotherapy and
improve survival.                                               radiotherapy protocols have varied widely from one trial
   Postoperative, adjuvant chemotherapy has been used           to the next, as did the extent of preoperative staging,
in an attempt to improve survival for patients with             making the results difficult to interpret. Second, patients
resected stage IIIA (N2) NSCLC. Until recently, how-            in these phase II trials are not randomized, and there-
ever, this strategy has not been shown to be of signifi-        fore no control groups exist other than historical data.
cant benefit in the adjuvant setting. In this regard, a            Three small phase III trials do exist comparing induc-
meta-analysis of 52 previously conducted randomized             tion chemotherapy and surgical resection to surgical
trials of adjuvant chemotherapy for completely resected         resection alone in the treatment of patients with N2 dis-
NSCLC suggested only a small advantage (5% at five              ease (Table 10.1.3). Although different chemotherapy
years) of cisplatin-based chemotherapeutic regimens             protocols were utilized and the numbers were small,
given in the adjuvant setting.25 As a result of the meta-       the survival rates were significantly higher in two of
analysis, the International Adjuvant Lung Cancer Trial          these studies30,31 in the chemotherapy groups compared
(IALT) randomized 1867 patients with completely                 to the control arms, with the third showing a similar
resected NSCLC to either observation or cisplatin-based         trend.32 Surprisingly, in all three studies, the rate of
chemotherapy.26 Of these, nearly 40% had stage III dis-         complete resection was no different in the treatment
ease. The overall survival rate across all stages was           arms compared to the control arms. These three small
significantly higher in the chemotherapy group (44.5%           phase III trials and the phase II trials that have been
at five years) versus the surgery alone group (40.4%),          matched to historical controls seem to suggest an improve-
representing a small, but significant advantage. Sub-           ment in survival for these patients, at least with induc-
group analysis, however, revealed that the patients             tion chemotherapy, but the results of current, larger
which received the most benefit were those with stage           phase III trials for N2 disease will be important, espe-
III disease.                                                    cially since a French trial suggested no benefit of induc-
   Data from Japan has suggested a significant survival         tion chemotherapy for patients with N2 disease.33
advantage for patients receiving oral tegafur plus uracil          Treatment-related mortality in the induction trials
(UFT) following complete surgical resection of NSCLC            has resulted from the chemotherapy, radiation therapy,
compared with surgery alone. Although these results             and surgery, or a combination of these modalities. Most
have not been reproduced in all studies using this strat-       trials report a treatment-related death rate in the range
egy, and no data exist outside of Japan, a recent meta-         of 5–15%. Chemotherapy-related deaths are dependent
analysis including data from 2003 patients demonstrated         on the specific agent and dose, as well as the immuno-
that adjuvant therapy with UFT does indeed provide a            suppressive effects of these drugs. Morbidity following
survival advantage.27 However, this agent is not avail-         induction chemotherapy can be manifested in several
able for use in the USA.                                        organ systems. Pulmonary function studies should be
                                                                                                          Treatment of NSCLC: surgery 129

 Table 10.1.3 Three phase III trials of induction chemotherapy for NSCLC with ipsilateral mediastinal lymph node metastases

 Author                 Number of patientsa                Chemotherapy agents           Percent resectablea           Median survivala,b

 Pass32                 13/14                              Cisplatin                     85/86                         29/16
 Roth30                 26/32                              Cisplatin                     61/66                         64/11
 Rosell31               30/30                              Mitomycin                     85/90                         26/8
     Induction chemotherapy followed by surgery group/surgery alone group.
     Overall median survival in months.

repeated after induction chemotherapy to assess the                          Perioperative corticosteroids can effectively treat both
pulmonary effects of such drugs as mitomycin and cyclo-                      mitomycin and radiation-induced pulmonary toxicity
phosphamide, which appear to be toxic to both the pul-                       as well. Tight control over fluid administration should
monary endothelium and epithelium, resulting in impaired                     be realized, thereby avoiding pulmonary edema as a
diffusion of gases. Cardiac toxicity of doxorubicin should                   result of impaired cardiac and renal function, but still
be assessed with a myocardial imaging study following                        maintaining enough volume for adequate end organ
the administration of this drug, and creatinine clear-                       perfusion.
ance should be measured following treatment with cis-                           Finally, the role of surgical resection itself for patients
platin and the vinca alkaloids if the serum creatinine                       with N2 disease was addressed by the results of the
level has become elevated. These chemotherapy-                               North American Intergroup 0139 Trial.34 In this study,
specific toxicities demand that the induction chemo-                         patients who received induction chemoradiotherapy were
therapy patient be monitored more closely in the                             randomized to either surgical resection or continued
perioperative period to prevent failure of an already                        radiotherapy without an attempt at resection. Although
compromised organ system.                                                    the initial survival analysis revealed no difference in
   Bronchial obstruction needs to be relieved prior to                       overall survival, progression-free survival was signifi-
the administration of cytotoxic drugs to avoid postob-                       cantly prolonged in the patients undergoing resection.
structive pneumonia and death during leukopenic                              This observation, combined with the higher treatment-
events. This can be handled either with radiation ther-                      related mortality in the surgical arm (mainly in pneu-
apy or endobronchial resection techniques/stents. Radi-                      monectomy patients), suggests that if perioperative care
ation therapy is also associated with toxicity that, when                    can be optimized, especially for patients undergoing
given in combination with chemotherapy and surgery,                          pneumonectomy, surgical resection may offer these
can result in the patient’s demise. Examples include the                     patients the best chance for long-term survival.
enhanced pulmonary toxicity when radiation therapy is
used with mitomycin, the myocardial damage when                              Stage IIIB (T4 or N3) disease
used with doxorubicin, and the higher incidence of                           Patients with this stage of locally advanced NSCLC are
bronchopleural fistula in irradiated patients following                      considered inoperable. Exceptions do exist, however,
pulmonary resection.                                                         and generally apply to selected patients with T4 dis-
   Morbidity and mortality from the surgical procedure                       ease. Tracheal sleeve pneumonectomy can be considered
itself can be minimized by careful anesthetic management,                    for the occasional patient with endobronchial tumor
close perioperative monitoring of cardiac, pulmonary,                        involving the main carina; however, involvement of
and fluid status, as well as some specific interventions                     peribronchial tissue or lymph nodes should preclude
to treat certain toxicities. For example, mitomycin pul-                     this procedure. The five-year survival for patients with
monary toxicity appears to be exacerbated by high inspired                   T4 (carina) N0 tumors undergoing tracheal sleeve
oxygen fractions. Therefore, the lowest possible oxygen                      pneumonectomy has been reported to approach 20%;
concentration in the inspired gases should be used,                          however, the operative mortality from this procedure
while maintaining adequate oxygenation of the blood.                         can be as high as 15–30%.35,36
130 Textbook of Lung Cancer

   It is presently debated whether subclavian artery            Brain metastases
invasion represents T3 or T4 disease, but apical tumors         Approximately one-third of patients with NSCLC and
invading this vessel should be resected if a complete           brain metastases present initially with neurologic symp-
resection can be performed. This vessel can be recon-           toms, with the lung cancer being found only after a
structed either primarily or with a synthetic graft. Again,     search for the primary tumor has been carried out. In
for patients to benefit from such an extended resection,        addition to the patients with stage IV disease at presen-
node-negative status should be confirmed prior to               tation, recurrences following resection of NSCLC are
resection using cervical mediastinoscopy.                       most commonly distant metastases, and of these, nearly
   Sporadic reports exist concerning aortic resection for       30% are located in the brain. It is now accepted that
T4 tumors with an occasional long-term survivor,37 but          patients with solitary brain metastases from NSCLC are
no significant survival benefit has been demonstrated in        best treated by resection of the brain lesion followed by
these patients. Similarly, although technically possible,       postoperative whole-brain radiation therapy. Using this
resection of tumors involving the vertebral body has            strategy, five-year survival in these patients should
not been shown to provide a survival advantage.38 These         approach 20%. Even if a cure is not obtained, survival
last two scenarios should be considered for clinical pro-       is prolonged and quality of life improved when com-
tocols involving induction chemo(radio)therapy, fol-            pared to a non-surgical approach.40
lowed by reassessment. If a significant response is seen,          When patients present with NSCLC and a single, syn-
resection can be considered in the protocol setting.            chronous brain metastasis, and both lesions are resect-
   If, at thoracotomy for presumed T3 disease, an incom-        able, the brain tumor should be resected prior to the
plete resection is all that can be done due to involvement      primary tumor, provided that no urgent intrathoracic
of mediastinal organs or vessels (T4), partial resection        process is occurring (i.e. massive hemoptysis). This strat-
with implantation of radioisotopes combined with post-          egy is based on the observation that recovery from
operative external beam radiation may provide some              intracranial surgery is less intensive than that from tho-
benefit with up to a 10% salvage rate, but has never been       racotomy. If the resectability of either lesion is in question
compared to primary (external) radiotherapy as an alter-        prior to surgery, one should approach the questionable
native approach.                                                lesion first to ensure that both lesions can be completely
   Although technically considered to be T4 disease, patients   resected prior to undertaking a potentially unnecessary
with multiple lesions in the same lobe (‘satellite’ lesions)    operation. If a brain metastasis is found but a search for
constitute a unique subgroup of stage IIIB NSCLC. Fol-          the primary tumor is negative, one should proceed with
lowing anatomic resection, patients with T4 disease due         resection of the intracranial tumor.
to the presence of satellite lesions enjoy appreciably
longer survival than other subgroups of stage IIIB lung         Adrenal metastases
cancer.39 As a result, when satellite lesions are detected      Solitary metastases to the adrenal glands are being diag-
preoperatively, patients should undergo lobectomy and           nosed with greater frequency due to routine scanning of
mediastinal lymph node dissection whenever possible.            the upper abdomen with newer generation, spiral CT
                                                                scanners. The utility of adrenalectomy for a solitary NSCLC
                                                                metastasis has been reported in small case series and indi-
STAGE IV DISEASE                                                vidual reports. In a relatively large series of patients with
                                                                solitary adrenal metastases (23 patients), an overall sur-
Surgery for stage IV disease is limited to young, healthy       vival of 23.3% was obtained after resection of the lung and
patients with a solitary site of metastatic disease, and an     adrenal lesions.41 Patients with metachronous lesions and
easily resectable primary tumor contained within the            a disease-free interval of more than six months received
chest. An exhaustive search should be carried out prior         the greatest benefit from this aggressive approach.
to consideration of resection of stage IV disease, looking
for other sites of metastatic disease not clearly evident
by history and physical examination. Positron emission          SPECIAL CONSIDERATIONS
tomography (PET) may emerge as a useful test for this
purpose, and all suspicious lesions should be biopsied          Superior sulcus tumors
to obtain a histologic diagnosis. Solitary bone, liver, and     Superior sulcus tumors are apical lung cancers that are
skin metastases are rare, but the following sites warrant       at least T3 by definition, since they invade the chest
mentioning due to their more frequent occurrence.               wall. In addition to chest wall invasion, these tumors
                                                                                             Treatment of NSCLC: surgery 131

also invade neighboring vital structures including the           synchronous primaries or one lesion is a metastasis
brachial plexus, vertebral body, and subclavian ves-             from the other. When the tumors are of different his-
sels.42 Presenting symptoms almost always include pain           tologies, the diagnosis of synchronous primary lung
in the shoulder radiating down the upper, inner aspect           cancers is made. If the lesions are of the same histology,
of the arm (T1 nerve root) as well as into the ulnar dis-        cervical mediastinoscopy should be routinely performed
tribution in the hand (C8 nerve root). Patients may also         because if positive mediastinal nodes are discovered,
have Horner’s syndrome, resulting from invasion of the           the chance of one lesion being metastatic rises. Patho-
stellate ganglion in the sympathetic chain, a condition          logic evidence of two separate primary tumors is the
which implies advanced local invasion.                           presence of carcinoma in situ in both lesions; however,
    Treatment of these lesions is by surgical resection. Prior   this information is rarely present at the time of sur-
to resection, mediastinal node metastases must be ruled          gery.46 In many equivocal instances, the ‘benefit of the
out using cervical medastinoscopy owing to the poor              doubt’ is given to the patient and the tumors are labeled
prognosis of these patients after resection when N2 dis-         as synchronous primaries.
ease is present. Several different operative approaches             Optimal oncologic treatment for patients with syn-
have been described, depending on whether the tumor              chronous primary NSCLC is two staged lobectomies for
invades the anterior or posterior aspect of the first rib.       contralateral tumors, and bilobectomy or pneumonec-
It is agreed that posterior lesions should be approached         tomy for ipsilateral tumors. In cases where the resectabil-
through a posterolateral thoracotomy extending up to             ity of one lesion is questioned, the questionable tumor
the neck, as described by Shaw et al.42 This enables the         should be resected first. If the patient’s lung function
scapula to be lifted off the chest wall and access to the        permits only one lobectomy, a decision must be made
apex of the hemithorax from outside the chest wall.              as to which lesion will be resected via lobectomy and
Tumors that appear to invade more anteriorly can be              which will be approached with a limited resection.
approached through any number of anterior approaches,            Generally, the limited resection should be reserved for
the most common being an L-shaped transcervical inci-            the smaller, squamous cell cancers, since these are less
sion43 and the hemiclamshell approach.44 The advan-              likely to spread via lymphatics than adenocarcinomas.
tage of the hemiclamshell incision is easy access to the         Limited resection should consist of segmentectomy
pulmonary hilum for the performance of lobectomy                 instead of wedge resection whenever possible. A third
with mediastinal lymph node dissection. In addition to           option is to perform multiple segmentectomies in
lobectomy, the standard operation for superior sulcus            patients with limited pulmonary reserve.
tumors includes the resection of at least the first rib, the
transverse processes of the vertebral bodies associated          Bronchioloalveolar carcinoma
with each resected rib, and the T1 nerve root.                   Bronchioloalveolar carcinoma represents a unique sub-
    Following complete resection, the five-year survival         type of NSCLC which appears to be increasing in inci-
of patients with superior sulcus tumors approximates             dence. This increase may be real, or may represent
30%. Unfortunately, many patients do not have a com-             heightened recognition of this variant by pathologists.
plete resection due to invasion of the previously men-           This disease seems to occur mainly in elderly women
tioned vital structures. To address this issue, the              with a negligible smoking history. Three distinct clinical
Southwest Oncology Group Trial 9416 administered                 scenarios seem to be able to arise with BAC.
induction chemoradiotherapy in a phase II design to                 First, and most common, patients may present with
111 patients with superior sulcus tumors.45 Of the 83            a solitary pulmonary nodule. These lesions are usually
patients who underwent subsequent thoracotomy, 92%               picked up by routine chest radiograph and are asymp-
had a complete resection. The five-year survival was             tomatic. Mediastinal lymph nodes are uncommonly
44% for all patients and 54% for those who underwent             involved. Treatment is lobectomy and long-term sur-
a complete resection. Given these encouraging results,           vival seems to be excellent.
induction chemoradiotherapy followed by surgical                    Second, some patients with BAC will present with
resection has become the standard for patients with              small lesions that resemble infiltrates, termed ground-
superior sulcus tumors in most centers.                          glass opacities (GGOs). These lesions are not visible on
                                                                 standard chest radiography and are increasingly being
Multiple primary tumors                                          detected on screening, low-dose, computed tomography
It is not uncommon for patients to present with more than        (Figure 10.1.2). In addition, they tend to be multiple
one lung malignancy. Either these tumors represent               and also recur frequently following resection, especially
132 Textbook of Lung Cancer

                                                                   be used to confirm negative margins, and when posi-
                                                                   tive, further tissue should be resected. A positive bron-
                                                                   chial resection margin can be treated by reresection of
                                                                   the bronchus and performance of a bronchoplastic pro-
                                                                   cedure, or even pneumonectomy if necessary. Carcinoma
                                                                   in situ remaining at the bronchial stump may not adversely
                                                                   effect prognosis,49 but this has not conclusively been
                                                                   proven and even this early disease should currently be

                                                                   Completion pneumonectomy
                                                                   Patients with locally recurrent NSCLC or second pri-
                                                                   mary tumors following resection should be evaluated in
                                                                   a similar fashion to those who present with their first
                                                                   cancer. If there is no evidence of distant disease and the
                                                                   remaining pulmonary function is adequate, these patients
Figure 10.1.2
                                                                   should be considered for completion pneumonectomy.
CT of the chest revealing a ground-glass opacity, a lesion not        Completion pneumonectomy is a technically chal-
visible on chest radiography. Biopsy revealed bronchioloalveolar   lenging operation, requiring that the surgeon review
carcinoma.                                                         the previous operative notes to learn about the anatomy
                                                                   and potential hazards of the reoperation. Mobilization
in areas of lung distant from the primary tumor (multi-
                                                                   of the lung should be performed intrapleurally when-
focal BAC). This implies that this form of BAC may be
                                                                   ever possible to avoid excessive bleeding and damage
spread throughout the airway by means of aerosol.
                                                                   to neighboring structures. Intrapericardial ligation of
Standard treatment is presently resection, but care must
                                                                   the vessels also serves to reduce the chance of hemor-
be given to the conservation of lung, since these tumors
                                                                   rhage. Intraoperative use of topical hemostatic agents as
tend to recur with great frequency. Whether or not
                                                                   well as efficient coagulating devices is helpful.
these patients benefit from repeated attempts at resec-
                                                                      Operative mortality following completion pneumo-
tion as opposed to observation is currently unknown.
                                                                   nectomy is in the range of 10%, slightly higher than
   Third, a minority of patients will present with a lobar
                                                                   that seen with standard pneumonectomy.50 Postopera-
infiltrate representing lobar replacement with BAC.
                                                                   tive morbidity is in the 20% range, with a significant
Radiologic studies give the appearance of dense con-
                                                                   proportion of complications related to bleeding. Long-
solidation that has arisen over a period of weeks to
                                                                   term survival in patients with NSCLC who undergo this
months. This presentation of BAC carries a poor prog-
                                                                   operation is approximately 30%, indicating that com-
nosis, with many patients recurring with widespread
                                                                   pletion pneumonectomy is a worthwhile procedure in
infiltrative disease and respiratory failure following
                                                                   selected patients.50
resection. For this reason, it is unknown whether these
patients benefit at all from resection.
   Prognosis in patients with BAC seems to correlate
most with the radiographic appearance of the lesion(s).47          PALLIATIVE SURGERY
Other factors that have been implicated as poor prog-
nosticators in some studies, but not in others, are a              Pleural disease
mucinous histology and the presence of vascular inva-              Patients with diffuse pleural disease (T4) typically pres-
sion. The effect of chemotherapy remains unknown in                ent with dyspnea and a pleural effusion. The diagnosis
patients with BAC. Isolated reports of successful dou-             should be confirmed and is most easily obtained by place-
ble-lung transplantation for recurrent BAC with long-              ment of a chest tube and examining the fluid for malig-
term survivors have been described, but this procedure             nant cells. Once the diagnosis of a malignant pleural
remains investigational in the treatment of BAC.48                 effusion is confirmed, pleurodesis with sterile talc or other
                                                                   pleural irritant is warranted to prevent recurrence.
Positive resection margins                                            If a patient presents with obvious end-stage meta-
Every attempt should be made intraoperatively to resect            static disease and a new pleural effusion, a simple tho-
with negative margins. Frozen section analysis should              racentesis may relieve some of the dyspnea and allow
                                                                                                Treatment of NSCLC: surgery 133

the patient to be discharged home to their family. This        SUMMARY
strategy should be reserved for patients who are antici-
pated to expire within the next few weeks.                     Surgery for NSCLC has evolved considerably over the
   Thoracoscopic exploration is warranted in the fol-          past 50 years. Resection is currently indicated for patients
lowing selected instances. First, if the fluid is negative     with early stage (I, II, selected IIIA) disease, while che-
for malignant cells and a malignant diagnosis will affect      motherapy and radiation are used for more advanced
the treatment plan. Second, if the lung fails to re-ex-        disease. The mainstay of surgical therapy remains ana-
pand after drainage of fluid, thoracoscopic intervention       tomic lobectomy with complete mediastinal lymph node
may be necessary just for the strategic placement of           dissection, provided the patient can physically tolerate
chest tubes to facilitate expansion, and third, after a        this procedure. Care must be taken to ensure a complete
poor result from a bedside pleurodesis as manifested by        resection since incomplete resections do not cure.
the rapid reaccumulation of fluid. The role of formal             Recent developments in the care of resectable lung
decortication is very limited in these patients due to         cancer patients include the adoption of adjuvant che-
their extremely short life expectancy.                         motherapy for patients with completely resected stage
                                                               II–III disease, the importance of surgical resection in
Endobronchial disease                                          the multimodal therapy regimen for stage IIIA NSCLC,
Unresectable endobronchial tumor is a not infrequent           as well as the use of induction chemoradiotherapy for
occurrence in patients with NSCLC. Typically, these            superior sulcus tumors. With increasing use of low-
patients may present with airway occlusion with distal         dose, screening CT for individuals thought to be at high
pulmonary collapse and pneumonia, dyspnea, and                 risk for the development of lung cancer, the discovery
hemoptysis. The endobronchial disease may be the               of much smaller tumors is increasing in frequency, and
manifestation of either the primary tumor extending            further studies are necessary to establish the standard of
proximally in the airway or of nodal disease eroding           care for these lesions.
into the proximal tracheobronchial tree. Many times
the patient has had a previous pulmonary resection and
has a recurrence at the bronchial stump.                       REFERENCES
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18.   Martini N, Burt ME, Bains MS et al. Survival after resection of        pneumonectomy for bronchogenic carcinoma: a report of 55
      stage II non-small cell lung cancer. Ann Thorac Surg 1992; 54:         cases. Ann Thorac Surg 1988; 46: 68–72.
      460–6.                                                             36. Tsuchiya R, Goya T, Naruke T, Suemasu K. Resection of tra-
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      invasion and survival in patients with lung cancer. Ann Thorac         mortality. J Thorac Cardiovasc Surg 1990; 99: 779–87.
      Surg 1999; 68: 188–93.                                             37. Tsuchiya R, Asamura H, Kondo H et al. Extended resection of
20.   Martini N, Yellin A, Ginsberg RJ et al. Management of non-             the left atrium, great vessels, or both for lung cancer. Ann Tho-
      small cell lung cancer with direct mediastinal involvement. Ann        rac Surg 1994; 57: 960–5.
      Thorac Surg 1994; 58: 1447–51.                                     38. Grunenwald D, Mazel C, Girard P et al. Total vertebrectomy for
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      1984; 37: 279–85.                                                  39. Detterbeck FC, Jones DR, Kernstine KH, Naunheim KS. Lung
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      Thorac Surg 1988; 46: 178–81.                                      40. Burt M, Wronski M, Arbit E et al. Resection of brain metastases
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      Surg Clin North Am 1987; 67: 1037–49.                                  rac Cardiovasc Surg 1992; 103: 399–411.
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      static disease in subaortic lymph nodes. Ann Thorac Surg 1987;         solitary adrenal metastasis from non-small cell lung cancer.
      43: 155–9.                                                             J Thorac Cardiovasc Surg 2005; 130: 136–40.
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      apy in non-small cell lung cancer: a meta-analysis using updated       sulcus tumor by irradiation followed by resection. Ann Surg
      data on individual patients from 52 randomized, clinical trials.       1961; 154: 29–40.
      BMJ 1995; 311: 899–909.                                            43. Dartevelle P, Chapelier AR, Macchiarini P et al. Anterior trans-
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      vant chemotherapy in patients with completely resected non-            invading the thoracic inlet. J Thorac Cardiovasc Surg 1993;
      small cell lung cancer. N Engl J Med 2004; 350: 351–60.                105: 1025–34.
                                                                                                        Treatment of NSCLC: surgery 135

44. Korst RJ, Burt ME. Cervicothoracic tumors: results of resection        bronchioloalveolar carcinoma. Ann Thorac Surg 2002; 74:
    by the ‘hemiclamshell’ approach. J Thorac Cardiovasc Surg              1640–6.
    1998; 115: 286–95.                                                 48. Etienne B, Bertocchi M, Gamondes J-P et al. Successful double-
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    tion and surgical resection for superior sulcus non-small cell         1997; 112: 1423–4.
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    Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 2007;           Survival in resected stage I lung cancer with residual tumor at
    25: 313–8.                                                             the resection margin. Ann Thorac Surg 1998; 65: 212–16.
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    pathologic stage but not histologic features predict outcome for
10.2 Treatment of NSCLC: radiotherapy
              Merideth MM Wendland, William T Sause

              Contents Introduction • Early disease • Locally advanced disease • Superior sulcus tumors
               • Altered fractionation radiation therapy • Toxicity and patient selection • Prophylactic cranial irradiation
               • Palliative therapy • Conclusion

INTRODUCTION                                                    still offers curative potential. Although outcomes with
                                                                radiation alone are inferior compared to those obtained
In the USA, lung cancer is the number one cause of              with complete surgical resection, five-year cause-specific
cancer-related death for both men and women.1 In                survival rates of approximately 30% in stage I and II
2005, an estimated 175 000 new cases of lung cancer             disease have been obtained with the use of modern radi-
will be diagnosed and roughly 159 000 deaths from               ation therapy planning and delivery techniques.7–9 Doses
lung cancer will occur. Approximately 80% of patients           considered to be ‘curative’ when using radiation ther-
with primary lung cancer are diagnosed with non-small           apy alone are considered to be approximately 65 to 70
cell lung cancer (NSCLC).2                                      Gray (Gy) with standard fractionation (1.8 to 2.0 Gy per
   Radiation therapy remains a valuable therapeutic             fraction, five fractions per week), or a radiobiologically
modality in the treatment of NSCLC. In early stage dis-         equivalent dose when altered fractionation is utilized.
ease, definitive radiation therapy may be employed for             Dose escalation with conventionally fractionated radi-
patients who refuse or are medically unfit to undergo           ation therapy has demonstrated a dose–response relation-
surgical resection. Radiation therapy may also be used          ship with respect to both local control and survival.10,11
as adjuvant therapy for patients with incomplete resec-         Such dose escalation has not been associated with an
tion or node-positive disease. At initial presentation, many    increase in acute toxicity when three-dimensional con-
patients who receive a diagnosis of NSCLC have locally          formal radiation techniques are utilized.12,13 Stereotactic
advanced disease. Historically, these patients were treated     body radiation therapy using hypofractionation has been
with primary thoracic radiation therapy with poor long-         shown to produce excellent local control rates with
term survival rates secondary to both progression of            acceptable toxicity.14,15 A current phase II Radiation
local disease and development of distant metastases.            Therapy Oncology Group (RTOG) protocol will evalu-
With the goal of improving clinical outcomes, multiple          ate the safety and efficacy of delivering 60 Gy in three
permutations of combined-modality therapy for locally           fractions using stereotactic techniques in patients with
advanced NSCLC have been investigated. The optimal              early stage NSCLC.
treatment for locally advanced NSCLC continues to                  When considering combined-modality therapy,
evolve, but combined-modality therapy has led to                potential advantages of radiation therapy in the preop-
improved survival rates versus treatment with radiation         erative setting include possible improvement of the resec-
alone, and is the standard of care.                             tability of large tumors, prevention of dissemination of
                                                                tumor at the time of surgical resection, and the use of
                                                                lower doses of radiation. Disadvantages of this approach
EARLY DISEASE                                                   include the inability to determine the precise surgical
                                                                stage and an increased risk of postoperative complica-
In general, patients with stage I and II disease who are        tions such as wound healing. Randomized data have
medically fit undergo definitive surgical resection with        failed to demonstrate a statistically significant survival
good results. Newer data have demonstrated that adju-           benefit for the use of preoperative radiation therapy in
vant chemotherapy after complete surgical resection             the treatment of early stage NSCLC.16
can improve overall survival.3–6 For patients who are              Postoperative radiation therapy (PORT) has also been
medically unfit for or refuse surgery, definitive radia-        investigated in the context of randomized trials. The
tion therapy is an alternative treatment modality that          Lung Cancer Study Group (LCSG) evaluated the role of
                                                                                        Treatment of NSCLC: radiotherapy 137

PORT consisting of 50 Gy in 25 fractions to the medi-            Single-modality therapy
astinum following complete surgical resection in patients        While treatment with radiation therapy alone for patients
with stage II and III squamous cell lung carcinoma.17            with locally advanced NSCLC is potentially curative,
The rate of local failure as the site of first failure was       long-term survival rates are disappointing and gener-
reduced from 20% to 1% (p <0.01) with the addition of            ally are less than 15%.28,29 Analyses of the patterns of
PORT for patients with node-positive disease. This did           failure following treatment with radiation therapy alone
not result in an overall survival benefit for stage II           demonstrate that the poor survival rates are related not
patients, as approximately two-thirds of first failures          only to the inability of local therapy to control the pri-
were distant. For patients with N2 disease, there was an         mary tumor, but also to the development of distant
improvement in overall survival, although this differ-           metastases.29,30
ence was not significant.                                           The RTOG established prognostic groups determined
   In a randomized trial by the Medical Research Council         by recursive partitioning analysis (RPA) based on four
(MRC), patients with stage II and III disease were ran-          RTOG trials of patients with inoperable NSCLC treated
domized to receive 40 Gy of PORT or no further thera-            with definitive radiation therapy.31 Patterns of failure of
py.18 In subgroup analysis, patients with N1 disease did         1547 patients with stage II, IIIA, or IIIB NSCLC treated
not have improved outcomes with the addition of PORT.            with radiation therapy alone were then determined
For patients with N2 disease, the addition of PORT               based on RPA prognostic group.32 The median survival
resulted in a one month improvement in median over-              and the rates of primary and distant failures varied sig-
all survival, delayed time to local recurrence, and a lon-       nificantly based on RPA class, suggesting that specific
ger interval to the development of bone metastases.              cohorts of patients may benefit from more aggressive
   A meta-analysis performed by the PORT Meta-analysis           treatment directed at specific sites of failure.
Trialists Group confirmed that PORT does not confer a
survival benefit for patients with early stage NSCLC and         Combined-modality therapy
may actually decrease survival for patients with stage I and     When local control is defined by complete clinical,
II disease, with a reduction in two-year survival rate from      radiographic, endoscopic, and histologic remission, the
55% to 48% with the addition of PORT.19 Other studies            local failure rate is as high as 92% at 5 years.30 Distant
have supported the conclusion that PORT may result in            failure rates after radiation therapy alone are approxi-
increased toxicity without survival benefit in stage I and II    mately 80%.29 These findings have led to the exploration
disease, but it may be advantageous in stage III disease.20–24   of combined-modality therapy utilizing chemotherapy
                                                                 in the treatment of such patients.
                                                                    Many possible combinations of induction therapy
LOCALLY ADVANCED DISEASE                                         have been investigated in a multitude of trials evaluat-
                                                                 ing the role of combined-modality therapy in the treat-
Definition                                                       ment of locally advanced NSCLC. Interpretation of the
It is estimated that 30% of patients with NSCLC have             data and comparisons of results between even well
locally advanced disease without distant metastases at           designed trials are difficult for many reasons. There have
presentation, but few such patients present with disease         been several changes in the staging systems over time
amenable to primary surgical resection with curative             and the terms ‘unresectable’, ‘marginally resectable’, and
intent.25 The term locally advanced as applied to NSCLC          ‘locally advanced’ have been variably defined. Addition-
generally implies stage III disease.26 Stage III disease is      ally, no standards exist regarding the extent of surgical
subdivided into IIIA and IIIB. Generally speaking, patients      staging or resection, the dose of radiation therapy deliv-
with stage IIIA disease (e.g. ipsilateral mediastinal nodal      ered, or the chemotherapeutic agents used and in what
involvement) have potentially resectable disease at pre-         combinations and doses. The optimal treatment of
sentation, while those with stage IIIB disease (e.g. medi-       locally advanced NSCLC continues to be defined, but
astinal invasion, contralateral nodal involvement) do            long-term survival rates have improved with combined-
not. Further, the volume of ipsilateral mediastinal nodal        modality therapy, which is now considered the standard
disease has prognostic value.27 Thus, individuals with           of care.33–35
stage III NSCLC comprise a heterogeneous group of                   There are two basic treatment protocols for adminis-
patients with a range of prognoses based upon disease            tering combined chemotherapy and radiation. Sequential
extent at diagnosis. As such, these patients present a           treatment with chemotherapy followed by radiation ther-
unique therapeutic challenge.                                    apy was the first widely utilized combination in locally
138 Textbook of Lung Cancer

advanced NSCLC. Concurrent chemoradiation has dem-                               In North America, the Cancer and Leukemia Group
onstrated promising results with respect to prolonging                        B (CALGB) 8433 trial is the landmark study of sequen-
survival, and is considered the current standard of care.                     tial chemoradiation versus radiation therapy alone for
                                                                              the treatment of locally advanced NSCLC.39 A total of
Sequential chemoradiation                                                     155 eligible patients with clinical or surgical T3 or N2
When radiation therapy follows induction chemother-                           NSCLC without evidence of distant metastases were
apy, the effects of chemotherapy decrease the local                           randomized to induction chemotherapy with cisplatin
tumor burden and may permit delivery of radiation to                          and vinblastine followed by radiation therapy or radia-
a reduced tumor volume. Induction chemotherapy may                            tion therapy alone. Radiation therapy to a total dose of
also eliminate or prevent the growth of subclinical sys-                      60 Gy in 30 fractions was the same in both arms and
temic disease. Increased drug delivery with less overall                      began on day 50 in the combined-modality arm. All
toxicity is also more likely compared to concurrent                           patients had a good performance status and minimal
administration. Potential drawbacks of sequential admin-                      weight loss prior to study entry. The addition of chemo-
istration include a prolonged overall treatment time,                         therapy did not impair the ability to deliver radiation
excessive toxicity due to chemotherapy preventing or                          therapy, with 88% of patients in the combined-modality
delaying the delivery of radiation, induction of acceler-                     arm and 87% of patients on the radiation therapy alone
ated repopulation, and chemotherapy-induced tumor                             arm completing radiation therapy per protocol. Long-
cell resistance resulting in reduced radiation efficacy.36–38                 term seven-year followup confirms that induction
Many phase II trials have been designed to evaluate                           chemotherapy improves median survival compared to
whether or not survival is improved with the addition of                      radiation therapy alone.40 Three other modern cisplatin-
induction chemotherapy to radiation therapy in patients                       based trials have confirmed the CALGB experience.
with locally or regionally advanced NSCLC. Although                              A US Intergroup trial randomized 458 eligible patients
these trials have had conflicting results, several phase                      with good performance status, minimal weight loss, and
III trials (Table 10.2.1) and three meta-analyses have                        unresectable, localized NSCLC to receive once daily
demonstrated a survival benefit, and recent updates have                      radiation therapy to 60 Gy in 2 Gy fractions with or
provided relatively long-term data.                                           without induction cisplatin and vinblastine.41 Patients

 Table 10.2.1 Randomized trials of chemotherapy and radiation therapy versus radiation therapy alone

 Trial                             CT            RT dose (Gy)         Median survival (months)             p value          Three-year survival (%)

                                   VP                 60                          13.7                        0.012                    23
                                                      60                           9.6                                                 11
 US Intergroup41,42
                                   VP                60                           13.8                                                     5b
                                                     60                           11.4                        0.03                         8b
                                                  69.6 BID                        12.3                                                     6b
                                 VCPC                 65                          12.0                        0.02                         6b
                                                      65                          10.0                                                     3b
                                  MIC                 50c                         13.0                        0.056                    14
                                                      50c                          9.9                                                 10
 CT: chemotherapy; RT: radiation therapy; CALGB: Cancer and Leukemia Group B; MRC: Medical Research Council; VP: vinblastine, cisplatin;
 VCPC: vindesine, cyclophosphamide, cisplatin, lomustine; MIC: mitomycin, ifosfamide, cisplatin; BID: twice daily.
   Versus the sequential arm.
   Five-year rates.
   Median RT dose.
                                                                                      Treatment of NSCLC: radiotherapy 139

randomized to a third arm received radiation therapy           include sensitization of tumor cells to radiation and
alone twice daily to a total dose of 69.6 Gy. Median sur-      reduced overall treatment time.53 Potential disadvantages
vival was statistically superior for the combined-modality     of concurrent chemoradiation include increased mor-
arm versus either the standard radiation therapy arm or        bidity requiring reductions in the dose intensity of che-
the twice-daily radiation therapy arm. Final results of this   motherapy and unplanned delays in the administration
study confirmed combined-modality therapy improves             of radiation therapy.37,38,54
median survival, but five-year survival rates remained            An important early European Organization for Research
poor at less than 10%.42                                       and Treatment of Cancer (EORTC) trial randomized 331
   In another phase III trial conducted in France, 353         patients with unresectable stage I, II, or III NSCLC to
patients with unresectable locally advanced squamous           treatment with radiation therapy alone, radiation ther-
cell or large cell lung carcinoma were randomized to           apy with weekly cisplatin (30 mg/m2), or radiation ther-
receive either radiation therapy alone (65 Gy in 2.5 Gy        apy with daily cisplatin (6 mg/m2).55 On all three arms,
fractions) or three monthly cycles of cisplatin-based          the same definitive split-course radiation therapy sched-
chemotherapy followed by the same radiation therapy            ule consisting of 60 Gy in 20 fractions with a three-week
regimen.43 There was a significant decrease in distant         rest after the first 30 Gy was utilized. The administra-
metastases for the combined-modality arm and the median        tion of daily cisplatin was shown to significantly improve
and two-year survival rates (21% vs 14%, p = 0.02,             overall survival (16% vs 2% at three years, p = 0.009
overall).44 Re-analysis revealed that only 8% of patients      overall) and disease-free survival (31% vs 19% at two
had continued local control at five years.30 Five-year         years, p = 0.003 overall) compared to radiation therapy
survival rates remained poor at 6% and 3%, likely sec-         alone. The weekly cisplatin arm also revealed a trend
ondary to the high rate of local failure on both arms.         towards improved survival compared to the radiation
   The MRC randomized 447 eligible patients with good          alone arm. The survival benefit observed with the addi-
performance status and localized, inoperable NSCLC to          tion of low-dose daily cisplatin was likely due to radia-
receive radiation therapy alone or cisplatin-based induc-      tion sensitization and improved local control.
tion chemotherapy followed by radiation therapy.45 On             While the EORTC trial above addressed the feasibility
both arms, the median radiation therapy dose was low           of administering chemoradiation in a multicenter setting
at 50 Gy. Median survival was improved with the addi-          and confirmed a survival benefit for combined-modality
tion of chemotherapy, although this difference was of          therapy, it still did not address the optimal timing of
borderline significance.                                       the two modalities. Several additional randomized trials
   As demonstrated by the above randomized trials, the         were designed to answer this question (Table 10.2.2).
addition of platinum-based induction chemotherapy to              The West Japan Lung Cancer Group (WJLCG) con-
radiation therapy results in improved survival as com-         ducted a large phase III trial to directly compare sur-
pared to radiation therapy alone. This is particularly         vival for sequential versus concurrent cisplatin-based
true for short-term survival, but modest improvements          chemoradiation.56 A total of 314 eligible patients with
in long-term survival have been observed as well. Sev-         unresectable stage III NSCLC were entered on the trial.
eral smaller randomized trials have failed to confirm a        Both the response rate and the median survival were
survival benefit for the addition of induction chemo-          significantly improved for patients who received con-
therapy, but these trials may have lacked the power to         current chemoradiation as compared to sequential
detect small differences in survival.46–49 Three large         treatment.
meta-analyses have demonstrated a small but consistent            The RTOG also compared sequential versus concurrent
survival benefit in the order of 5–10% at one year for         chemoradiation in a phase III randomized trial (RTOG
the addition of induction chemotherapy to radiation            94-10).57,58 In this trial, patients with unresected stage
therapy for locally advanced NSCLC.50–52                       II–III NSCLC and good performance status were ran-
                                                               domized to receive sequential chemoradiation, or con-
Sequential versus concurrent chemoradiation                    current chemoradiation with radiation delivered either
The benefit of combined-modality treatment with radi-          once or twice daily. With a median follow-up of 6.0 years,
ation therapy and chemotherapy was established by the          the concurrent arm receiving once-daily radiation ther-
CALGB 8433 trial and confirmed by other randomized             apy had an improved median survival compared to the
phase III studies.40,42,44,45 These trials, however, did not   sequential arm. The median survival of patients on the
address the optimal sequencing of the two modalities.          concurrent twice-daily radiation therapy arm was not
Potential advantages of concurrent chemoradiation              statistically different from the sequential arm.
140 Textbook of Lung Cancer

 Table 10.2.2 Randomized studies evaluating sequential versus concurrent administration of chemotherapy and radiation

 Trial                    Arm                               Response rate (%)          p value           Median survival (months)   p value

 WJLCG56                  Sequential                              66.6                                             13.3
                          Concurrent                              84.0                   0.0002                    16.5             0.04
 RTOG 94-10               Sequential                              NR                                               14.6
                          Concurrent, RT qd                       NR                   NR                          17.0             0.046a
                          Concurrent, RT BID                      NR                   NR                          15.2             0.296a
 Czech59                  Sequential                              47                                               12.9
                          Concurrent                              80                     0.001                     16.6             0.023
 French                   Sequential                              NR                                               13.8
                          Concurrent                              NR                   NR                          15.0             0.41
 WJLCG: West Japan Lung Cancer Group; RTOG: Radiation Therapy Oncology Group; qd: once daily; BID: twice daily; NR: not reported.
  Versus the sequential arm.

   Two additional randomized phase III trials, one con-                       versus 10 months, and three-year survival of 44% vs
ducted in the Czech Republic and another conducted                            18% (p = 0.0005).
in France, both demonstrated a significant improve-                              With the encouraging results of the above SWOG
ment with respect to median survival for concurrent                           phase II trial and others, an Intergroup phase III trial
chemoradiation versus sequential treatment.59,60 Based                        conducted by the RTOG was initiated.63 In this trial, all
in part on the results of the above randomized trials, the                    patients received induction chemoradiation and were
administration of chemotherapy and radiation therapy                          then randomized to surgical resection or further chemo-
concurrently, rather than sequentially, is considered                         radiation. Induction chemoradiation consisted of cis-
the standard of care for patients with locally advanced                       platin and etoposide given concurrently with 45 Gy of
NSCLC.                                                                        radiation therapy. Patients with responsive or stable
                                                                              disease following induction therapy underwent surgical
Induction chemoradiation                                                      resection followed by two postoperative cycles of che-
Once the efficacy and feasibility of concurrent chemo-                        motherapy, or continued radiation therapy to a total
radiation for locally advanced NSCLC was established,                         dose of 61 Gy concurrent with two additional cycles of
this approach replaced chemotherapy alone as the induc-                       chemotherapy. A total of 429 patients were entered on
tion regimen prior to surgery in many trials. An impor-                       the study, all with stage IIIA, N2 disease. These patients
tant example is SWOG 8805, a phase II trial designed                          were highly selected in that they had to be potential
to test the feasibility of concurrent chemoradiation fol-                     candidates for pulmonary resection and eligibility crite-
lowed by surgical resection in 126 patients with stage                        ria also required a Karnofsky Performance Status (KPS)
IIIA and IIIB disease.61 Induction therapy consisted of                       of 70 or greater. Of the 396 analyzable patients, 202
cisplatin and etoposide given concurrently with tho-                          were randomized to undergo surgical resection following
racic irradiation to 45 Gy. Patients with unresectable                        induction chemoradiation and 194 received definitive
disease, incomplete resection, or positive mediastinal                        chemoradiation. The most recent results were reported
nodes received an additional two cycles of chemother-                         with a minimum of 2.5 years of follow-up per patient
apy and radiation therapy to a total dose of 59.4 Gy.                         (Table 10.2.3). There were 16 (7.9%) deaths on the
Morbidity and mortality associated with this trial were                       chemoradiation and surgery arm and 4 (2.1%) deaths on
high. Mature results revealed no survival difference                          the chemoradiation only arm. A higher rate of death was
between patients with stage IIIA and IIIB disease, with                       observed following pneumonectomy versus lobectomy
a median survival of 13 months and 17 months, respec-                         (26% versus 1%, respectively). Although progression-free
tively.62 Absence of tumor in mediastinal nodes at sur-                       survival was significantly improved with the addition of
gery was the strongest predictor of long-term survival                        surgery, median survival and five-year survival rates
after thoracotomy, with a median survival of 30 months                        were not significantly different between the two arms.
                                                                                           Treatment of NSCLC: radiotherapy 141

 Table 10.2.3 Results of Intergroup trial 0139 (RTOG 9309), comparing induction chemoradiation followed by surgical resection
 versus definitive chemoradiation63

 Arm                           Number of patients         Progression-free survival       Median survival         Five-year
                                                          (months)                        (months)                survival (%)

 ChemoRT                               194                         10.5                        22.2                 20.3
 ChemoRT + S                           202                         12.8                        23.6                 27.2
 p value                                                            0.017                       0.24                 0.10
 ChemoRT: chemoradiation; S: surgery; NR: not reported.

Pathologic N0 disease at the time of surgical resection             induction therapy consisting of cisplatin and etoposide
predicted for long-term survival. These results suggest             given concurrently with thoracic irradiation to 45 Gy.66,67
that, while surgical resection after induction chemora-             This induction regimen was identical to that given in
diation increases progression-free survival compared to             SWOG 8805.61 A total of 95 (86.4%) patients had stable
definitive chemoradiation in patients with stage IIIA               disease or response to induction chemoradiation and
NSCLC, the addition of surgery may also increase the                underwent surgical resection followed by an additional
morbidity and mortality of treatment without improv-                two cycles of chemotherapy. Complete resection was
ing overall survival. Surgical resection following induc-           performed in 83 (94.3%) of the 88 patients who under-
tion chemoradiation may be considered in fit patients,              went thoracotomy. Pathologic complete response was
particularly if a lobectomy is to be performed.                     seen in 32 (36.4%) of the thoracotomy specimens and
   The German Lung Cancer Cooperative Group (GLCCG)                 an additional 26 (39.5%) revealed minimal microscopic
conducted a phase III randomized study to investigate               disease. The five-year and median survivals were 53% and
the timing and fractionation of radiation therapy when              71 months, respectively, for patients who had a com-
surgery is planned in patients with locally advanced                plete resection, and 41% and 33 months, respectively,
NSCLC.64 In this trial, 558 patients with stage IIIA and            for all patients who were eligible for resection. This rep-
IIIB disease received induction chemotherapy consist-               resented a significant improvement over historical data
ing of three cycles of cisplatin and etoposide. Patients            for NSCLC of the superior sulcus.
were then randomized to receive hyperfractionated
radiation therapy with concurrent carboplatin and vin-
desine followed by surgery, or surgery followed by                  ALTERED FRACTIONATION RADIATION THERAPY
standard fractionated radiation therapy to 54 Gy with-
out concurrent chemotherapy. There was no difference                Hyperfractionated and accelerated fractionation radiation
between the two arms with respect to response rate                  therapy have been investigated as potential approaches
after induction, complete resection rate (45% in both               to improve outcomes in patients with locally advanced
arms), treatment-related mortality, and three-year pro-             NSCLC. Delivering multiple fractions per day works to
gression-free survival and overall survival.                        counteract the effect of accelerated repopulation that
                                                                    occurs during normal treatment breaks. An adequate
                                                                    interval between fractions, generally six hours or longer,
SUPERIOR SULCUS TUMORS                                              allows for repair of sublethal damage in normal tissues,
                                                                    thus minimizing any increase in acute side-effects. Late
Tumors of the superior sulcus, also known as Pancoast’s             effects are also decreased due to the lower dose per
tumors, are a distinct subset of locally advanced NSCLC.            fraction.53
Previously considered inoperable and fatal, the use of                 A European multicenter trial randomized 563
single-modality radiation therapy has led to five-year              patients with locally advanced NSCLC and good
survival rates as high as 46%.65                                    performance status to either conventional radiation
   The use of trimodality therapy is now considered stan-           therapy or continuous hyperfractionated accelerated
dard of care for patients with tumors of the superior               radiotherapy (CHART).68 The CHART regimen con-
sulcus. This is based primarily on a phase II (Intergroup           sisted of 36 fractions of 1.5 Gy each given three times
0160, SWOG 9416) study in which 110 eligible patients               per day on 12 consecutive days. The use of CHART was
with T3–4, N0–1 tumors of the superior sulcus received              associated with a 9% improvement in overall survival at
142 Textbook of Lung Cancer

two years (29% vs 20%, p = 0.004). CHART was also                toxicity. Without exception, patients enrolled on the
associated with an increase in severe dysphagia (19%             combined-modality or ‘more aggressive’ treatment arms
vs 3%), but this occurred primarily after the comple-            of clinical trials experience increased toxicity as com-
tion of radiation therapy and thus did not interfere with        pared to single-modality controls.39,41,55–57
radiation delivery. Subgroup analyses revealed the great-           Important factors that influence outcome in patients
est benefit was for patients with squamous cell histology.       with locally advanced NSCLC include age, performance
   Jeremic and colleagues randomly assigned 131 patients         status, and degree of weight loss.71–73 Aggressive combined-
with stage III NSCLC to receive twice daily radiation            modality treatments require a ‘fit’ cohort of patients and
therapy to a total dose of 69.6 Gy with or without low-          proper patient selection is critical, as highlighted by the
dose daily carboplatin and etoposide.69 The combined-            results of RTOG 90-15.74 This phase I/II trial utilized
modality arm demonstrated an improved median                     cisplatin and vinblastine concurrent with twice-daily
survival (22.0 vs 14.0 months) and an improved four-year         radiation (1.2 Gy twice daily to 69.6 Gy) to treat patients
survival (23% vs 9%, p = 0.021). This represents an              with unresected stage II, IIIA, or IIIB NSCLC. All patients
approximately six-month improvement in median sur-               had a good performance status (KPS ≥70), but this trial
vival as compared to the concurrent chemoradiation arms          was initiated while RTOG 88-08 was still in progress
utilizing once daily radiation (Table 10.2.2).56,57,59,60        and, due to competition for enrollment, minimal weight
   A randomized study by the Eastern Cooperative Oncol-          loss was not included in the eligibility criteria. Of the
ogy Group (ECOG 2597) compared once-daily radiation              42 eligible patients, 76% had greater than 5% weight
therapy to hyperfractionated accelerated radiation therapy       loss preceding study entry. Grade 4 or higher acute tox-
(HART) following two cycles of induction chemotherapy            icity was observed in 45% of patients, with 7% of patients
with carboplatin and paclitaxel.70 Once-daily radiation          dying of sepsis related to chemotherapy-induced leu-
therapy was delivered with 2.0 Gy fractions to a total dose      kopenia. Median survival was 12.2 months in all patients
of 64 Gy. HART consisted of a total dose of 57.6 Gy using        and 17.5 months for the ten patients with less than 5%
1.5 Gy fractions delivered three times per day. The study        weight loss.
was closed early due to poor accrual. Based on the 141              Consideration must also be given to the timing of
patients who were enrolled, median survival was 20.3             surgical resection and the type of surgery that is planned
months on the HART arm and 14.9 months on the daily              after induction therapy. In general, preoperative che-
radiation therapy arm (p = 0.28). This also represents an        motherapy has not been shown to increase postopera-
approximately 6-month improvement in median sur-                 tive morbidity and mortality.75,76 Review of the Memorial
vival as compared to the concurrent chemoradiation               Sloan Kettering experience, however, has revealed that
arms utilizing once-daily radiation (Table 10.2.2).56,57,59,60   right pneumonectomy following induction chemother-
   While the initial results of altered fractionation radia-     apy significantly increases the risk of surgical complica-
tion therapy in the treatment of locally advanced NSCLC          tions, with 24% of patients dying postoperatively.76 The
are promising, at this time there is no confirmed addi-          mechanism behind the increased mortality after right
tional survival benefit for altered fractionation radiation      pneumonectomy is not well understood and the role of
therapy alone over concurrent chemotherapy and radi-             radiation therapy, if any, in increasing the risk of death
ation therapy. The hyperfractionated radiation therapy           is not known.
arms of the United States Intergroup trial and RTOG
94-10 trial were unable to confirm a significant sur-
vival benefit when compared to conventional radiation            PROPHYLACTIC CRANIAL IRRADIATION
therapy, even with long-term follow-up.42,58 Combin-
ing chemotherapy with altered fractionation radiation            The risk of central nervous system (CNS) failure is low
therapy has shown promise, but this approach has yet             in patients with early stage disease who undergo surgical
to be optimally defined and continued investigation is           resection. For patients with locally advanced disease,
warranted.                                                       15–30% will experience CNS failure as the site of first
                                                                 relapse.62,77,78 The overall CNS failure rate increases with
                                                                 increasing survival and is on the order of 20–50%.62,77–79
TOXICITY AND PATIENT SELECTION                                      Prophylactic cranial irradiation (PCI) has been shown
                                                                 in prospective randomized trials to delay and reduce
In locally advanced NSCLC, combined-modality ther-               the incidence of failure within the brain, but it has not
apy improves disease control at the cost of increased            been shown to improve survival.80,81 These studies have
                                                                                          Treatment of NSCLC: radiotherapy 143

been criticized for poor control of extracranial disease,         Superior vena cava (SVC) syndrome results from
which was the cause of death in the majority of patients       compression of the SVC with compromised return of
and also likely contributed to reseeding of the brain          venous blood flow to the heart. SVC syndrome occurs
after whole brain radiation therapy was completed.             in approximately 5% of all patients with lung cancer
   An ongoing North American Intergroup phase III              and it is characterized by presentation with dyspnea,
trial conducted by the RTOG randomizes patients with           facial and neck swelling, and distention of the veins of
stage III NSCLC who have been treated with definitive          the upper chest wall. Initial management may consist of
combined-modality therapy and have responsive or               medical therapy such as diuretics and/or corticoster-
stable disease to receive 30 Gy in 15 fractions of whole       oids. Effective palliation is often quickly achieved by
brain radiation therapy or no PCI. A study by the West         the use of radiation therapy. Commonly, several large
German Cancer Center will randomize patients with              fractions of 4 Gy are given for the first several days of
locally advanced NSCLC to one of two fractionation             treatment.89,90 Palliation of the symptoms associated
schemes of PCI (24 Gy in 12 fractions or 30 Gy in 15           with SVC syndrome is seen in approximately 90% of
fractions), or no PCI. These trials, which will collect data   patients within three weeks of initiation of therapy.91,92
on both survival and neuropsychologic sequelae of treat-
ment, will hopefully clarify the role of PCI in patients       CONCLUSION
with locally advanced NSCLC.
                                                               Lung cancer is a very common disease and even rela-
                                                               tively small advances in treatment have the potential to
PALLIATIVE THERAPY                                             impact the survival of thousands of patients. In the past
                                                               two decades, many trials of combined-modality therapy
Palliative endobronchial therapy can provide symptom-          have been conducted in an attempt to improve the sur-
atic improvement for bronchial symptoms such as                vival of patients with NSCLC. The role of radiation
hemoptysis and obstructive pneumonia. Radiation can            therapy is limited in patients with early stage disease
be delivered with low-dose rate sources or, more com-          and is best suited to treat patients who are medically
monly, with a high-dose-rate source using a remote after-      unfit or refuse to undergo surgery. Radiation therapy
loading device. Common treatment regimens include              may also be used in this setting for patients who do not
21 Gy in three fractions delivered at 1.0 cm depth with        undergo a complete surgical resection.
a high-dose-rate source and 30 Gy delivered at 1 Gy per           The best overall therapeutic regimen remains unclear
hour for low-dose-rate sources. No significant differ-         in patients with locally advanced disease, but the use of
ences between the two techniques with respect to bron-         combined-modality therapy in the treatment of such
choscopic response rate or complications have been             patients has resulted in a modest but reproducible sur-
identified.82,83 Symptomatic improvement is usually            vival benefit compared to single-modality therapy.
rapid and is generally seen in 50% of patients.84,85           Concurrent administration of chemotherapy and radia-
   Radiation therapy remains a useful palliative tool in       tion therapy for patients with locally advanced NSCLC
the treatment of patients with distant metastatic NSCLC.       has been shown to significantly improve survival as
Common sites of metastatic disease include brain and           compared to sequential therapy in randomized trials
bone. For patients with brain metastases, radiation ther-      and is the standard of care. The role of surgery in this
apy is generally employed, either as a sole modality or        setting continues to be defined.
in combination with surgical resection. The role of ste-          Based on patterns of failure, attention has focused on
reotactic radiosurgery, particularly in patients with con-     improving local control and preventing progression of
trolled extracranial disease, continues to be defined.86       distant disease. It is hoped that with continued advances
   Between 20 and 40% of patients with NSCLC will              in all therapeutic modalities, the survival of patients
develop osseous metastases.87 Focal external beam radia-       with NSCLC will continue to improve.
tion therapy is the most common method used to treat
symptomatic bone metastases. Several fractionation schemes
are commonly employed, but recent data in patients with
metastatic breast or prostate cancer suggest that 8 Gy in
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    mall cell lung cancer. Results of Radiation Therapy Oncology        90. Scarantino C, Salazar OM, Rubin P et al. The optimum radia-
    Group 90-15. Cancer 1995; 75: 2337–44.                                  tion schedule in treatment of superior vena caval obstruction:
75. Siegenthaler MP, Pisters KM, Merriman KW et al. Preoperative            importance of 99mTc scintiangiograms. Int J Radiat Oncol Biol
    chemotherapy for lung cancer does not increase surgical mor-            Phys 1979; 5: 1987–95.
    bidity. Ann Thorac Surg 2001; 71: 1105–11.                          91. Davenport D, Ferree C, Blake D et al. Response of superior vena
76. Martin J, Ginsberg RJ, Abolhoda A et al. Morbidity and mortal-          cava syndrome to radiation therapy. Cancer 1976; 38: 1577–80.
    ity after neoadjuvant therapy for lung cancer: the risks of right   92. Slawson RG, Scott RM. Radiation therapy in bronchogenic
    pneumonectomy. Ann Thorac Surg 2001; 72: 1149–54.                       carcinoma. Radiology 1979; 132: 175–6.
10.3 Treatment of NSCLC: chemotherapy
              Athanasios G Pallis, Sophia Agelaki, Vassilis Georgoulias

              Contents Introduction • Adjuvant chemotherapy after surgical resection • Preoperative (neoadjuvant)
              chemotherapy • Chemotherapy for locally advanced unresectable (IIIA and IIIB) NSCLC • Chemotherapy
              for patients with advanced NSCLC • Patients populations with special considerations • Second-line therapy
               • Targeted therapies in advanced NSCLC

INTRODUCTION                                                  ADJUVANT CHEMOTHERAPY AFTER
                                                              SURGICAL RESECTION
The clinical development of chemotherapeutic agents
in non-small cell lung cancer (NSCLC) was initially           Surgery remains the only curative treatment modality
focused in the setting of stage IV disease. During the        for patients with NSCLC. However, even after complete
1980s and early 1990s, six drugs, namely cisplatin,           resection the overall survival remains disappointing,
ifosfamide, mitomycin C, etoposide, vindesine, and            with the five-year survival rates ranging from 67% for
vinblastine, were considered active against NSCLC,            patients with T1N0 disease to 23% for patients with N2
with response rates reported in excess of 15%.1,2             disease.6 Efforts to improve the survival of patients with
Combination chemotherapy, most commonly cispla-               operable NSCLC have examined the addition of che-
tin-based, was also investigated. Generally, higher           motherapy (CMT) and/or radiotherapy (RT) in the
objective responses were achieved but still the benefit       postoperative setting. The rationale for the use of sys-
for the patients was unclear by that time. Subsequent         temic therapy in completely resected NSCLC lies in the
randomized trials and meta-analyses established the           detection of early micrometastatic disease at the time of
value of chemotherapy in the treatment of patients            surgery and in the clinical observation that distant
with advanced NSCLC.3,4 The next steps were aimed             recurrence is the predominant cause of relapse and
at the development of chemotherapy from a palliative          death after surgery.
measure to a curative one, through its incorporation
into aggressive combined modality treatments for              From the first randomized trials to the 1995
locoregionally advanced disease, and/or its adminis-          meta-analysis
tration as adjuvant to radical surgery. More recently,        Early trials of postoperative chemotherapy started in
during the 1990s, a new generation of compounds               the 1960s failed to demonstrate any benefit on survival
such as the taxanes (paclitaxel and docetaxel), the topo-     by the incorporation of alkylating and immunothera-
isomerase inhibitors (irinotecan, topotecan), active          peutic agents.7 The vast majority of subsequent trials
analogs (gemcitabine), antimetabolites (pemetrexate),         employing cisplatin-based regimens8–11 did not show
and vinka alkaloids (vinorelbine) were integrated in          any significant effect of chemotherapy on survival.
the treatment of NSCLC.5 These drugs administered             Common drawbacks in these studies were the overesti-
in patients with metastatic disease obtained single-          mation of the potential benefit of adjuvant chemother-
agent activity in the range of 20–30%. When used in           apy in the calculation of the sample size, the imbalance
combination with other active agents such as the plat-        in patient and treatment characteristics, the unfeasibil-
inums, significant response rates, often in excess of         ity of reaching the planned accrual, and, finally, the low
40%, were reported in pilot phase II studies. The             compliance with most chemotherapy regimens used.
newer agents have been also successfully used in che-            In 1995 a meta-analysis on the role of chemotherapy in
motherapy regimens for the treatment of patients with         the treatment of NSCLC separately reviewed eight tri-
earlier stages of disease as well as in combined-modal-       als, assigning a combined total of 1394 patients to cis-
ity treatment programs.                                       platin-based adjuvant chemotherapy.12 A 13% reduction
148 Textbook of Lung Cancer

in the risk of death [hazard ratio (HR) 0.87 (95% CI:       started in an additional 9%, mainly due to consent
0.74–1.02)] corresponding to an absolute survival ben-      withdrawal. Radiotherapy was completed in 65% of the
efit of 3% at two years (95% CI: 0.5% detriment to 7%       patients initially planned in the MVP arm and in 83%
benefit) and 5% (95% CI: 1% detriment to 10% benefit)       of the control group.
at five years, in favor of chemotherapy, was reported.12
Despite the marginal statistical significance (p = 0.08),   International Adjuvant Lung Cancer trial (IALT trial)
these findings encouraged the initiation of several ran-    The IALT trial randomly allocated patients with surgi-
domized trials investigating the role of platinum-based     cally resected stage I, II, or III NSCLC to receive cispl-
regimens in patients with completely resected stage I,      atin-based chemotherapy or observation.16 The primary
II, and IIIA NSCLC (Table 10.3.1). These trials used        endpoint was overall survival and secondary endpoints
different types of chemotherapy and included different      were disease-free survival (DFS), second-primary can-
proportions of stages I to IIIA NSCLC.                      cers, and adverse events. A total of 3300 patients was
   The North American Intergroup Trial INT0115 was          required for the trial to have 83% power with a two-
the only trial that compared the combination of chemo-      sided test to detect an absolute improvement of 5%,
therapy plus thoracic radiotherapy versus radiotherapy      and 90% power to detect a 5.6% difference in overall
alone in patients with completely resected stage II or      survival at five years. However, the trial was terminated
IIIA NSCLC.13 INT0115 was negative, but yet, the trial      prematurely after the enrollment of 1867 patients out
was underpowered to detect the small survival benefit       of the 3300 initially planned because of a slow down in
suggested by the meta-analysis and used thoracic radio-     patient recruitment rate.
therapy as the comparator that is not considered as the        Each participating center had to determine the patho-
standard reference arm. The Big Lung Trial was also         logic stage of the disease to include, the dose of cisplatin
clearly underpowered to look at differences in survival     (80, 100, 120 mg/m2 per cycle for 3–4 cycles), the drug
in the range of 5%. With a median follow-up of only         to be combined with cisplatin (etoposide, vinorelbine,
2.9 years no significant benefit was shown by the addi-     vindesine, or vinblastine) and the administration of
tion of cisplatin-based chemotherapy pre- (4%) or post-     sequential chest radiotherapy.
operatively (96%).14                                           Finally, 932 patients were enrolled in the chemother-
   In the next sections the most important recent trials    apy arm and 935 in the control group. Approximately
of adjuvant chemotherapy are presented.                     37% had disease stage I, 24% stage II, and 39% stage
                                                            III. Twenty-seven percent of patients received postop-
Adjuvant Lung Project Italy (ALPI trial)                    erative radiotherapy, while cisplatin plus etoposide was
The ALPI trial randomized 1209 patients with surgi-         the most frequently utilized regimen.
cally staged I–IIIA NSCLC to receive MVP (mitomycin            After a median follow-up period of 56 months, the
8 mg/m2, day 1; vindesine 3 mg/m2, days 1 and 8; CDDP       DFS rate at five years was 39.4% for the chemotherapy
100 mg/m2, day 1, every three weeks) for three cycles       arm vs 34.3% for the observation arm [HR 0.83 (95%
(n = 606), or no treatment (n = 603).15 Stratification      CI: 0.74–0.94; p <0.003)]. Furthermore, overall sur-
factors included center, tumor size, lymph node involve-    vival favored the chemotherapy arm [44.5 vs 40.4% at
ment, and the intention to perform radiotherapy.            five years; HR 0.86; (95% CI: 0.76–0.98); p <0.03].
   After a median follow-up of 64.5 months the study        Compliance with chemotherapy was relatively poor, with
failed to demonstrate any significant difference in terms   74% of the patients in the chemotherapy arm receiving
of overall survival [HR 0.96 (95% CI: 0.81–1.13); p =       at least three treatment courses. Moreover, 70% of the
0.589] and progression-free survival [HR 0.89 (95%          patients treated with chemotherapy and assigned to
CI: 0.76–1.03); p = 0.128]. Median overall survival was     chest radiotherapy completed their course, compared
55 months in the chemotherapy arm and 48 months in          with 84% of these who did not receive chemotherapy.
the surgery alone arm, while progression-free survival      Seven (0.8%) patients died of chemotherapy-related
was 37 and 29 months for the treatment and control          toxicity.
arms, respectively. No significant effect between treat-       The results observed in the IALT trial are in the same
ment and stage of the disease emerged.                      range as those reported in the 1995 meta-analysis.7 The
   Treatment compliance data indicate that 69% of the       large number of patients in the IALT analysis may explain
patients received the per protocol planned three cycles     the significance of the results compared with the smaller
of chemotherapy, although half of them required some        number of analyzed patients in the ALPI trial. More-
dose adjustment or omission. Chemotherapy was never         over, the use of a three-drug regimen and the higher
Table 10.3.1 Reported phase III trials of adjuvant chemotherapy in NSCLC

Trial              No of             Disease          CT regimen/           Compliance     Median     Five-year    Hazard       p
                  patients            stages          control arm            to CT (%)   follow-up    absolute     ratio of
                                    included                                              (months)     survival     death
                                                                                                     benefit (%)

INT011513            488             II–IIIA          VP-16 (120 mg/m2,        69           44          −6a         0.93        0.56
                                                      d 1–3); CDDP
                                                      (60 mg/m2, d 1)/
                                                      radiotherapy only
                                                      (both arms received
                                                      a total of 50.4 Gy
ALPI trial15       1209              I–IIIA           Mit 8 mg/m2, d 1;        69          64.5          1          0.96        0.589
                                                      VND 3 mg/m2,
                                                      d 1 & 8; CDDP
                                                      100 mg/m2, d 1,
                                                      q3w, for three
IALT trial16       1867              I–IIIA           CDDP + vinka             74           56          4.1         0.86       <0.03
                                                      alkaloids or
Big Lung             381             I–IIIA           CDDP/VND,                64          34.6         −2b         1.02        0.90
Trial14                                               CDDP/mit/If,
                                                      vinblastine or
JCOG 9304            119           IIIA (N2)          CDDP 80 mg/m2,           58          NR          −7.9c         —          0.89
trial28                                               d 1; VND 3 mg/m2,
                                                      d 1 & 8: ×3 cycles/


Table 10.3.1 Continued

Trial                   No of               Disease               CT regimen/                              Compliance                  Median              Five-year               Hazard               p
                       patients              stages               control arm                               to CT (%)                follow-up             absolute                ratio of
                                           included                                                                                   (months)              survival                death
                                                                                                                                                          benefit (%)

UFT trial17               999                   I                UFT                                           74                        72                     3                     —                 0.047
                                                                 (250 mg/m2/day)                          (at 12 mo)
                                                                 for 2 years/                                  61
                                                                 observation                              (at 24 mo)
UFT meta-                2003                I–III               UFT/observation                               80                      6.44                   4.6                    0.77               0.011
analysis18                                                                                                                            (years)
NCIC-JBR10                482                IB–II               CDDP (50 mg/m2,                                65                      60                     15                    0.69               0.011
trial19                                                          d 1 & 8 q 4w);
                                                                 VNB (25 mg/m2)/
CALGB 9633                344                  IB                PCL 200 mg/m2/                                 85                       48                     3                    0.80               0.32
trial22,23                                                       carboplatin AUC
ANITA trial24             840              IB–IIIA               CDDP 100 mg/m2/                               56d                      >70                   8.6                    0.79               0.013
                                                                 VNB 30 mg/m2/
  Estimated 5-year survival rates were 39% for the RT only group and 33% for the CT-RT group.
  Estimated 2-year survival rates were 60% for the observation group and 58% for the CT group.
  5-year survival rates were 28.2% in the chemotherapy arm and 36.1% in the control group.
  Dose density of vinorelbine.
CT: chemotherapy; RT: radiotherapy; q3W: every three weeks; VP-16: etoposide; UFT: oral uracil-tegafur; CDDP: cisplatin; Mit: mitomycin; VND: vindesine; If: Ifosfamide; VNB: vinorelbine; PCL: paclitaxel;
carboplatin AUC 6: carboplatin Area Under Curve 6.
                                                                                    Treatment of NSCLC: chemotherapy 151

frequency of postoperative radiotherapy in the ALPI           lbine (25 mg/m2, reduced from 30 mg/m2 for unaccept-
trial might also have led to the negativity of this trial.    able toxicity, weekly for 16 weeks) or no chemotherapy.19
                                                              The study endpoints were overall survival, recurrence-
UFT adjuvant trials                                           free survival, quality of life, and toxicity.
Uracil-tegafur (UFT) is a combination of uracil, an              At five years of follow-up, the five-year survival rates
inhibitor of dihydropyrimidine dehydrogenase (DPD),           were 69% for the chemotherapy arm and 54% for the
and tegafur, a prodrug of 5-fluorouracil, that has been       control arm [HR 0.69 (95% CI: 0.52–0.92); p = 0.011],
extensively studied in Japanese patients with NSCLC.          with an absolute survival benefit of 15% for patients
UFT has been studied either as single-agent therapy fol-      receiving chemotherapy. Subgroup analyses according
lowing surgery or following one or more cycles of cis-        to stratification factors did not demonstrate significant
platin-based chemotherapy. In all those trials, UFT was       improvement in survival for patients with disease stage
administered as a single daily oral dose over a pro-          IB receiving chemotherapy compared to the observation
longed period of time.                                        group (p = 0.79). In the planned stratified Cox regres-
   The largest trial on postoperative UFT therapy ran-        sion analysis, significant factors associated with improved
domly assigned 999 patients with completely resected          survival included chemotherapy as compared with obser-
pathologic stage I adenocarcinoma to receive either oral      vation (HR for the difference in survival, 0.67; 95% CI:
uracil-tegafur (250 mg/m2/day) for two years (498             0.51–0.89; p = 0.006) and squamous histology as com-
patients) or no treatment (501 patients).17 Stratification    pared with adenocarcinomas (p = 0.005). Despite the
factors were tumor stage (T1 vs T2), sex, and age. The        positive results, compliance with chemotherapy was
median follow-up period was 72 months in the UFT              relatively low, with only 65% of the patients receiving
group and 73 months in the control group. The five-           three or four cycles. Moreover, 77% had at least one
year overall survival rate was 88% (95% CI: 85–91) for        dose reduction or omission and 55% required one or
the UFT group and 85% (95% CI: 82–89) for the con-            more dose delays. Nineteen percent of the patients who
trol group. Survival benefit was significant in patients      received at least one dose required hospitalization for
with T2 tumors (85% vs 74% for the UFT and observa-           medical problems related to toxicity. There were two
tion groups, respectively; HR 0.48; 95% CI: 0.29–0.81;        chemotherapy-related deaths. Furthermore, treatment
p = 0.005), while for patients with T1 disease no sig-        was associated with a significant negative impact on
nificant difference was observed. Although toxicity was       quality of life.20
minimal, compliance was only 74% at 12 months and                A retrospective analysis evaluated the influence of age
61% at 24 months.                                             on survival, chemotherapy delivery, and toxicity in the
   Recently, a meta-analysis examining the effectiveness      BR.10 trial.21 Overall survival for patients older than
of UFT as postoperative treatment of NSCLC was pub-           65 years was better with chemotherapy versus observa-
lished.18 This meta-analysis included 2003 eligible           tion [HR 0.61 (CI: 0.38–0.98); p = 0.04) despite the fact
patients; most (98.8%) had squamous cell carcinoma            that older patients received significantly fewer doses of
or adenocarcinoma, and stage I disease; the tumor clas-       cisplatin and vinorelbine. Fewer elderly patients com-
sification was T1 in 1308 (65.3%), T2 in 674 (33.6%), and     pleted treatment and more refused treatment compared
the nodal status was N0 in 1923 (96.0%). The median           to the young (p = 0.03). The authors concluded that
duration of follow-up was 6.44 years. The survival rates      patients older than 75 years require further study.
at 5 and 7 years were significantly higher in the surgery
plus UFT group (81.5% and 76.5%, respectively) than in        Cancer and Leukemia Group B (CALGB) 9633 trial
the surgery alone group (77.2% and 69.5%, respectively;       This trial randomly assigned 344 patients with com-
p = 0.011 and 0.001, respectively). The overall pooled        pletely resected stage IB (T2N0) NSCLC to four cycles
hazard ratio was 0.74 (95% CI: 0.61–0.88; p = 0.001).         of paclitaxel/carboplatin chemotherapy (paclitaxel 200
                                                              mg/m2/carboplatin AUC 6) versus surgery alone. Like
National Cancer Institute of Canada (NCIC)                    the NCIC CTG study, there was no planned thoracic
JBR10 trial                                                   radiotherapy. In this trial compliance with chemother-
This trial randomly assigned 482 patients with com-           apy was high, with 85% of the patients receiving three
pletely resected, pathologic stage IB and II (patients with   or four treatment cycles. In the first report of the trial,22
T3N0 disease were excluded) to receive either postop-         after a median follow-up time of 34 months, 71% of
erative adjuvant chemotherapy with cisplatin (50 mg/m2,       patients who had received chemotherapy were alive
days 1 and 8 every 4 weeks for four cycles) and vinore-       compared with 59% of those who had surgery alone
152 Textbook of Lung Cancer

[HR 0.62 (95% CI: 0.41–0.95); p = 0.028]. Overall sur-            A second meta-analysis based on abstracted data from
vival at four years and failure-free survival also favored     19 randomized adjuvant trials that enrolled 7200 patients
the chemotherapy group. However, an updated analy-             was reported by Sedrakyan et al.26 This meta-analysis
sis after 54 months of median follow-up showed a non-          added summary data from seven trials and approxi-
significant trend towards improvement of overall               mately 5000 patients to information provided by the
survival by the addition of chemotherapy [HR 0.80              1995 meta-analysis.12 An 11% reduction in the mortal-
(90% CI: 0.60–1.07); p = 0.1]. A significant prolonga-         ity was reported for cisplatin-based regimens and 17%
tion in DFS favoring adjuvant chemotherapy was still           for UFT treatment, as compared to surgery alone. It
present [HR 0.74 (90% two-sided CI: 0.57–0.96); p =            should be noted that neither meta-analysis included the
0.027].23 It should be noted though that the trial does        newer trials that reported substantial benefits associ-
not have adequate power to detect small differences in         ated with adjuvant chemotherapy.19,22,24
overall survival that may be clinically significant.              A third meta-analysis pooled individual patient data
                                                               from the five largest trials (ALPI, ANITA, BLT, IALT, and
Adjuvant Navelbine International Trialists                     JBR10) of cisplatin-based chemotherapy in completely
Association (ANITA) trial                                      resected patients conducted after the 1995 meta-analy-
Patients participating in the ANITA trial were required        sis.27 With a median follow-up of 5.1 years the overall
to have completely resected, stage IB–IIIA NSCLC. This         HR of death was 0.89 (95% CI: 0.82–0.96; p <0.005),
trial randomized 840 patients to postoperative chemo-          corresponding to a five-year absolute benefit of 4.2% by
therapy (four cycles of cisplatin 100 mg/m2 every              the addition of chemotherapy. The benefit varied with
4 weeks and 16 cycles of vinorelbine at 30 mg/m2 weekly)       stage, with the HR for stage IA 1.41 (95% CI: 0.96–2.09),
or observation only.24 The five-year survival rates favored    stage IB 0.93 (95% CI: 0.78–1.10), stage II 0.83 (95%
the chemotherapy arm; 51.2% vs 42.6% of the patients           CI: 0.73–0.95), and stage III 0.83 (95% CI: 0.73–0.95).
were alive in the chemotherapy and the control group,             The recent data from randomized adjuvant trials
respectively [HR 0.79 (95% CI: 0.66–0.95); p = 0.013]. In      have changed the standard of care for patients with
a subset analysis, chemotherapy significantly improved         completely resected NSCLC. Consistent reductions in
survival in stages II and IIIA, but not in stage IB.           the risk of death have been observed with cisplatin-
   ANITA confirmed the results of the NCIC and CALGB           based adjuvant chemotherapy. Subset analysis of the
trials in a less selected population (disease stage IB–IIIA)   large randomized trials,16,19,24 as well as the recent meta-
observed for a longer follow-up period (>70 months).           analysis,27 suggests that the benefit is greatest in patients
However, in this trial significant chemotherapy-related        with stages II and III. The role of chemotherapy in ear-
toxicity was also reported, with 84.6% and 12.5% of            lier disease stages and the optimal drug to combine
the patients experiencing grade 3–4 neutropenia and            with cisplatin remain to be determined. Advantages in
febrile neutropenia, respectively. The median percent-         disease-free survival and three-year survival might sup-
age of chemotherapy dose delivered was only 56% and            port the consideration of adjuvant paclitaxel/carbopla-
76% for vinorelbine and cisplatin, respectively.               tin in stage IB NSCLC. Up to now there are no
                                                               confirmatory data on the efficacy of UFT in the adju-
Recent meta-analyses                                           vant treatment of NSCLC outside of Japan.
Eleven randomized controlled trials including a total of          Considering the significant chemotherapy-associated
5716 patients reported after the 1995 meta-analysis were       toxicity, one might suggest that this treatment should
reviewed in an abstracted-data-based meta-analysis.25          be restricted to those patients with good performance
In this analysis, hazard ratio estimates suggested that        status, rapid recovery from surgery, and no significant
adjuvant chemotherapy yielded a significant survival           comorbidity. No prospective data are available on the
advantage over surgery alone [HR 0.872 (95% CI: 0.805–         postsurgical management of elderly patients with
0.944); p = 0.001]. In a subgroup analysis, cisplatin-         resected disease.
based chemotherapy regimens (3786 patients) showed
consistent results, with the HR estimates in most trials
favoring adjuvant chemotherapy (HR 0.891 (95% CI:              PREOPERATIVE (NEOADJUVANT) CHEMOTHERAPY
0.815–0.975); p = 0.012). In addition, single-agent UFT
therapy (1751 patients) resulted in a significant survival     Induction chemotherapy before surgery
benefit, with an HR of 0.799 (95% CI: 0.668–0.957;             Preoperative chemotherapy presents several theoretic
p = 0.015).                                                    advantages, including reduction of tumor volume that
                                                                                                              Treatment of NSCLC: chemotherapy 153

could enhance local control, evaluation of response to                           subsequent analyses after almost seven years of follow-
chemotherapy, early eradication of micrometastatic dis-                          up.31,32 It should be noted that the small number of
ease, and higher patient compliance compared to post-                            patients included in these studies weakens the power of
operative chemotherapy.                                                          their observations. Furthermore, the trial by Rosell et
   Phase II studies evaluating the role of preoperative                          al29 has been criticised because of the poor survival out-
chemotherapy in patients with stage IIIA disease dem-                            comes of the control arm.
onstrated an average response rate of 60%, with 55% of                              One study randomly assigned patients with stage
patients undergoing thoracotomy and 49% having                                   IIIA (T0–3) or T3 (N0–1), or locally treatable stage IIIB
complete resections; median survival time was approx-                            (T4, N3), NSCLC to receive neoadjuvant docetaxel
imately 16 months, and five-year survival rate was 30%                           (100 mg/m2 every three weeks) (n = 134) or no chemo-
in chemoresponsive patients, with 50% of patients                                therapy (n = 140) before surgery or curative-intention
achieving a pathologic complete response.5 Phase III                             radiotherapy.33 Median survival was 14.8 months in the
trails of neoadjuvant therapy in NSCLC, are presented                            docetaxel group and 12.6 months in the control group
in Table 10.3.2. In a randomized trial by Rosell et al,                          (p = non-significant). Median times to disease progres-
patients with stage IIIA NSCLC were randomly assigned                            sion were 9.0 months (docetaxel arm) and 7.6 months
to undergo either immediate surgery, or surgery pre-                             (control arm).
ceded by three cycles of chemotherapy with mitomycin                                Preoperative chemotherapy might also have a role in
(6 mg/m2), ifosfamide (3 g/m2), and cisplatin (50 mg/m2).29                      earlier disease stages. In a multicenter phase III study
In another trial, patients with stage IIIA NSCLC                                 conducted by the French Thoracic Cooperative Group,
were randomly allocated to three cycles of preoperative                          355 patients with clinical IB–IIIA disease were randomly
chemotherapy with cyclophosphamide (500 mg/m2,                                   assigned to receive two cycles of induction mitomycin
day 1), etoposide (100 mg/m2, days 1 to 3), and cispla-                          (6 mg/m2, day 1), ifosfamide (1.5 g/m2, days 1 to 3), and
tin (100 mg/m2, day 1) or to upfront surgery alone.30 In                         cisplatin (30 mg/m2, days 1 to 3) followed by surgery
both studies, radiotherapy was administered in over                              and two postoperative cycles or surgery alone.34 Patients
half of the patients. An interim analysis revealed a sta-                        with pT3 or pN2 received postoperative radiation. The
tistically significant difference in favor of the induction                      overall response to induction chemotherapy was 64%.
chemotherapy arm in both studies, resulting in a termi-                          Although median survival favored the chemotherapy
nation of the accrual after only 60 patients (out of the                         arm, the difference failed to reach statistical significance
120 initially planned) had been enrolled. The observed                           (37 months for the chemotherapy arm vs 26 months
survival differences also remained highly significant in                         for the surgery alone arm, p = 0.15). Subgroup analysis

 Table 10.3.2 Phase III trials of neoadjuvant chemotherapy in NSCLC

 Trial                      No of patients         Disease stages                    CT regimen/                       Median survival            p
                                                   included                          control arm                       (months)

 MD Anderson30                    60               IIIA (N2), some IIIB              CEP ×3→surgery→                   64 vs 11                   0.008
                                                                                     CEP ×3 vs surgery
 Spain29                          60               IIIA (N2)                         PIM→surgery→RT                    26 vs 8                    <0.001
                                                                                     vs surgery→RT
 NCI36                            27               IIIA (N2) biopsy                  PE ×2→surgery→                    28.7 vs 15.6               NS
                                                                                     PE ×4 vs surgery
 French Thoracic                355                IB–IIIA                           MIP ×2 → surgery →                37 vs 26                   NS
 Cooperative                                                                         MIP ×2 vs surgery
 Mattson et al33                274                III                               T×3→surgery vs                    14.8 vs 12.6               NS
 Pisters et al35                354                IIA–IIIA                          Ta/Carbo ×3→                      42 vs 37                   NS
                                                                                     surgery vs surgery
 C: cyclophosphamide; E: etoposide; P: cisplatin; I: ifosphamide; M: mitomycin; T: docetaxel; Ta: paclitaxel; Carbo: carboplatin, NS: non-significant.
154 Textbook of Lung Cancer

revealed a significant benefit in patients with N0–1 disease   arm (14.0 vs 11.7 months; p = 0.02), overall survival was
[relative risk (RR) 0.68 (95% CI: 0.49–0.96); p = 0.027],      not different (22 months) between arms. There were
but not for the group with N2 disease [RR 1.04 (95%            more early non-cancer deaths on the surgical arm, but
CI: 0.68–1.60); p = 0.85].                                     overall survival curves crossed so that, by year 3, the
   Finally, a recently reported phase III study evaluated      overall survival favored the surgery arm (38% vs 33%).
neoadjuvant chemotherapy in patients with clinical             Long-term follow-up of the INT 0139 confirmed the
stage T2N0, T1–2N1, and T3N0–1 (excluding superior             superior progression-free survival and showed a trend
sulcus tumors). Patients were stratified by clinical stage     for superior five-year overall survival for the trimodality
(IB/IIA vs IIB/IIIA) and were randomized to receive            therapy.38 In a subgroup analysis, patients who achieved
either paclitaxel and carboplatin (every three weeks for       pathologic N0 disease had a favorable long-term sur-
three cycles) plus surgery or surgery alone.35 The pri-        vival. Moreover, patients who underwent lobectomy
mary endpoint was a 33% increase in overall survival           had superior survival over patients receiving definitive
over the expected 2.7 years median for surgery alone.          chemoradiotherapy (p = 0.002).
After a median follow-up of 28 months during which                The German Lung Cancer Cooperative Group ran-
354 patients had been enrolled, the trial was prema-           domly assigned 558 patients with selected pathologic
turely terminated due to the positive data coming from         stages IIIA and IIIB NSCLC subsets to chemotherapy
the adjuvant chemotherapy trials. Median progression-          with cisplatin/etoposide for three cycles followed by
free survival was 29 months for the neoadjuvant group          hyperfractionated radiotherapy to 45 Gy concurrently
and 20 months for the surgery only group [HR 0.85              with carboplatin/vindesine and then surgery or chemo-
(CI: 0.63–1.14); p = 0.26]. Median overall survival was        therapy with cisplatin/etoposide for three cycles followed
42 months and 37 months, for the preoperative and sur-         by surgery and then radiotherapy to 54 Gy.39 Both
gery only arms, respectively [HR 0.88 (CI: 0.63–1.23);         groups received additional radiotherapy if a complete
p = 0.47].                                                     resection was not achieved. Of note, both arms received
   In general, preoperative chemotherapy induces a high        radiotherapy but the timing and fractionation, as well
rate of objective responses. Further investigation is          as the chemotherapy drugs, differed. No significant dif-
required to select the ideal regimen in terms of efficacy      ferences were observed regarding the three-year pro-
and safety and to identify subgroups of patients and/          gression-free survival (18% vs 20%, p = non-significant)
or predictive factors associated with greater benefit.         and the three-year survival (26% vs 25%, p = non-sig-
Randomized trials evaluating the comparative efficacy          nificant). This study has been criticized because of the
of adjuvant and neoadjuvant chemotherapy are also              low resection rates, and the inclusion of radiotherapy in
warranted.                                                     both arms.
                                                                  The role of aggressive induction therapies in the
Induction chemoradiotherapy before surgery                     management of resectable stage III disease remains to
The concurrent administration of chemotherapy with             be determined. It seems that in N2 disease, patients
radiotherapy has been used before surgery in patients          who achieve significant downstaging experience pro-
with stage III disease in an effort to improve survival        longed survival. However, the optimal management of
outcomes. Although surgery might be associated with            these patients with surgery versus definitive chemora-
higher morbidity and mortality after preoperative treat-       diation needs further clarification. The role of chemo-
ment, the feasibility of this approach has been demon-         radiation before surgery in earlier disease stages needs
strated in several phase II studies.                           to be identified.
   In the North American Intergroup trial 0139 (INT
0139), 429 patients with T1–3 pN2 disease deemed
resectable at presentation were randomized either to           CHEMOTHERAPY FOR LOCALLY ADVANCED
induction concurrent chemoradiotherapy with 45 Gy              UNRESECTABLE (IIIA AND IIIB) NSCLC
and cisplatin (50 mg/m2 on days 1, 8, 29, and 35) and
etoposide (50 mg/m2 days 1 to 5 and 29 to 33) followed         Up to one-third of patients with NSCLC present with
by surgery (for non-progressors) or to definitive chemo-       disease that remains localized to the thorax, but is
radiation (with cispaltin and etoposide) to 61 Gy.37 Both      considered too extensive for surgical treatment (stages
groups received consolidation chemotherapy with two            IIIA and IIIB). Historically, radiotherapy (RT) repre-
cycles of cisplatin and etoposide. Although progression-       sented the standard of care for these patients.40 How-
free survival was significantly prolonged in the surgery       ever, results were disappointing with five-year survival
                                                                                                             Treatment of NSCLC: chemotherapy 155

rates of less than 5%, due to the high incidence of                             Concurrent chemoradiotherapy
both locoregional relapses and distant metastases. This                         The simultaneous administration of chemotherapy and
observation led to efforts for the development of more                          RT provides the advantages of early administration of
active, multimodality therapies that incorporate                                systemic treatment as well as the additional theoretic
chemotherapy.                                                                   benefit of increasing locoregional control. Furthermore,
                                                                                concurrent chemoradiotherapy offers a reduction in the
Chemotherapy followed by radiotherapy                                           treatment time compared to the sequential approach.
Several randomized phase III studies compared RT with                           In the clinical setting, concomitant chemoradiother-
the bimodality therapy of induction chemotherapy, fol-                          apy is associated with significant toxicities including
lowed by RT. Generally, studies with larger sample size                         esophagitis, risk of radiation pneumonitis, and increased
incorporating more intensive chemotherapeutic regi-                             myelosuppression.
mens demonstrated a significant survival benefit in                                The results of several phase II studies provided pre-
favor of the combined modality treatment (Table 10.3.3).                        liminary evidence supporting the feasibility of the addi-
It was also suggested that the main impact of systemic                          tion of chemotherapy to RT.45 Subsequent randomized
chemotherapy was a reduction in the rate of distant                             trials, employing either the concurrent or the sequential
relapses.41 The positive results of these randomized tri-                       mode, compared the combined therapy with RT alone
als have been confirmed by two meta-analyses.12,42                              (Table 10.3.4). Several trials demonstrated a significant

 Table 10.3.3 Selected phase III trials comparing sequential chemo-RT vs RT only, in patients with advanced NSCLC

 Trial                      n            Stage         Regimen                                            Survival (median)

 CALGB 843343               155          III           PV→RT (60 Gy) vs RT (60 Gy)                        CMT + RT 13.8 months; RT 9.7
                                                                                                          months (p = 0.0066)
                                                                                                          3-year survival: CMT + RT 23%;
                                                                                                          RT 10% (p = 0.012)
                                                                                                          7-year survival: CMT + RT 13%;
                                                                                                          RT 6% (p = 0.012)
 RTOG, ECOG,                452          III           PV→RT (60 Gy) vs RT (60 Gy)                        Median survival: CMT + RT 13.2
 and SWOG44                                            vs HFx-RT (69.6 Gy)                                months (p = 0.04 vs RT); RT 11.4
                                                                                                          months; HFx-RT 12 months (NS)
                                                                                                          3-year survival; CMT+RT 17%; RT
                                                                                                          11%; HFx-RT 14%
                                                                                                          5-year survival: CMT+RT 8%
                                                                                                          (p = 0.04 vs RT); RT 5%; HFx-RT
                                                                                                          6% (NS)
 P: cisplatin; V: vindesine; HFx-RT: hyperfractionated RT; CMT: chemotherapy.

 Table 10.3.4 Randomized phase III trials comparing combined chemoradiotherapy versus radiotherapy alone

 Trial                          n              Regimen                                             Survival (median)

 Le Chevalier46                 354            PLVC + RT (65 Gy) vs RT (65 Gy)                     2-year survival: 21% vs 14% (p = 0.02)
 Schaake-Koning47               331            P (weekly) + RT vs P                                2-year survival: 19% vs 26% vs 13%
                                               (daily) + RT vs RT                                   (p = 0.009; daily P + RT vs RT)
 Soresi48                        95            P + RT (50 Gy) vs RT (50 Gy)                        16 months vs 11 months; p = NS
 Morton49                       121            MACCu + RT vs RT                                    2-year survival: 21% vs 16%; p = NS
 Blanke50                       215            P + RT ×3 cycles vs RT                              43 weeks vs 46 weeks; p = 0.394
 P: cisplatin; V: vindesine; L: lomustine; C: cyclophosphamide; M: methotrexate; A: doxorubicin; Cu: CCNU; NS: non-significant.
156 Textbook of Lung Cancer

survival benefit in favor of the combined modality                                 sequential administration. Median survival was 15–17
treatment,46,47 whereas others did not.48–50 Two large                             months in the concurrent arm versus 12.9–14.6 months
meta-analyses suggested a small, but statistically sig-                            in the sequential arms.52–55 It is interesting that the two
nificant improvement in survival with the combined-                                largest randomized trials have demonstrated remark-
modality regimens. In the meta-analysis by Pritchard                               ably similar results.52,54
and Anthony, a significant decrease in the relative risk                              The West Japan Lung Cancer Group randomly assigned
of death with combined therapy was shown at both                                   320 patients to a combination of cisplatin (80 mg/m2,
one and three years in patients with unresectable stage                            days 1 and 29), vindesine (3 mg/m2, days 1, 8, 29, and
III disease.51 Similarly, Marino et al reported a 24%                              36), and mitomycin (8 mg/m2, days 1 and 29) given
reduction in the risk of death at one year and a 30%                               concurrently with 56 Gy of radiotherapy, split into two
reduction at two years for combined cisplatin-based                                28 Gy courses separated by 10 days, versus the same
chemotherapy and radiotherapy.42                                                   chemotherapy given as induction followed by 56 Gy of
   Definitive testing of concurrent chemoradiotherapy                              continuous radiotherapy.52 The concurrent approach
versus the sequential approach in the phase III setting                            was significantly superior (p = 0.03998), with a median
has been also performed (Table 10.3.5). The concur-                                survival of 16.6 versus 13.3 months and five-year sur-
rent administration of platinum-based chemotherapy                                 vival rates of 15.8% versus 8.9%, respectively.
with radiotherapy demonstrated a modest although sta-                                 RTOG 9410 evaluated the use of cisplatin (100 mg/m2,
tistically significant survival benefit compared with the                          days 1 and 29) and vinblastine (5 mg/m2 weekly for five

 Table 10.3.5 Phase III trials comparing sequential versus concurrent chemoradiotherapy

 Trial                            n              Regimen                                    Survival (median)                                    p

 West Japan52                     320            P/Vin/M + RT                               Concurrent 16.6 months;                              0.03998
                                                 (56 Gy; split course) vs                   sequential 13.3 months
                                                 P/Vin/M → RT (56 Gy;
                                                                                            Two-year survival: concurrent                        NR
                                                                                            34.6%; sequential 27.4%
                                                                                            Five-year survival: concurrent                       NR
                                                                                            15.8%; sequential 8.9%
 GLOT-GFPC57                      212            PE + RT (66 Gy) → PV                       Concurrent 15 months;                                NS
                                                 vs PV → RT (66 Gy)                         sequential 13.8 months
                                                                                            Two-year survival: concurrent                        NS
                                                                                            35%; sequential 23%
 RTOG 94–1054                     610            PVi → RT (60 Gy) vs                        Sequential 17 months;                                0.046
                                                 PVi + RT (60 Gy) vs                        concurrent (daily RT)
                                                 PE + HFx-RT (69.6 Gy)                      14.6 months; concurrent
                                                                                            (HFx-RT) 15.6 months
                                                                                            Four-year survival: sequential                       0.046
                                                                                            12%; concurrent (daily RT)
                                                                                            21%; concurrent (HFx-RT)
 Czech Republic55                 102            PV + RT (60 Gy) vs                         Concurrent 16.6 months;                              0.023
                                                 PV → RT (60 Gy)                            sequential 12.9 months
                                                                                            Three-year survival:                                 NR
                                                                                            concurrent 18.6%;
                                                                                            sequential 9.5%
 P: cisplatin; Vin: vindesine; M: mitomycin; E: etoposide; V: vinorelbine; Vi: vinblastine; HFx-RT: hyperfractionated RT; NS: non-significant;
 NR: not reported.
                                                                                     Treatment of NSCLC: chemotherapy 157

doses) followed by once-daily radiotherapy (60 Gy) ver-           Two hundred and eighty-three patients with inoper-
sus cisplatin and vinblastine at the same doses given con-     able stage III NSCLC were entered into a randomized trial
currently with the same radiotherapy, or cisplatin (50         by the Cancer and Leukemia Group B (CALGB) and the
mg/m2, days 1, 8, 29, and 36) and oral etoposide (50 mg        Eastern Cooperative Oncology Group.58 All received
twice daily for 10 doses on weeks 1, 2, 5, and 6) given        induction chemotherapy with vinblastine and cisplatin
concurrently with hyperfractionated radiotherapy (69.6         for five weeks followed by radiation therapy or radio-
Gy given in 1.2 Gy fractions twice daily). In this trial 610   therapy concomitantly with weekly carboplatin. There
patients with unresectable NSCLC were randomly                 was no difference with respect to overall survival (13%
assigned to one of three arms. Both the median survival        with carboplatin and 10% with radiotherapy alone) at
and the four-year survival were significantly better in the    four years.
concurrent daily radiotherapy arm when compared with              CALGB also conducted a trial which randomly
the sequential arm (17 vs 14.6 months; p = 0.038) and          assigned 303 patients with stage IIIA/B disease to receive
(21% vs 12%), respectively. The hyperfractionated radio-       induction paclitaxel (200 mg/m2) and carboplatin (AUC
therapy arm showed a median survival of 15.6 months,           6) for two cycles, followed by either radiotherapy alone
that did not reach statistical significance compared with      (60 Gy) or the same radiotherapy concurrently with
the sequential treatment.54 Movsas et al reported on the       weekly paclitaxel (60 mg/m2). Median survival was
quality adjusted time without symptoms of toxicity anal-       19.2 months versus 14.6 months in favor of the concur-
ysis of RTOG 9410.56 Although reversible non-hemato-           rent chemoradiotherapy arm, but the difference did not
logic toxicity was higher in the sequential arm, the           reach statistical significance.59
overall mean toxicity was highest in the sequential arm,          Another CALGB trial randomly assigned 366 patients
further supporting the use of concurrent chemoradiation        to either induction paclitaxel (200 mg/m2) and carbo-
in locally advanced unresectable disease.                      platin (AUC 6) followed by chemoradiotherapy [66 Gy
   Multiple efforts in the phase I/II setting focused on       concurrently with weekly carboplatin (AUC 2) and
the incorporation of the newer chemotherapeutic agents         paclitaxel (50 mg/m2)] versus immediate chemoradio-
such as paclitaxel, gemcitabine, vinorelbine, and topo-        therapy alone. Both median and one-year survival were
isomerase I inhibitors into chemoradiotherapy treat-           similar between the two arms (14.0 months, 48% versus
ment. In general, acceptable toxicity and high response        11.4 months, 58%; p = 0.154).60
rates have been demonstrated. In a randomized phase               The role of consolidation therapy after concurrent
III trial by Fournel et al, a trend towards better survival    chemoradiation has also been investigated. Southwest
was observed in favor of the concurrent approach.57            Oncology Group (SWOG) reported on a phase II study
However, chemotherapy was different between the two            of concurrent chemoradiation with full doses of cispla-
arms. In the sequential arm, cisplatin (120 mg/m2 days         tin (50 mg/m2, days 1, 8, 29, and 36) and etoposide
1, 29, and 57) and vinorelbine (30 mg/m2 weekly for            (50 mg/m2, days 1 through 5, and days 29 through 33)
12 doses) was followed by thoracic irradiation (66 Gy in       followed by three cycles of docetaxel single agent (75 to
33 fractions). In the concurrent arm, cisplatin and etopo-     100 mg/m2). In this group of patients with pathologi-
side for two cycles were given with the same radiation         cally documented stage IIIB disease, a promising median
dose. Patients received consolidation chemotherapy             survival of 27 months was achieved.61 However, only
with cisplatin (80 mg/m2 on days 78 and 106), plus             59% of the 83 relevant patients received all three cycles
vinorelbine (30 mg/m2 weekly for eight cycles). The            of docetaxel, illustrating the difficulties of consolidation
median survival was 13.8 months for the sequential and         chemotherapy after definitive chemoradiation.
15 months for the concurrent arm (p = non-significant).           In a randomized phase II non-comparative study by
The two-year survival showed a trend in favor of con-          Belani et al, patients with unresected stage IIIA and IIIB
current chemoradiotherapy (35% vs 23% for sequential),         disease received two cycles of induction paclitaxel and
with updated results awaited.                                  carboplatin followed by sequential RT (n = 91), or two
                                                               cycles of induction paclitaxel and carboplatin followed
Induction chemotherapy followed by concurrent                  by weekly paclitaxel and carboplatin with concurrent
chemoradiotherapy                                              RT (n = 74), or weekly paclitaxel and carboplatin plus
The potential advantage of using both induction and            concurrent RT followed by two cycles of paclitaxel and
concurrent modality treatments lies in the enhancement         carboplatin (n = 92).62 The three arms were to be com-
of both the exposure to systemically active doses of che-      pared with a historical control using the sequential chemo-
motherapy and locoregional control of the disease.             radiotherapy arm of the RTOG 8808 trial, for which the
158 Textbook of Lung Cancer

available reported median survival time was 13.7 months.63       Le Chevalier et al were the first to compare the com-
Median survival times for the sequential and concur-          bination of a second-generation over a first-generation
rent arms were 13 and 12.7 months, respectively. The          cisplatin-based doublet.72 In this trial, patients treated
concurrent/consolidation arm was associated with the          with cisplatin/vinorelbine had significantly longer median
best outcome (median overall survival 16.3 months,            survival compared to those treated with cisplatin/
p = 0.34) and greater toxicity rates.                         vindesine (40 weeks vs 32 weeks; p = 0.04). Moreover,
   Currently, concomitant chemoradiotherapy is con-           this study demonstrated that cisplatin was necessary
sidered the standard therapy of unresectable stage III        since a cisplatin/vinorelbine combination was superior
NSCLC. However, it applies only to patients with good         to vinorelbine alone (40 weeks vs 31 weeks; p = 0.01)
performance status. For the present, there is no value of     (see Table 10.3.6.). Further randomized trials addressing
adding induction chemotherapy with currently estab-           the same question demonstrated that second-generation
lished agents. The role of consolidation chemotherapy         regimens are generally associated with improved efficacy,
remains to be confirmed in randomized trials.                 toxicity, quality of life, or a combination of these end-
                                                              points, although statistically significant survival gain was
                                                              not uniformly found.
CHEMOTHERAPY FOR PATIENTS WITH                                   More recently, second-generation cisplatin-based
ADVANCED NSCLC                                                regimens have been more widely used. Direct compari-
                                                              son of these regimens in randomized phase III trials
Patients with advanced NSCLC (stage IIIB with pleural         failed to demonstrate a particular combination to be
or pericardial effusion or stage IV), treated with best       clearly superior for NSCLC. The results of appropriately
supportive care (BSC) alone, have a median survival of        sized trials comparing second-generation platinum-
4–5 months and a one-year survival of approximately           based doublets are presented in Table 10.3.7.
10%.64 Throughout the 1970s and 1980s, combination               ECOG 1594, one of the largest randomized trials,
chemotherapy (usually cisplatin-based) resulted in objec-     assigned a total of 1207 patients with advanced NSCLC
tive responses rates in 20 to 30% of lung cancer patients,    to a reference regimen of cisplatin and paclitaxel or to
but median survival was only six to eight months, and         one of three experimental regimens: cisplatin and gem-
few patients survived longer than one year. The most          citabine, cisplatin and docetaxel, or carboplatin and
frequently used regimens were the combinations of cis-        paclitaxel. Patients were stratified according to ECOG
platin with etoposide, vindesine, or vinblastine. Several     performance status (0 or 1 vs 2), weight loss in the previ-
randomized trials, addressing the question of whether         ous six months (<5% vs ≥5%), the stage of disease (IIIB
the benefit of chemotherapy outweighed the cost of            vs IV or recurrent disease), and the presence or absence
toxicity over best supportive care alone, demonstrated        of brain metastases. In this study no difference was
a small, but statistically significant survival benefit for   observed in terms of response rate or overall survival
patients receiving chemotherapy.5 Due to limitations in       between the different chemotherapy regimens; response
most of these studies, meta-analyses were performed to        rates ranged from 17 to 22% and median survival from
address the same question.42,65,66 In the largest of these    7.4 to 8.1 months. The cisplatin/gemcitabine arm showed
meta-analyses, alkylating agents were associated with a       significantly longer time to tumor progression when
detrimental effect on survival, while cisplatin-based         compared with the reference arm (4.2 vs 3.4 months,
chemotherapy conferred a 27% reduction in the risk of         p = 0.001). Differences in the toxicity profiles of each
death, and a 10% absolute increase in one-year survival       regimen were identified, with cisplatin/gemcitabine caus-
rates.12 Thus systemic cisplatin-based chemotherapy           ing more thrombocytopenia, cisplatin/docetaxel caus-
has since been considered as standard care in most            ing more neutropenia, and the carboplatin/paclitaxel
patients with advanced NSCLC.67                               arm causing the lowest rate of potentially life-threatening
                                                              adverse events.81
First-line therapy
                                                                 TAX 326 was another large trial that randomized
Platinum-based chemotherapy                                   1218 patients to one of three treatment groups: docetaxel/
Between 1981 and 1991, several randomized trials,             cisplatin (DC regimen), docetaxel/carboplatin (DCb
with more than 1900 patients enrolled, evaluated a wide       regimen), or the control arm of vinorelbine/cisplatin (VC
range of first-generation cisplatin-based chemotherapy        regimen). Patients treated with DC had a median sur-
regimens.68–71 No significant differences emerged between     vival of 11.3 versus 10.1 months for VC-treated patients
regimens, or between studies.                                 (p = 0.044). The two-year survival rate was 21% and
                                                                                                                 Treatment of NSCLC: chemotherapy 159

 Table 10.3.6 Randomized trials of cisplatin plus a new agent versus cisplatin plus an old agent

 Trial                 Therapy              No of patients        Odds ratio (%)       Median survival (weeks)          One-year survival (%)            p

 Le Chevalier72 V/P                               206                 30                         40                            40                        0.04
                Vi/P                              200                 19                         32                            32
 Bonomi73       Ta (low)/Pa                       198                 25.3                       41.2                          37.4
                Ta (high)/P                       201                 27.7                       43.3                          40.3                      0.048b
                E/P                               200                 12.4                       32.9                          32
 Giaccone74     Ta/P                              166                 28                         42.9                          41                       NS
                Ten/P                             166                 41                         42.0                          43
 Cardenal75     G/P                                68                 41                         37.7                          26                       NS
                E/P                                67                 22                         30.3                          32
 Niho76         CPT/P                             100                 29                         45                            43                       NS
                Vi/P                              103                 22                         50                            48
 Negoro77       CPT/P                             129                 44                         50                            46                   NSc
                Vi/P                              122                 32                         46                            38
 Kubota78       T/P                               151                 37                         49.3                          48                       NS
                Vi/P                              151                 21                         41.9                          43
   Paclitaxel (low): 135 mg/m2 intravenously over 24 hours; paclitaxel (high): 175 mg/m2 intravenously over 24 hours plus granulocyte colony-stimulating
   Comparing the two paclitaxel groups combined with the etoposide/cisplatin group; other comparisons were not significant.
  Survival differences were significant in the stage IV subset.
 P: cisplatin; Vin: vindesine; E: etoposide; V: vinorelbine; Carbo: carboplatin; Ta: paclitaxel; Ten: Teniposide; G: gemcitabine; T: docetaxel; Vi: vindesine;
 CPT: irinotecan; NS: non-significant; NR: not reported.

 Table 10.3.7 Selected phase III trials comparing second-generation platinum-based doublets

 Trial                           n                 Regimen                                                   Median survival (months)                     p

 SWOG 950979                     408               P/V vs Carbo/Ta                                           8.0 vs 8.0                                   NS
 ILCSG80                         607               Carbo/Ta vs P/V vs P/G                                    9.9 vs 9.5 vs 9.8                            NS
 ECOG 159481                     1207              P/Ta vs P/G vs P/T vs Carbo/Ta                            7.8 vs 8.1 vs 7.4 vs 8.1                     NS
 TAX 32682                       1218              P/V vs P/T vs Carbo/T                                     10.1 vs 11.3 vs 9.4                          0.04a
  P/V vs P/T, p = 0.04 in favor of P/T.
  P/V vs Carbo/T, p = NS.
 P: cisplatin; V: vinorelbine; Carbo: carboplatin; Ta: paclitaxel; G: gemcitabine; T: docetaxel; Vi: vindesine; CPT: irinotecan; NS: non-significant;
 NR: not reported.

14% for DC and VC, respectively. Overall response rate                              Non-cisplatin-containing chemotherapy
was 31.6% for DC and 24.5% for VC (p = 0.029).                                      Cisplatin-based chemotherapy is associated with con-
Median survival (9.4 vs 9.9 months, p = 0.657) and                                  siderable cisplatin-related toxicity.83 Thus, nausea and
objective response rate (23.9% vs 24.5%) were similar                               emesis are often severe and delayed, whereas neurotox-
for patients treated with DCb and VC, respectively. The                             icity, renal toxicity, and ototoxicity are dose-related
incidence of neutropenia, thrombocytopenia, infection,                              and difficult to handle. Cisplatin administration requires
and febrile neutropenia was similar with all three regi-                            additional hydration that is intolerable to a significant
mens. Patients treated with either docetaxel regimen                                proportion of NSCLC patients due to old age and/or
had a consistently improved quality of life compared to                             concomitant cardiac or cardiopulmonary diseases.
those treated with VC.82                                                            Additionally, a prolonged hospital stay is mandatory,
160 Textbook of Lung Cancer

critical from the convenience as well as the economic                               the substitution of cisplatin for carboplatin. Cisplatin-
aspects.84,85                                                                       based chemotherapy resulted in higher response rates
                                                                                    without any difference in overall survival [HR 1.050
Cisplatin versus carboplatin                                                        (95% CI: 0.907–1.216); p = 0.515). Based on the above
The substitution of cisplatin for carboplatin has been                              data it is reasonable to conclude that cisplatin might be
employed as a means to overcome cisplatin-related inco-                             slightly superior to carboplatin. Although this differ-
venience. Several randomized trials have compared cis-                              ence is slim, it might have an impact for earlier disease
platin with carboplatin doublets.82,86,87 In a trial by Rosell                      stages. The choice of the compound to be used should
et al, 618 patients were randomized to receive pacli-                               be made on a case to case basis and should be tailored
taxel in combination with either cisplatin or carboplatin.                          to the patient’s needs.88
The study was designed to demonstrate a non-inferior
response rate with carboplatin.This was the only trial to                           Platinum versus non-platinum doublets
demonstrate a statistically significant improvement                                 The development of the newer agents led to novel, effec-
in overall survival in favor of the cisplatin arm (9.8 vs                           tive non-platinum-containing chemotherapy regimens
9.2 months, p = 0.019).86                                                           and to the initiation of several randomized trials designed
   TAX 326, although not designed to directly compare                               to determine whether these regimens are comparable to
the 814 patients randomized to docetaxel/cisplatin and                              platinum-based combinations in terms of efficacy.89–95
docetaxel/carboplatin arms, demonstrated a statistically                            In general, these trials did not demonstrate a statisti-
significant improvement in survival for docetaxel/cis-                              cally significant survival benefit in favor of patients
platin compared to the control arm of cisplatin/vinore-                             treated with platinum-based doublets (see Table 10.3.8).
lbine. Cisplatin/vinorelbine itself resulted in numerically                         In three trials, a trend towards better overall survival
superior survival outcomes compared to the carbopla-                                was observed in patients treated with platinum-based
tin/docetaxel combination.82                                                        combinations.91,92,95 On the other hand, another study
   Finally, a meta-analysis using abstracted data identi-                           demonstrated that the combination of vinorelbine and
fied eight trials including 2948 patients that evaluated                            gemcitabine was superior to vinorelbine plus carboplatin

 Table 10.3.8 Platinum- versus non-platinum-based doublets

 Author                    Regimen                No of            Response            Median TTP             Median OS                  p        One-year
                                                  patients         rate (%)            (months)               (months)                            survival (%)

 Georgoulias89             T/P                      441              32                  9.5                   10                                  NR
                           T/G                                       31                  8                      9.5                  NS
 Kosmidis90                Ta/C                     248              28                  6.3                   10.4                   0.32         41.7
                           Ta/G                     254              35                  6.1                    9.8                                41.4
 Gridelli91                G/V                      501              25                 17 weeks               32 weeks                0.08        NR
                           G/P                                      }30                 22 weeks               38 weeks
                           P/V                                                          22 weeks               38 weeks
 Smit92                    G/P                      490              37                  5.6                    8.9                  NS             32.6
                           Ta/P                                      32                  4.4                    8.1                                 35.5
                           Ta/G                                      28                  3.9                    6.7                                 26.5
 Alberola93                G/P                      557              42                  6.3                    9.3                                 38
                           G/P/V                                     41                                                              NS
                           G/V → V/If                                27                  5.7                    8.1                                 34
 Laack                     GVP                      287              28.3               19.3                   32.4 weeks            NS             27.5
                           GV                                        13                 22.3                   35.9 weeks                           33.6
 Georgoulias95             V/P                      117              39.2                8.5                    9.7                    0.96         34.3
                           T/G                      134              30                  8                      9                      5            40.8
 P: cisplatin; V: vinorelbine; G: gemcitabine; T: docetaxel; If: Ifosfamide; Ta: paclitaxel; C: carboplatin; Epi: epirubicin; NR: not reported;
 NS: non-significant; TTP: time to tumor progression; OS: overall survival.
                                                                                      Treatment of NSCLC: chemotherapy 161

in terms of response rate, progression-free survival,             Most studies evaluated a platinum-based doublet
overall survival, and clinical benefit.96                      versus the corresponding non-platinum mono-
   In most trials, non-platinum doublets were associated       therapy,102–104,106,107 some tested a new drug versus a
with a more favorable toxicity profile.89,91,93–95 However,    platinum older drug combination,99,101 and others com-
in two of them no significant differences in terms of          pared cisplatin monotherapy versus a platinum new
toxicity were reported.90,92 Two trials evaluating the issue   drug combination.84,85,105,108
of cost-effectiveness reported contradictory results,             In general, new single agents were shown to be
with one study demonstrating superiority of platinum-          equally effective and less toxic than the old cisplatin-
based doublets,92 whereas in the other no difference           based doublets.99,101 However, most of the studies eval-
between the two arms was reported.90                           uating the newer agents over a platinum new drug
   It should be noted here that none of the above men-         combination have clearly demonstrated a superiority
tioned trials was adequately sized to test equivalence,        for the combination therapy.85,102,104,105 Similarly, most
precluding safe conclusions regarding the comparative          of the studies comparing platinum agents to newer
activity of platinum versus non-platinum doublets.             platinum-based doublets demonstrated a superiority
   A recently published meta-analysis reviewed 37 ran-         for the combination therapy.105,108
domized phase II and III studies comparing a platinum-            Based on the above data, ASCO guidelines98 suggest
based regimen with the same regimen either without             that two-drug combination chemotherapy remains the
cisplatin or with cisplatin replaced by a non-platinum         standard first-line treatment of patients with advanced
compound, in patients with advanced NSCLC.97 This              NSCLC.
meta-analysis included a total of 7633 patients and
reported on the response rates, activity, and survival of      Triplets for the treatment of advanced NSCLC
platinum- versus non-platinum-based chemotherapy.              Several randomized trials evaluated the potential role of
A 62% increase in the odds ratio (OR) for response was         three-drug combinations as a means of improving sur-
attributable to platinum-based therapy (p <0.0001).            vival outcomes in NSCLC. The most recent studies are
When the analysis was restricted in trials that had com-       presented in Table 10.3.10. Although three drug com-
binations of the newer agents as the comparator, the           binations led to significantly higher response rates, they
benefit was 17% in favor of platinum (14 trials including      failed to demonstrate any benefit in terms of time to
3204 patients; p = 0.042).                                     tumor progression and overall survival, while they were
   Overall, the one-year survival rate was 34% and 29%         associated with significantly higher toxicity.
for the platinum- and non-platinum-containing regimens,
respectively (p = 0.0003). However, when platinum-             Duration and timing of first-line therapy
based therapies were compared to combinations of the           The optimal duration of treatment in patients with
newer agents, no statistically significant increase in one-    advanced NSCLC has also been evaluated in random-
year survival was found (36% vs 35%, p = 0.17). When           ized trials. In a trial by Smith et al, 308 patients were
the toxicity of platinum-based regimens was compared           randomized to receive three or six cycles of mitomycin-
with newer, non-platinum combinations, significantly           vinblastine and cisplatin.112 No survival difference was
higher hematologic toxicity, nausea and vomiting, and          observed between the two arms, while patients receiv-
toxic death rate were observed, but no significant increase    ing six treatment cycles experienced significantly higher
in febrile neutropenia rate, neurotoxicity, or nephro-         toxicity. In a randomized trial by Socinski et al, 230
toxicity was reported.97                                       patients received the paclitaxel/cisplatin doublet for
   Accordingly, the current American Society of Clinical       either four cycles, or until disease progression.113 Upon
Oncology (ASCO) guidelines make no distinction between         progression, all patients were treated with weekly pacli-
platinum-based and non-platinum doublets as the pre-           taxel. The median survival did not differ significantly
ferred first-line treatment in patients with advanced          between the two arms (8.5 months for the ‘until pro-
NSCLC.98                                                       gression’ group vs 6.7 for the ‘four cycles’ group, p = 0.63).
                                                               It is interesting to note that in the treat ‘until progres-
Two drugs versus one drug                                      sion’ arm the median number of cycles administered was
A third way to deal with the chemotherapy toxicity in          four. Toxicity was higher in this arm due to the cumu-
patients with advanced NSCLC is to use a single-agent          lative neuropathy. Accordingly, ASCO guidelines sup-
chemotherapy rather than combination treatments.               port the administration of no more than six cycles of
Several trials have compared a doublet versus a single-        first-line chemotherapy. In non-responding patients
agent therapy (Table 10.3.9).                                  treatment should be stopped at four cycles.98
162 Textbook of Lung Cancer

 Table 10.3.9 Randomized studies comparing single-agent versus combination therapy

 Author                    Regimen            No of patients          ORR (%)        Median TTP           Median OS             p                One-year
                                                                                     (months)             (months)                               survival (%)

 Manegold99                G                         156               17.2              4.2               NR                   NR                  NR
                           P/E                                          7                3.7
 Negoro100                 P/Vin                     398               31.7             NR         45.6 weeks                    NS                  38.3
                           P/CPT-11                                    43.7                        46 weeks                                          41.8
                           CPT-11                                      20.5                        50 weeks
 Vansteenkiste101          G                         169               20.2              9.2        6.7                             0.13            22
                           P/Vin                                       20               13.7        5.5                                             19.3
 Le Chevalier102           P/Vin                     612               19               NR          8.0                             0.01a           NR
                           P/V                                         30                           9.2
                           V                                           14                           7.2
 Sederholm103              G/C                       229               30                6         11                            NS                 NR
                           G                                           12                4          9
 Lilenbaum104              Ta/P                      586               30                           8.5                             0.023            36
                           Ta                                          16               NR          6.5                                              31
 Sandler105                P/G                       522               30.4              5.6        9.1                             0.004            39
                           P                                           11.1              3.7        7.6                                              28
 von Pawel85               P/Tir                     446               27.5             12.9 weeks 34.6 weeks                       0.0078           33.9
                           P                                           13.7             11.6 weeks 27.7 weeks                                        22.5
 Georgoulias106            T/P                       319               36.5              4.0       10.5                          NS                  44
                           T                                           21.7              2.5        8                                                43
  P/V vs V.
 G: gemcitabine; P: cisplatin; E: etoposide; Vin: vindesine; V: vinorelbine; C: carboplatin; T: docetaxel; Ta: paclitaxel; Tir: tirapazamine; NR: not reported;
 NS: non-significant; ORR: overall response rate; TTP: time to tumor progression; OS: overall survival.

 Table 10.3.10 Randomized trials comparing triplets versus doublets for the treatment of advanced NSCLC

 Author                      Regimen                   No of patients                 ORR (%)                Median survival (months)                    p

 Alberola93                  P/G                            370                          42                               9.3                            NS
                             P/G/V                                                       41                               8.2
 Laack94                     G/V                            287                          13                               8.3                            NS
                             G/V/P                                                       28                               7.5
 Crino109                    P/G                            307                          38                               8.6                            NS
                             M/I/P                                                       26                               9.6
 Danson110                   Ca/G                           372                          30                               8.5                            NS
                             M/I/P                                                       33                               8.7
 Comella111                  P/V                            180                          25                              8.1                             NS
                             P/G                                                         30                              9.7
                             P/G/V                                                       47                             11.8
 P: cisplatin; G: gemcitabine; V: vinorelbine; M: mitomycin; I: ifosfamide; Ca: carboplatin; Vin: vinblastine.

   The optimal time for the patients to be started on                              (PS) demonstrate poor tolerance to chemotherapy, the
chemotherapy has not been studied in randomized tri-                               current recommendations suggest the initiation of treat-
als. However, since chemotherapy clearly prolongs sur-                             ment as soon as possible, prior to any deterioration of
vival and patients with impaired performance status                                patients’ PS.98
                                                                                   Treatment of NSCLC: chemotherapy 163

PATIENT POPULATIONS WITH SPECIAL                              from subgroup analysis of larger trials. It should be
CONSIDERATIONS                                                noted though that PS 2 patients constitute only a small
                                                              proportion of patients enrolled in first-line treatment
Elderly populations                                           trials, despite the fact that they account for 30–40% of
About 40% of patients diagnosed with NSCLC are aged           the total NSCLC population.
70 years or older. It is estimated that only 25% of elderly      In an interim analyis of ECOG 1594 trial, PS 2 patients
patients finally receive chemotherapy.114 Elderly patients    experienced high rates of severe toxicity in all three
were frequently excluded from large co-operative group        cisplatin-based doublets.81 However, patients treated in
trials due to considerations for increased toxicity. How-     the carboplatin/paclitaxel arm had acceptable toxicity
ever, in an analysis of the Statistics, Epidemiology, and     rates, suggesting that this regimen could be suitable for
End Results (SEER) database, the efficacy of chemo-           further evaluation in this patient population.81 Sub-
therapy in the elderly is equivalent to that in younger       group analysis of PS 2 patients from a CALGB trial that
patients.115 Moreover, age has not been established as        randomized patients to receive paclitaxel monotherapy
an independent prognostic factor for survival.                or a combination of carboplatin and paclitaxel demon-
   The Elderly Lung Vinorelbine Italian Study (ELVIS)         strated significantly superior survival and tolerable tox-
was one of the first large prospective randomized trials to   icity for patients treated with the combination.104
evaluate the role of chemotherapy in elderly patients.116        Until definitive data derived from trials focusing on
A total of 161 patients 70 years of age or older were         this particular group of patients emerge, single-agent
randomized to receive vinorelbine (30mg/m2, days 1            chemotherapy with the newer agents should be the pre-
and 8, every three weeks) or BSC. Overall survival was        ferred option for PS 2 patients.121 Carboplatin- or low-
significantly better in the vinorelbine arm (28 weeks         dose cisplatin-based chemotherapy might also be used.121
versus 21 weeks, p = 0.03) and quality of life was signifi-   In any case, patient preferences, the existing co-mor-
cantly improved with chemotherapy. The same group             bidities, and the anticipated chemotherapy-related tox-
of investigators subsequently conducted the Multicenter       icity should be considered prior to the final decision.
Italian Lung Cancer in the Elderly Study (MILES),
designed to test whether the combination of vinorel-
bine and gemcitabine was superior to either single agent      SECOND-LINE THERAPY
alone.117 This trial, which enrolled 698 patients, failed
to demonstrate any difference in terms of response rate       The availability of new active regimens in the first-line
or overall survival between arms. However, a smaller trial    setting has prompted several investigators to consider
(n = 120) that compared vinorelbine monotherapy to            second-line therapy for patients with advanced NSCLC,
the vinorelbine-gemcitabine combination reported a sur-       since a substantial percentage of patients maintain a
vival benefit in favor of the combination arm (median         good PS upon recurrence. Initial studies employing the
overall survival 6.7 months vs 4.2 months, p <0.01).118       newer agents either alone122,123 or in combination124,125
Currently, ASCO guidelines recommend single-agent             showed significant activity in pretreated patients with
therapy for the treatment of elderly patients with            advanced NSCLC. However, most of these studies were
NSCLC.98                                                      small, and many did not report details on prior treat-
                                                              ment or patient characteristics; in addition, although all
Patients with poor performance status                         the studies reported response rates, very few provided
PS has been consistently identified as one of the most        median survival times or one-year survival rates, thus
important prognostic factors in patients with advanced        precluding safe conclusions for the value of second-line
NSCLC.5 It has also been established that patients with       chemotherapy.
ECOG PS of 0–1 derive significant benefit from sys-              Docetaxel was the first agent to be tested as second-
temic chemotherapy, while patients with ECOG PS 3–4           line therapy in randomized phase III trials. In a study
should be offered palliative care.5 However, it is less       by Fossella et al, 373 patients pretreated with platinum-
clear which is the optimal treatment of patients with PS 2.   containing regimens were randomized either to two
Generally, these patients have short survival and are         dose levels of docetaxel (75 mg/m2, or 100 mg/m2) or to
anticipated to experience high toxicity rates when com-       a single agent (ifosfamide or vinorelbine) control arm.126
bination chemotherapy is considered.81,119,120 For the        Although no statistically significant difference was
present, most of the data regarding the management of         observed in terms of overall survival between the three
this particular patient population are mainly derived         arms, docetaxel 75 mg/m2 resulted in a longer time to
164 Textbook of Lung Cancer

progression and higher one-year survival rates compared            adjuvant strategies and second-line chemotherapy, treat-
to the control arm (32% vs 19%, p = 0.025). Further-               ment outcomes for NSCLC continue to be disappointing.
more, about 30% of patients in the control group even-             Fortunately, the picture is changing with the introduc-
tually received docetaxel, a fact that may have diminished         tion of targeting therapies. Inhibition of the epidermal
observable differences between the two arms. In a trial            growth factor receptor (EGFR) family is at the forefront,
by Shepherd et al, 204 patients with platinum refrac-              led by the tyrosine kinase inhibitors gefitinib (Iressa®)
tory disease were randomized to receive docetaxel 100              and erlotinib (OSI-774 Tarceva®), but angiogenesis
mg/m2 or best supportive care alone.127 An interim                 inhibition with bevacizumab (Avastine®) has also pro-
analysis that identified significant toxicity in the doc-          duced interesting data from recent trials. The basis for
etaxel arm led to the reduction of docetaxel dose to 75            the development of this mode of therapy is described
mg/m2. The final analysis showed that, although the                elsewhere in this book.
response rate was only 7%, patients treated with doc-                 Erlotinib has been approved by health authorities in
etaxel achieved a higher time to tumor progression (2.5            many countries for the treatment of patients with locally
vs 1.6 months, p <0.001) and overall survival (7 vs                advanced or metastatic NSCLC after failure of at least
5 months, p = 0.047) compared to the control group. The            one prior chemotherapy regimen. The study by the
study by Shepherd et al established docetaxel as the stan-         Canadian Clinical Trials Group delivered the backbone
dard comparator arm for subsequent randomized trials.              of the data for this decision. The study included a total
Based on the results of these studies, the FDA approved            of 731 patients randomized using a 2:1 randomization
docetaxel as second-line therapy in NSCLC.                         scheme: 488 in the erlotinib arm and 243 in the pla-
   A non-inferiority phase III study compared docetaxel            cebo arm. EGFR status was determined for 238 of the
with pemetrexed, a multitargeted antifolate, as second-            731 study patients for whom tissue samples were avail-
line therapy in NSCLC.128 Five hundred and seventy-one             able prior to the study. A positive EGFR expression sta-
patients were randomized to receive docetaxel (75 mg/m2)           tus was defined as having at least 10% of cells staining
or pemetrexed (500 mg/m2) plus vitamin supplementa-                for EGFR. Survival of erlotinib-treated patients was
tion. No significant difference was observed in overall            superior to that of placebo-treated patients and median
(pemetrexed 8.3 months vs docetaxel 7.9 months) or                 survival duration of erlotinib-treated patients was 6.7
one-year survival (29.7% for both drugs). Furthermore,             months, compared with 4.7 months for placebo-treated
neutropenia and febrile neutropenia were significantly             patients. Exploratory univariate analysis showed a larger
lower with pemetrexed. This trial led to the approval of           survival prolongation in two subsets of patients: those
pemetrexed in the second-line treatment of NSCLC.                  who never smoked and those with EGFR-positive
   A weekly schedule of docetaxel was compared with                tumors. Erlotinib was also superior to placebo in terms
the classic every three weeks schedule in two random-              of progression-free survival, and had a response rate of
ized phase III trials.129,130 In the trial by Gridelli et al,129   8.9 versus 0.9%. Severe rash occurred in 8% and severe
comparable overall survival rates were reported (6.7 vs            diarrhea occurred in 6% of erlotinib-treated patients.132
5.8 months for the weekly arm) but the weekly schedule                Similar results have been obtained in phase II trials
was associated with better safety and quality of life pro-         with erlotinib. The clinical and biologic features associ-
files. In contrast, in the trial by Schuette et al,130 a trend     ated with EGFR have been analyzed in studies per-
towards better survival was observed for patients in the           formed in the US, Europe, South Korea, Taiwan, China,
weekly arm (>8 months versus 5.8 months, p = 0.08).                and Japan, and considerable efforts have been made to
   Additional investigations in the field of second-line           identify predictive factors for response to elucidate the
therapy focused on the introduction of two-drug com-               molecular mechanisms involved. The most important
binations in the second-line setting that generally resulted       advance has been the identifiation of somatic mutations
in high toxicity rates without any survival benefit over           in the 90% or so of patients with objective responses to
monotherapy.131                                                    gefitinib or erlotonib. In addition to non-smoker females
                                                                   and adenocarcinoma, Asian descent has turned up as
                                                                   an important predictive prognostic factor associated
TARGETED THERAPIES IN ADVANCED NSCLC                               with the response and survival benefit of both gefitinib
                                                                   and erlotinib.
Although chemotherapy has resulted in some progress                   In addition to the phase III trials with the two tyrosine
in the overall management of patients with lung cancer             kinase inhibitors, several articles have been published
in recent years, with increasing use of neoadjuvant and            based on experience with a compassionate-use program
                                                                                                Treatment of NSCLC: chemotherapy 165

in patients with advanced NSCLC who have failed prior                  10. Feld R, Rubinstein L, Thomas PA. Adjuvant chemotherapy
chemotherapy or were unfit for chemotherapy. Some of                       with cyclophosphamide, doxorubicin, and cisplatin in patients
                                                                           with completely resected stage I non-small-cell lung cancer.
the studies have specifically analyzed the efficacy and
                                                                           The Lung Cancer Study Group. J Natl Cancer Inst 1993; 85:
tolerability of gefitinib in patients with poor perfor-                    299–306.
mance status or in elderly patients. All studies have                  11. Ohta M, Tsuchiya R, Shimoyama M et al. Adjuvant chemo-
shown that gefitinib has clinical antitumor activity and                   therapy for completely resected stage III non-small-cell lung
also good tolerability, with higher response rates in the                  cancer. Results of a randomized prospective study. The Japan
Asian studies than in European or European-heritage                        Clinical Oncology Group. J Thorac Cardiovasc Surg 1993;
                                                                           106: 703–8.
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directed against the vascular endothelial growth factor                    clinical trials. Non-small Cell Lung Cancer Collaborative
(VEGF), the results of a randomized trial in 444 patients                  Group. BMJ 1995; 311: 899–909.
with metastatic NSCLC were presented at the ASCO                       13. Keller SM, Adak S, Wagner H et al. A randomized trial of
meeting in 2005. Bevacizumab was added to paclitaxel                       postoperative adjuvant therapy in patients with completely
                                                                           resected stage II or IIIA non-small-cell lung cancer. Eastern
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    11           Treatment of small cell lung cancer

11.1 Treatment of SCLC: surgery
                 Hisao Asamura, Riken Kawachi

                 Contents Introduction • Primary surgery • Induction chemotherapy plus adjuvant surgery
                  • Salvage surgery

INTRODUCTION                                                      Since these earlier studies, the arrival of new diag-
                                                               nostic tools, such as the higher resolution CT scan and
The role of surgery in the management of small cell            positron emission tomography, has enabled identifica-
lung cancer (SCLC) remains a controversial and as yet          tion of very limited disease with a higher potential for
undecided issue despite re-examination of this role over       cure. In addition, platinum-based combination chemo-
the past 30 years. The British Medical Research Council        therapeutic regimens have become available since the
performed two large, randomized, prospective trials of         early 1980s, with an objective response rate as high as
surgery versus radiotherapy in the 1960s and 1970s,            80%. With the addition of postoperative chemotherapy,
which reported the failure of surgery alone to control         even better long-term survival in this very early stage of
this disease when compared to radiotherapy.1,2 Although        disease has been reported. In stage I disease, up to 70% of
the results of this trial set the standards for non-surgical   patients will be cured. In more advanced disease (stages
treatment for SCLC thereafter, this study must be criticized   II and IIIA), when the tumor is totally excised at surgery
from the present view point for the following issues:          and treated with postoperative chemotherapy, five-year
                                                               survivals in the range of 20–30% can be expected.7,8
•   SCLC located in the peripheral lung was excluded           However, as for non-small cell lung cancer (NSCLC),
    from the study since only tumors diagnosed by rigid        the prognosis of patients with N2 disease is quite poor,
    bronchoscopy prior to the treatment were enrolled.         and the chance of surgical intervention is least.9,10
•   Complete resection of the tumor could be achieved             The role of surgery in multimodality therapy to improve
    in only 48% of the patients assigned to the ‘sur-          control of the primary site has been investigated by uti-
    gery’ arm.                                                 lizing induction chemotherapy prior to surgical
•   No intraoperative staging was done.                        resection.11–13 These programs have also included con-
•   Modern clinical staging techniques (CT scan and            solidation chemotherapy as well as mediastinal radio-
    mediastinoscopy) were not used. As a result, these         therapy with or without prophylactic cranial irradiation.
    studies included very few patients with very early         The final role that has been suggested for surgery in the
    stage disease (T1–2N0M0) who are thought to                treatment of SCLC is that of ‘salvage’ treatment when
    benefit from surgery most.                                 primary chemo-irradiation fails to control the local dis-
                                                               ease or when recurrence occurs and only the primary
   In the late 1960s and mid-1970s, surgery for early          site is affected.14 In these instances, surgical treatment
stage SCLC was championed by other reports, where              after reinduction chemotherapy has been utilized as a
survival was significant for tumors located in the periph-     ‘salvage’ procedure.
ery of the lung confined to the lung, with N0 status,             In summary, the present-day role of surgery in the
and treated by lobectomy.3,4 Reports in the late 1970s         management of SCLC can be categorized into four
and early 1980s further demonstrated that surgical             groups:
therapy alone could provide curative treatment in up to
25% of such patients.5,6 A report by the Veterans              •   primary surgery (surgery alone);
Administration Surgical Oncology Group showed a                •   primary surgery followed by systemic adjuvant
23% five-year survival rate for 132 patients resected,             chemotherapy;
and concluded that resection was definitely indicated in       •   induction (neoadjuvant) chemotherapy/chemora-
patients with T1N0 lesions, and probably indicated in              diotherapy followed by surgery; and
those with T1N1 or T2N0 lesions.6                              •   salvage surgery after definitive chemoradiotherapy.
                                                                                             Treatment of SCLC: surgery   171

   Upfront surgery without any following additional treat-     courses of chemotherapy consisting of cisplatin and
ment is becoming less common since the higher activity         etoposide. Three-year survival was 61%, 68% in clinical
in extensive disease (ED) SCLC has been established            stage I disease.
and become well known. Another reason for upfront                 Badzio and co-workers, in their retrospective analysis,
surgery is preoperatively undiagnosed tumors, espe-            demonstrated a beneficial effect for surgical resection.21
cially clinical T1 and T2N0 diseases in peripheral loca-       They used matched case–control methodology to minimize
tions, which continue to be resected by surgeons and           selection bias. A group of 134 patients were selected for
are found to be SCLC postoperatively.                          comparative analysis; 67 were treated with surgical resec-
                                                               tion followed by chemotherapy and 67 were managed
PRIMARY SURGERY (SURGERY ALONE AND SURGERY                     with chemoradiotherapy. They demonstrated a significant
WITH POSTOPERATIVE CHEMOTHERAPY)                               difference in survival between operated and non-operated
                                                               patients. Five-year survival in patients treated with and
Complete resection of SCLC, often without prior knowl-         without surgery was 27% and 4%, respectively. The rela-
edge of the cell type, will result in significant five-year    tive hazard ratio of death in patients treated with sur-
survival. Several reports have suggested that early stage      gery was 0.42 (95% confidence interval 0.28–0.61). In
SCLC can be cured by surgical resection alone                  their study, survival advantage was observed in patients
(Table 11.1.1).10,12,15–29 For instance, Shah et al15 retro-   with N0/N1 except for N2 disease, and they suggested
spectively analyzed the prognosis of 28 patients who           that surgery added to chemotherapy might benefit in
received surgery alone for SCLC; and reported a five-          limited SCLC.
year survival of 43.3%. They have stated that the pros-           However, it is still difficult to compare this multimo-
pects of cure by operation are similar to those with           dality surgical approach to chemoradiation alone, since
NSCLC. However, the most recent series reporting their         medical oncologists on the whole do not classify these
data suggest that postoperative chemotherapy is a nec-         ‘very limited’ tumors as a separate entity.31 Despite this,
essary part of treatment (Table 11.1.1).23 In most cen-        some retrospective analyses have been performed. Oster-
ters, following surgical resection, a minimum of four to       lind and co-workers, in their retrospective analysis,
six courses of adequate two- or three-drug regimen che-        failed to demonstrate any beneficial effect for surgical
motherapy is advised. In a co-operative international          resection.32 While they demonstrated a significantly
lung cancer multimodality treatment trial, 112 patients        better prognosis for 79 patients who met criteria for sur-
with SCLC underwent initial surgical resection and             gical resectability prior to treatment than for 696 patients
were then randomized to receive one of two intensive           who did not, there was no significant difference in sur-
postoperative chemotherapy regimens.30 The projected           vival between 33 operated and 46 non-operated patients.
36-month survival rate for 43 patients with N0 disease         Again in this study, however, only 33% of the operated
was 65%; for 43 with N1 disease, 52%; and for 26 with          patients underwent complete resection, which suggested
N2 disease, 29%. If hilar and mediastinal lymph node           that the criteria for resectability were not predictive
disease is found at the time of surgery, postoperative         enough, and the authors’ unfavorable statement regarding
mediastinal irradiation is also advised, although its role     the benefit of surgery was not conclusive. On the other
is not certain. The role of prophylactic cranial irradia-      hand, Shepherd and co-workers have suggested a two-
tion has yet to be decided as well.                            fold improvement in survival utilizing surgery as part of
   More recently, Brock and co-workers emphasized that         the treatment, by improving control of the primary site.12
highly selected patients with SCLC might benefit from          It must be emphasized that the description of stage of
surgery and adjuvant chemotherapy, particularly if the         patients in such a study, by not only limited disease
chemotherapy was platinum-based.23 In the retrospec-           (LD)–ED but also the tumor, node, metastasis (TNM)
tive study, the five-year survival for patients with stage     system is crucial to make the comparison possible
I disease who received adjuvant chemotherapy was 63%,          between primary surgery and chemoradiation alone.
and among them, the five-year survival for patients
receiving platinum chemotherapy was 86%. In the Japan
Clinical Oncology Lung Cancer Study Group trial                INDUCTION CHEMOTHERAPY PLUS ADJUVANT
(JCOG9101), the study also reported better survival for        SURGERY
early stage SCLC patients.22 Sixty-one patients with
completely resected SCLC received chemotherapy.                The role of surgery in more proximal tumors with clin-
Ninety percent of the patients received two to four            ical N1 or minimal N2 disease (but still resectable by
172 Textbook of Lung Cancer

 Table 11.1.1 The clinical outcome of patients who underwent primary surgery with or without postoperative adjuvant
 chemotherapy for SCLC

 Author                    No of patients             Median survival (months)               Five-year survival rate (%)

 (a) Surgery + chemotherapy
 ISC-LCSG16               183                                                                63a (TN0M0)
                                                                                             37b (TN2M0)
 Coolen17                                                        15                          27
                                                                                               60 (stage I)
 Davis18                         37                                                            50 (stage I)
                                                                                               35 (stage II)
                                                                                               21 (T3N2)
 Muller19                        45                              18                          36
                                                                                               57 (stage I)
                                                                                               28 (stage II)
                                                                                               34 (stage IIIA)
 Toronto Group12                 79                              21                          40
 Salzer10                        25                                                          25 (N2 disease)
 Cataldo20                       60                                                            40 (stage I)
                                                                                               36 (stage II)
                                                                                               15 (stage III)
 Badzio21                        67                                                          27
                                                                                               59 (stage I)
                                                                                               31 (stage II)
                                                                                                 4 (stage III)
 JCOG22                          61                                                          57
                                                                                               76 (stage I)
                                                                                               38 (stage II)
                                                                                               39 (stage III)
 Brock23                         45                                                            63 (stage I)
                                                                                               25 (stage II/III)
 (b) Surgery ± chemotherapy
 Lucchi24                 127                                    18                          22.6
                                                                                               47.2 (stage I)
                                                                                               14.8 (stage II)
                                                                                               14.4 (stage III)
 Miyazawa25                      12                                                          50 (latter period)
                                 25                                                           8 (former period)
 Merkle26                       170                                                          18
 Maassen27                      124                                                          20
 (c) Surgery alone
 Coolen17                        15                                                          13
                                                                                               12 (stage I)
 Shah15                          28                                                          43.3
                                                                                               57.1 (stage I)
                                                                                               55.5 (stage II)
 Sorensen28                      76                                                          12
 Shore29                         40                                                          27
  30-month survival.
  3-year survival.
                                                                                               Treatment of SCLC: surgery   173

 Table 11.1.2 The clinical outcome of patients who underwent induction (neoadjuvant) chemotherapy followed by surgery
 for SCLC

 Author                      No of patients                Median survival (months)                 Five-year survival rate (%)

 Prager33                         11                                 17
 Baker34                          37                                                                65a
 Williams35                       25                                33                              48
 Shepherd36                       38                                21                              36
                                  11                       Not reached (stage I)
                                  13                           16 (stage II)
                                  14                          12 (stage III)
 Salzer37                         14                                                                47
 Holoye38                         26                                 25
 Johnson39                        24                                 19
 Lad40                            70                                 15.4
 Wada41                           17                                                                30.70
                                                                                                      80 (c-stage I/II)
                                                                                                      50.3 (p-stage I/II)
 Fujimori43                       21                                 61.9                           66.7a
                                                                                                      73.3a (c-stage I/II)
 Eberhardt42                      46                                 36                             46
 Veronesi44                       23