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					   6                   The Forum for Early Diagnosis and Treatment of Lung Cancer




                       Frontiers
 January 2000


Lung
Cancer

 Comments may be
 submitted to:
                       New Support for Lung Cancer Frontiers
 Lung Cancer
                                  s Editor in Chief of Lung         lial lesions. We hope that all who read


                       A
 Frontiers
 1850 High Street                 Cancer Frontiers, I am            LCF will benefit from an expanding body
 Denver, CO 80218                 delighted to announce an unre-    of knowledge and technology that could
 or by e-mail at                  stricted grant made available     help us change the outcome of lung can-
 tlpdoc @aol.com       from Bristol-Myers Squibb to support         cer. The future promises more tools that
                       future issues of Lung Cancer Frontiers,      will ultimately lead to the solution of the
 Lung Cancer           (LCF). The Editorial Board joins me in       most common fatal malignancy of men
 Frontiers is funded   expressing its appreciation. For the year    and women not only in the United States,
 by The Snowdrift      2000, we plan quarterly issues. In keeping   but around the world.
 Pulmonary             with our original mission, we will focus        We welcome two new members to the
 Conference            upon new developments in lung cancer         LCF Editorial Board. Dr. James R. Mault,
 through Bristol-
 Myers Squibb
                       early identification and intervention,        is Assistant Professor of Cardiothoracic
                       where many exciting new developments         Surgery at the University of Colorado
                       are rapidly happening. We will also pro-     Health Sciences Center, in Denver. Jim’s
“The purpose of        vide news about new therapeutic strate-      main interest is treatment of lung cancer
 Lung Cancer           gies in more advanced stages of disease,     in all stages, with emphasis in early iden-
 Frontiers is to       whenever appropriate. It is the purpose of   tification and intervention. Jim is an
 acquire and           LCF to disseminate new information pri-      extremely enthusiastic young thoracic
 disseminate new       marily to pulmonologists and other spe-      surgeon who is representative of a new
 knowledge about
 lung cancer and
                       cialists who need to become involved in      group of thoracic surgeons who will
 how it can be most    lung cancer identification and treatment.     develop new surgical approaches to treat
 quickly and effec-    Historically, nihilism has permeated the     lung cancer.
 tively diagnosed      field of lung cancer diagnosis and treat-        Dr. M. Patricia Rivera is Assistant
 and treated.”         ment. This must be replaced by enlighten-    Professor of Medicine at the University of
                       ment, made possible through new knowl-       North Carolina in Chapel Hill. She is Co-
                       edge and technological developments.         director of the Multidisciplinary Thoracic
                          We will send copies of the first five       Oncology Program at her institution and
                       issues of LCF upon request, as long as       is Co-director of the Pulmonary Fellow-
                       our supply lasts.                            ship Training Program. She represents a
                                                                    growing group of pulmonologists who
                       Editorial Board News                         are taking a comprehensive approach to
                       Stephen Lam has agreed to serve as           lung cancer identification, staging, and
                       Deputy Editor of LCF. We welcome his         treatment.
                       increased involvement in this publication.
                       Steve has been a leader in promoting
                       techniques of early identification, most
                       notably, the application of fluorescent
                       endoscopy, to diagnose early intraepithe-
The Forum for Early Diagnosis and Treatment of Lung Cancer




                                                                         Geno Saccomanno, Ph.D., M.D.
Lung Cancer Frontiers Editorial Board                                    (1915–1999)


Thomas L. Petty, M.D.   Timothy C. Kennedy,      Louise M. Nett,
Editor in Chief         M.D.                     R.N., R.R.T.
Lung Cancer             Lung Cancer              HealthONE
Institute of            Institute of             Denver, CO
Colorado/               Colorado/
HealthONE               HealthONE                Branko Palcic, Ph.D.
Denver, CO              Denver, CO               University of British
                                                 Columbia
Stephen Lam, M.D.       Richard A. Matthay,      Vancouver, BC,
Deputy Editor           M.D.                     Canada
University of British   Yale University
Columbia                New Haven, CT            M. Patricia Rivera,
Vancouver, BC,                                   M.D.
Canada                  James R. Mault, M.D.     University of NC at
                        University of            Chapel Hill,
Marshall Anderson,      Colorado Health          Chapel Hill, NC
Ph.D.                   Sciences Center
University of           Denver, CO
Cincinnati                                       Melvyn S. Tockman,                his issue of Lung Cancer
Cincinnati, OH

Joel J. Bechtel, M.D.
St. Mary’s Hospital
and Medical Center
Grand Junction, CO
                        David E. Midthun,
                        M.D.
                        Mayo Clinic
                        Rochester, MN

                        York E. Miller,   M.D.
                                                 Ph.D., M.D.
                                                 H. Lee Moffitt
                                                 Cancer Center and
                                                 Research Institute
                                                 Tampa, FL
                                                                         T         Frontiers honors the memory of
                                                                                   Geno Saccomanno, the pioneer
                                                                                   who developed the current
                                                                         method of sputum cytology, which is used
                                                                         around the world. Geno was truly a
                        Veterans                                         renaissance man. Following training at St.
Denis A.Cortese, M.D.   Administration           Comments may be         Louis University, he returned to the
Mayo Clinic             Medical Center           submitted to:
Jacksonville            Denver, CO               Lung Cancer
                                                                         Rockies to join the staff of St. Mary’s
Jacksonville, FL                                 Frontiers               Hospital in Grand Junction, Colorado in
                        James L. Mulshine,       1850 High Street        1948. This city is near his childhood
Fred W. Hetzel,         M.D.                     Denver, CO 80218        home of Moab, Utah. In the early 1950's,
J.D., Ph.D.             National Cancer          or by e-mail at         until the time of his death on July 10,
HealthONE               Institute                tlpdoc @aol.com         1999, Geno was the prime mover in the
Denver, CO              Rockville, MD                                    development and promotion of sputum
                                                 See the Lung
James R. Jett, M.D.                                                      cytology. He knew that someday his tech-
                        Sreedhar Nair, M.D.      Cancer Frontiers
Mayo Clinic             Norwalk Hospital         web page at             nique would be valuable in the early iden-
Rochester, MN           Norwalk, CT              www.lungcancer-         tification and treatment of occult central
                                                 frontiers.org           lung cancers. Geno’s contributions, along
Harubumi Kato,          John A.                                          with new imaging techniques, including
M.D., Ph.D.             Nakhosteen, M.D.                                 rapid low-dose CT scanning, discussed
Tokyo Medical           Augusta Teaching                                 elsewhere in this issue, offer an effective
College                 Hospital
Tokyo, Japan
                                                                         strategy in lung cancer screening. New
                        Bochum, Germany
                                                                         endoscopic techniques, also provide new
                                                                         tools to find and treat most central lung
                                                                         cancers in their earliest and most treatable
                                                                         stages. The Editorial Board dedicates all
                                                                         four issues of LCF in 2000 to the spirit of
                                                                         Geno Saccomanno. He will be missed, but
                                                                         always remembered, not only for his
2
                        Lung
                        Cancer   Frontiers
                       enormous contributions to medicine, but       larly useful in Dr. Saccomanno’s mind
                       for his humanism and contributions to         because it revealed the position of the cell
                       the Grand Junction community.                 along the progressive transformation
                          The first two contributions to this issue   from squamous maturation toward squa-
                       of LCF were written especially for this       mous neoplasia. In the process of car-
                       issue. The other citations concentrate        cinogenesis, the normal regulation of cell
                       mightily to the armamentarium we are          cycle control is perturbed and for squa-
                       amassing to be able to identify and treat     mous cancer, this dysregulation is most
                       early stages of lung cancer.                  reliably reflected in the nuclear detail.
                                                                     Routine clinical identification of early
                                                                     lung cancer in high risk populations
                                                                     depends upon the consistent identification
                       Lung Cancer Identification Based               of discriminating signals to allow for reli-
                       on Molecular Markers                          able case detection. The complexity of
                                                                     cytopathology detection of cancer
                       James L. Mulshine, M.D., National             becomes evident as computerized image
                       Cancer Institute, National Institutes of      analysis has been applied to cervical can-
                       Health, Melvyn S. Tockman, Ph.D., M.D.        cer screening. Of the many companies
                       H. Lee Moffitt Cancer Center and               that attempted to provide this service,
                       Research Institute                            only a few still exist. As the experience
                                                                     with automated cellular detection of cer-
                                 espite Dr. Geno Saccomanno's        vical cancer matures, the prescience of


                       D         many decades of important and
                                 pioneering work, over the last
                                 several years he related a mild
                       sense of chagrin. He sensed that the tools
                       to finally bring lung cancer back under
                                                                     Saccomanno's approach to cytomorpho-
                                                                     logical detection becomes evident.
                                                                        As we move to molecular-based detec-
                                                                     tion of early lung cancer, the same princi-
                                                                     ples apply. Fastidiousness in defining the
                       control were coming into focus and he         specimen preservation and handling tech-
                       regretted that he was not going to play a     niques is essential. Defining conditions to
                       role in the resolution of the greatest        ensure optimal preservation of the infor-
“He had a prag-        scourge of the 20th century. Despite          mative signals is the challenge. From a
 matic approach        grave medical problems, Dr. Saccomanno        conceptual level, molecular detection
 to the problem        was still in the chase for his great white    techniques still involve an element of
                       whale. Immediately prior to his death, he     cytomorphological discrimination. As
 that was tem-
                       was developing a clinical trial to evaluate   Saccomanno and co-workers so clearly
 pered by the          a new technique for sputum induction.         demonstrated, in the airway of a chronic
 reality of clinical   His energy, dedication, and decency were      smoker, there are numerous scattered foci
 practice.”            a joy to all that had the privilege to work   of injured cells. The ones with the most
                       with him.                                     advanced cytomorphological changes are
                          In considering the future of molecular     typically from areas of dysplastic squa-
                       detection of lung cancer, it is useful to     mous growth. We think about such cells
                       reflect on how Dr. Saccomanno                  as being part of an evolving cancer clone.
                       approached early lung cancer detection.       With molecular approaches we still want
                       He had a pragmatic approach to the            to find those evolving cancer clones, but
                       problem that was tempered by the reality      we want to cast the net more broadly so
                       of clinical practice. The fixation fluid that   we find more than just early squamous
                       bears Dr. Saccomanno's name was devel-        cancers. The goal with image analysis is
                       oped because of the practical need to         to find all of the cells in the sputum that
                       standardize the conditions for evaluating     could be members of clonal populations
                       nuclear detail of the bronchial epithelial    of bronchial epithelial cells. Undifferen-
                       cells recovered in the sputum. The            tiated, metabolically active bronchial
                       appearance of the nucleus was particu-        epithelial cells have been recognized in
                                                                                                               3
                     The Forum for Early Diagnosis and Treatment of Lung Cancer




                     the sputum by early cytopathologists such      studies of heterogeneous nuclear ribonu-
                     as Doctors Geno Saccomanno and John            cleoprotein A2/B1 overexpression.
                     Frost, but many of these cells are from        Clin Cancer Res 1997;3:2,237-2,246.
                     individuals that will have a benign
                     course. The co-incidence of these cells in     2. Tockman MS, et al. Sensitive and spe-
                     the sputum which also display large            cific monoclonal antibody recognition of
                     amounts of the molecule, heterogeneous         human lung cancer antigen on preserved
“Fastidiousness in   nuclear ribonucleoprotein A2/B1 are the        sputum cells: A new approach to early
 defining the         cases that we have consistently found to       lung cancer detection. J Clin Oncol
 specimen preser-    go on to lung cancer. We think that            1988;6:1,685-1,693.
 vation and han-     hnRNP A2/B1 is a molecular beacon in
                     that setting. We have previously pub-          3. Fielding P, et al. Hetergeneous nuclear
 dling techniques    lished that in other settings. The over-       ribonucleoprotein A2/B1 up-regulation in
 is essential.”      expression of the molecule is not diagnos-     bronchial lavage specimens. A clinical
                     tic for cancer but rather this molecule        marker of early lung cancer detection.
                     may play an important role in lung devel-      Clin Cancer Res 1999;5:4,048-4,052.
                     opment. For example, since this molecule
                     is also widely expressed in inflammatory
                     cells, we must first use morphology to          Current Status of Fluorescence
                     identify bronchial epithelial cells. We
                     anticipate that this approach of analyzing     Bronchoscopy and the Future of
                     molecular expression in clonal popula-         Optics in Localisation and
                     tions of epithelial cells will be essential    Intervention of Early Lung Cancer
“We think that       for other markers that would indicate the
 hnRNP A2/B1 is      emergence of a bronchial epithelial can-       Stephen Lam, M.D., FRCPC
 a molecular         cer. In the face of intense cost pressure      Professor of Medicine, University of
                     for diagnostics, the logical path combines     British Columbia and the British
 beacon in that      economical, automated analyses of spu-         Columbia Cancer Agency, Vancouver,
 setting.”           tum morphology with molecular detec-           British Columbia, Canada
                     tion. We have started with one of the suc-
                     cessful, automated cervical cancer screen-          n 1990, fluorescence bronchoscopy
                     ing systems. This platform could be mod-
                     ified to add molecular analysis of the spu-
                     tum cells. This essential describes a devel-
                     opment process that we have engaged in
                     with Bayer Diagnostics and TriPath to
                                                                    I    using tissue autofluorescence without
                                                                         the use of exogenous fluorescence
                                                                         drugs such as porphyrin compounds
                                                                    was developed at the British Columbia
                                                                    Cancer Agency to enhance the ability of
                     enable high throughput cell-based early        endoscopists to visualize and biopsy pre-
                     lung cancer detection. To be successful,       invasive and micro-invasive cancers
                     such a system will have to automate the        (IEEE Eng Med Biol 1990;1291:1,142-
                     critical steps that Saccomanno outlined        1,143). Fluorescence bronchoscopy makes
                     forty years ago. As this process proceeds,     use of the absorption and fluorescence
                     continued attention to practical detail        properties of chromophores in bronchial
                     will also be essential, so even with           tissues to provide information on the bio-
                     sophisticated, high speed, image process-      chemical and functional changes in the
                     ing platforms we will remain Geno's            bronchial tissues. Upon illumination by
                     students.                                      violet or blue light (400 nm to 450 nm),
                                                                    normal tissues fluoresce strongly in the
                     Suggested Readings                             green (500 nm to 520 nm). As the
                     1. Tockman MS, Mulshine JL, et al.             bronchial epithelium changes from nor-
                     LCEWDG Investigators, YTC                      mal, to dysplasia, to carcinoma in situ,
                     Investigators. Prospective detection of        and then to invasive cancer, there is a
                     preclinical lung cancer: Results from two      progressive decrease in the fluorescence
4
 Lung
 Cancer   Frontiers
intensity especially in the green region,     light source is used.
with comparatively less reduction in the         Published data on the use of the LIFE-
red. This reduction in fluorescence inten-     Lung device in over 1,400 patients
sity is due to a decrease in the concentra-   worldwide showed that white light bron-       “The advantage of
tion of short lifetime chromophores such      choscopy alone localized 40% of the pre-       the system in
as reduced or protein-bound flavins,           invasive lesions with a range of 27% to        terms of instru-
increase in the epithelial thickness that     51% in different countries. The addition       mentation is its
impedes the emission of the fluorescent        of fluorescence examination increased the       compact size and
light to the bronchial surface and an         detection rate by an average of two-fold       the high quality of
increase in blood volume due to angio-        (range 71% to 88%) (Diagn Ther                 the fiberoptic
genesis in pre-malignant and malignant        Endosc 1994;1:75-78; 1997;3:197-201;           bronchoscope
tissues.                                      1999;5:77-84; 1999;5:85-90; Lam S et           that is specially
   The differences in fluorescence between     al. Chest 1998;113:696-702; Kurie JM et        adapted for
normal and abnormal tissues are very          al. J Natl Cancer Inst 1998;90:991-995;        fluorescence
subtle. In the current FDA-approved flu-       Khanavkar B et al. Pneumologie                 examination  ..”
orescence imaging device (LIFE-Lung           1998;52:71-76; Atemw Lungenkrkh
System, Xillix Technologies Corporation;      1997; 23:211-217; Vermylen P Eur Resp
Richmond, British Columbia, Canada),          J 1997;10:425S; J Bronchology
two image-intensified cameras are used to      1997;4:205-208;1998;5:280-283).
amplify the red and green fluorescence            There is a learning curve to achieve
intensity differences between normal and      optimal results. Most bronchoscopists
abnormal tissues. Other devices, such as      are familiar with the changes associated
the D-Light/AF system (Karl Storz,            with invasive cancer but have little expe-
Tuttlingen, Germany) and the SAFE-1000        rience in recognizing the subtle changes
(Pentax, Japan) are currently under clini-    of small, pre-invasive cancer. For exam-
cal trials. In the D-Light/AF system, a       ple, in the North American multi-center
non-image intensified color CCD camera         clinical trial (Lam S et al. Chest
is used. However, to record the weak flu-      1998;113:696-702), the number of pre-
orescence, the exposure time has to be        invasive lesions identified in part one of     “Published data on
increased to 1⁄8 to 1⁄15 second instead of    the study to become familiar with the          the use of the
the conventional video rate of 1⁄60 second    changes associated with these lesions was      LIFE-Lung device
to collect enough light for visualization.    much lower than that in the actual clini-      in over 1,400
In addition, a small amount of reflected       cal trial that followed (0.14 lesions per      patients world-
blue is used to increase the brightness of    subject in Part I versus 0.59 per subject      wide showed that
the image (Diagn Ther Endosc                  in Part II). The ability to perform a care-    white light bron-
1999;5:71-75). As a result, time-delay        ful examination without traumatizing the       choscopy alone
and movement artifacts may occur unless       bronchial mucosa is extremely important        localized 40% of
the endoscopist has steady hands and          in performing fluorescence bronchoscopy,        the pre-invasive
inserts the bronchoscope smoothly.            because trauma would result in a dark          lesions with a
Bronchial secretions may have a bluish        image due to absorption of the blue light      range of 27% to
hue from the reflected blue light. The         by blood. Minor degrees of trauma such         51% in different
advantage of the system in terms of           as from strong suctioning can create           countries.”
instrumentation is its compact size and       changes that mimic abnormal fluores-
the high quality of the fiberoptic bron-       cence. Optimal results also require
choscope that is specially adapted for flu-    pathologists who are experienced in the
orescence examination. The SAFE-1000          diagnosis of pre-invasive lesions. These
system is consisted of a single image-        factors may explain some of the discrep-
intensified camera (Diagn Ther Endosc          ancy in the literature from studies involv-
1999;5:91-98). The design is similar to       ing very small number of patients (Lam
an earlier version of the LIFE-Lung           S, Palcic B J Natl Cancer Inst
System (Palcic B et al. Chest                 1999;91:561-562). (continued)
1991;99:742-743), except a non-laser
                                                                                                              5
                        The Forum for Early Diagnosis and Treatment of Lung Cancer




“The ability to            With the development of early detec-        1995;17:350-357), may be able to deter-
 perform a care-        tion methods using sputum cells that are       mine the pathology of the lesion in vivo
 ful examination        more sensitive than conventional sputum        by measuring the nuclear size and density.
 without trauma-        cytology, examination such as computer-        Raman spectroscopy can be used to
 tizing the bron-       assisted image analysis of exfoliated spu-     probe the biochemical composition of
 chial mucosa is        tum cells (Payne PW et al. Mayo Clinic         molecules in cells such as lipids, proteins,
 extremely impor-       Proc 1997;72:697-704), immunostaining          and nucleic acids (J Biomedical Optics
 tant in perform-       of transformed epithelial cells (Tockman       1996;1:31-70) to fingerprint lesions.
 ing fluorescence        MS et al. Clin Cancer Res 1997;3:2,237-        These techniques are still in the develop-
 bronchoscopy,          2,246) and PCR-based assays to detect          mental stage. Hopefully, they will be
 because trauma         oncogene mutations (Mao L et al.               available for clinical use in a few years.
 would result in a      Cancer Res 1994;54:1,634-1,637), the              The importance of finding stage 0 lung
 dark image due         size of pre-invasive lesions discovered by     cancer is that a number of curative endo-
 to absorption of       these screening tests will likely be           bronchial treatment modalities are now
 the blue light by      smaller. The role of fluorescence bron-         available in addition to surgery. The 5-
 blood.”                choscopy to localize these lesions will        year survival for stage 0 lung cancer after
                        become even more important.                    photodynamic therapy (Furuse K et al. J
                           Although there is great excitement in       Clin Oncol 1993;11:1,852-1,857) electro-
                        the prospect of using low-dose spiral CT       cautery (van Boxem TJ Eur Resp J
                        in the detection of early, curable lung        1998;11:169-172) or YAG laser therapy
                        cancer in the peripheral airways not           (J Bronchology 1994;1:105-111) or
                        accessible by the conventional fiberoptic       surgery is > 90% (Cortese DA et al. J
                        bronchoscope, the specificity of spiral         Thorac Cardiovasc Surg 1983;86:373-
                        CT is low (Sone S et al. Lancet 1998;          380). Stage IA lung cancer also has a very
                        351:1,242-1,245; Henschke CI et al.            favorable 5-year survival of > 80% after
                        Lancet 1999;354:99-105; Kaneko M et            surgical resection.
                        al. Radiology 1996;201:798-802; Eur               The development of optical imaging
                        Radiol 1997;S143). Depending on the            methods to localize the source of the
                        geographic region, non-malignant lung          abnormal cells found in examination of
“With the develop-      nodules can be found in 20% to 40% of          sputum specimens or to determine the
 ment of early          the high risk subjects that are screened       nature of small lung nodules on spiral CT
 detection methods      by spiral CT. Less than 3% were ulti-          is an integral part of the diagnostic arma-
 using sputum cells     mately confirmed to have lung cancer.           mentarium in the overall management of
 that are more sen-     Instead of performing serial CT scans or       early lung cancer.
 sitive than conven-    a chest x-ray every few months or per-
 tional sputum          forming invasive diagnostic procedures
 cytology, examina-     to delineate the etiology of these lung        Early Lung Cancer Action Project
 tion such as com-      nodules, optical diagnostic methods may
 puter-assisted         provide a better alternative to localize                he study design and findings of
 image analysis of
 exfoliated sputum
 cells... the size of
 pre-invasive
 lesions discovered
                        and to determine the nature of these
                        nodules. Optical probes can be made
                        much smaller than the conventional
                        fiberoptic bronchoscope. Optical meth-
                        ods offer the possibility of real time, high
                                                                       T        the Early Lung Cancer Action
                                                                                Project, (ELCAP), published
                                                                                recently in Lancet (Henschke CI
                                                                       et al. Lancet 1999;354:99-105) received
                                                                       tremendous notoriety in both the medical
 by these screening     resolution imaging of the morphological        and lay press. In brief, ELCAP enrolled
 tests will likely be   and/or biochemical changes associated          1,000 symptom-free volunteers who were
 smaller. ”             with these lesions. For example, Optical       60 years or older and who had smoked at
                        Coherence Tomography (Tearney GJ               least 10 pack-years, and who had no pre-
                        Science 1997;276:2,037-2039; Optics            vious evidence of cancer. Subjects were
                        Express 1998;3:219-229) can provide in-        excluded if they were “not medically fit
                        depth information. Elastic scattering          to undergo thoracic surgery.” Low-dose
                        (Mourant JR et al. Lasers Surg Med             computer tomography, (CT), scanning for
 6
 Lung
 Cancer
          Frontiers
non-calcified nodules revealed 233 (23%)         Comment: These and other studies of
compared with only 68 (7%) with stan-        the efficacy of high resolution rapid low
dard chest x-rays. Malignant disease was     intensity CT scanning are convincing that
detected in 27 (2.7%) by CT, but only 7      this is the best way to detect peripheral
(0.7%) by ordinary chest x-rays. Stage I     malignant nodules, most of which are
disease was found in 23 of 27 patients.      adenocarcinoma. This approach may not
Of these 27 patients, 26 were resectable     be suitable for small central lesions,
for apparent cure. No participate had a      which are best detected by sputum cytol-
thoracotomy for a benign nodule. The         ogy and bronchoscopy. A recent compari-
key to the success of this screening by CT   son of fluorescent endoscopy with white
scanning, according to the protocol was,     light endoscopy, indicates a superiority of
recommended follow-up by high resolu-        fluorescent endoscopy with small lesions
tion CT three months later. There had        of approximately 3.0 mm in size (Lam S
been no growth of the high resolution CT     et al. Chest 1998;113:696-702).
scans at six, 12, and 24 months. If no
growth was noted over two years, the                                                       Figure 1
nodule was classified as benign, for                                                        Postoperative 5-
lesions 5.0 mm or less.                      The Impact of Lung Cancer                     year survival rate.
   For lesions 6.0 mm to 10.0 mm, the        Screening in Japan                            The 5-year sur-
protocol recommended assessment on an                                                      vival improved
                                                      he influence of lung cancer mass


                                             T
individual basis with the possibility of                                                   significantly, from
percutaneous transthoracic CT-guided                  screening on surgical results was    33.7% in the first
fine needle biopsy or video-assisted tho-              reported by Kioke et al., from       period to 51.8%
rascopic procedures. In patients where a              Japan (Kioke T et al. Lung           in the second and
biopsy was not possible, follow-up at        Cancer 1999;24:75-80). This study evalu-      then, 58.4% in the
intervals described above, was recom-        ated the effectiveness of lung cancer         third. Differences
mended. For lesions 11.0 mm or more in       screening on survival. A total of 177 pri-    between groups:
size, the protocol recommended a biopsy      mary lung cancer patients who under-          first versus second
according to current standards of care by    went surgery from 1963 to 1992 were           period, P < 0.01;
fine needle aspiration video-assisted tho-    retrospectively reviewed. They were           second versus
racostomy, bronchoscopy, or a combina-       grouped according to the changes in the       third period,
tion. Lesions that increased in size were    mass screening system from the first           P < 0.05.
the ones that were resected. Amazingly,
all were early stage adenocarcinomas. In
this study, malignant disease was detected
four times more frequently on low-dose       Figure 1 Percent of Survival
CT scanning than by standard chest
roentgenology. Of the 27 malignant nod-       100                                              * P < 0.05
ules, 22 were stage IA, one stage IB, one                                                     ** P < 0.01
stage IIA, two stage IIIA, and one stage
IIIB. Thus, all but one were potentially
resectable for cure.
                                                                                             3rd 58.4%
   In discussion, the authors emphasize        50                                                           *
                                                                                             2nd 51.8%
that the cost of low-dose CT scanning is
                                                                                             1st 33.7%      **
only slightly higher than standard chest                1st (‘63-’77) N= 98
roentgenology. Once low-dose CT screen-                 2nd (‘78-’86) N= 440
ing becomes commonplace, and the vol-                   3rd (‘87-’92) N= 639
ume of tests increase, the unit cost may        0
decrease further.                                   0         1       2        3   4       5 Year




                                                                                                                7
The Forum for Early Diagnosis and Treatment of Lung Cancer




period when screening was mostly done         Screening for Lung Cancer with
for tuberculosis (1963 to 1977). This was     Low-dose Spiral CT Scan of the
before lung cancer screening was initiated
in the second period (1978 to 1986), in       Chest and Sputum Cytology
this study supported by the local govern-
ment. Finally, in the third period screen-    James R. Jett, M.D., FCCP,
ing after 1987, after the launching of the    David E. Midthun, M.D., FCCP
national screening program was studied,       Steven J. Swensen, M.D.
the rate of cases detected by mass screen-    Mayo Clinic, Rochester, MN
ing over time and the 5-year survival rate
                                                   n 1999, there will be approximately


                                              I
improved markedly. Survival was 33.7%
in the first period, 51.8% in the second            170,000 new cases of lung cancer in
period, and 58.4% in the third period.             the United States. The overall 5-year
This improvement in the survival is due            survival is 14% (Landis SH et al. CA
to the increase in stage I cases. The         Cancer J Clin 1999;49:8-31). Lung can-
increase in the number of patients with       cer alone accounts for more cancer             “What is striking
stage IA peripheral-type lesions and          deaths than the next three most common          from Table 1 is
roentgenographically occult lung cancer       cancer causes of death combined (Table          the disparity of
by standard roentgenology, is remarkable.     1). Currently, 45% of all lung cancers          the 5-years sur-
The survival of the three periods is pre-     occur in women, and more women die of           vival for lung
sented in Figure 1 on page 7.                 lung cancer than breast cancer in               cancer compared
  Comment: There seems to be no doubt         America.                                        to the other most
that mass screening to identify early stage      What is striking from Table 1 is the         common cancer
disease results in improved survival. With    disparity of the 5-years survival for lung      causes of death.”
these data in hand, a randomized              cancer compared to the other most com-
prospective clinical trial to compare the     mon cancer causes of death. Of these
outcome of smokers at high risk of lung       four most common cancer killers, lung
cancer who were screened compared to          cancer is the only one for which screening
smokers at equal risk who were not            is not recommended. We know that
screened, would probably not be neces-        symptomatic lung cancer is usually an
sary. In fact, it would probably be unethi-   advanced cancer, stage IIIA/B or IV and
cal. Mass screening for lung cancer is        associated with a 5-year survival of 10%
now the standard of care in Japan where       or less. According to recent data from the
a mobile spiral computed scanner is used      SEER (National Cancer Institute’s              “Research in the
in rural areas (Sone S et al. Lancet 1998;    Surveillance Epidemiology and End               last 20 years has
351:1,242-1,245).                             Result Program), only 15% of lung can-          revealed a great
  Both airway cell markers of malignancy      cers are localized at the time of diagnosis.    deal about the
and imaging for peripheral lesions are           Why then is screening for lung cancer        biology of lung
necessary in the detection of early stages    not recommended? Past screening trials          cancer, and along
of lung cancer.                               with chest radiographs and sputum cytol-        with technologic
                                              ogy conducted at Mayo Clinic, Johns             advances, has led
                                              Hopkins and Memorial Sloan Kettering            to the develop-
                                              Cancer Center were unable to demon-             ment of a num-
                                              strate a decrease in lung cancer mortality      ber of promising
                                              in the screened population. These NCI-          new tools that
                                              sponsored studies were conducted in the         may lead to effec-
                                              1970's and are now 20 years old                 tive screening.”
                                              (Fontana RS et al. J Occup Med
                                              1986;28:746-750; Melamed MR et al.
                                              Chest 1984;86:44-53; Tockman MS
                                              Chest 1986;89:324S-325S).

8
    Lung
    Cancer
             Frontiers
   Research in the last 20 years has            At the 1999 American Society of
revealed a great deal about the biology of    Clinical Oncology meeting, the first of
lung cancer, and along with technologic       these groups updated their results
advances, has led to the development of a     (Ohmatsu H Proc Am Soc Clin Oncol            “The potential to
number of promising new tools that may        1999;18:463A). With a total of 9,452          detect 80% of
lead to effective screening. The most         low-dose spiral CT chest examinations,        lung cancers in
promising of the new tools is the spiral      they have detected 35 primary lung can-       stage I (while
CT chest scanner. Several recent reports      cers (0.37% detection rate). Of these, 27     few are
have documented the ability of low-dose       were stage IA, and the mean tumor diam-       detectable by
spiral CT scans to detect lung cancer at      eter was 15 mm. Their 3-year survival         standard chest
an early stage. Trials have been con-         was 83%. At the 1999 American                 radiograph)
ducted in Japan, Germany and the United       Thoracic Society meeting, Henschke and        could very well
States.                                       associates reported the results of their      lead to a reduc-
   Two different groups of Japanese inves-    1,000 subject spiral CT screening trial       tion in lung can-
tigators screened male smokers > 50           from New York (Henschke CI et al. Am J        cer mortality”
years (Kaneko M et al. Radiology              Respir Crit Care Med 1999;159:A60).
1996;201:798-802; Sone S et al. Lancet        They detected non-calcified nodules in
1998;351:1,242-1,245). The first group         24% (n= 240), and 22 of these individu-
reported 15 lung cancers detected by spi-     als were subsequently proven to have
ral CT, and only 4 of those were visible      lung cancer. Only 5 of the 22 cancers
by chest radiograph. Most promising was       were visible on standard chest radi-
the fact that 14 of 15 cancers were stage I   ograph. To date, none of their partici-
and had an average tumor diameter of          pants have had a thoracotomy for benign
1.6 cm (Kaneko M et al. Radiology             disease, but five individuals underwent
1996;201:798-802). The second group           percutaneous or video-assisted thoraco-
found similar results, reporting 80% of       scopic biopsy for benign disease.
detected lung cancer in stage I (Sone S et      In clinical practice today, only 20% to
al. Lancet 1998;351:1,242-1,245).             25% of all new lung cancers are diag-



Table 1 Three Most Common Cancer Causes of Death1

Primary Site                    No. of New Cases          No. of New Deaths        5-Year Survival
of Cancer                       (Estimated 1999)          (Estimated 1999)         (1989–1994)

Lung                            171,600                   158,900                   14%
Colorectal                      129,400                    56,600                   63%
Breast                          176,300                    43,700                   85%
Prostate                        179,300                    37,000                   93 %
1   Data from American Cancer Society (Landis SH et al. CA Cancer J Clin 1999;49:12-13).




                                                                                                            9
                      The Forum for Early Diagnosis and Treatment of Lung Cancer




                      nosed in stage I/II. The NCI screening tri-   1999;91:332-339; Wistuba II et al. J Natl
                      als used chest radiographs and sputum         Cancer Inst 1997;89:1,366-1,373). While
                      cytology as screening tools and detected      there are no sputum tests other than
                      40% to 50% of lung cancers as stage I.        cytology that are clinically proven and
                      The potential to detect 80% of lung can-      commercially available for detection of
                      cers in stage I (while few are detectable     early lung cancer, the monoclonal anti-
“In addition to       by standard chest radiograph) could very      body test against heterogeneous nuclear
 standard sputum      well lead to a reduction in lung cancer       ribonucleoprotein on sputum cells shows
 cytology, investi-   mortality (Mountain CF Chest                  great promise. In a preliminary report of
 gators are evalu-    1997;111:1,710-1,717). Screening with         patients with previously resected stage I
 ating sputum,        spiral CT scan is by far the most exciting    lung cancer, this sputum test demon-
 bronchoalveolar      and promising new tool in several             strated a sensitivity of 77% and speci-
 lavage fluid, and     decades for early lung cancer detection.      ficity of 82% for detection of a second
 bronchial biopsy        In the NCI screening trials, sputum        primary lung cancer (Tockman MS et al.
 specimens for        cytology detected 25% of all lung cancers     Clin Cancer Res 1997;3:2,237-2,246).
 DNA biomarkers       and was the only means of detection in        The positive predictive value was 67%
 indicative of pre-   15% of cases. Recently, physicians from       (10 of 15). This trial and others are
 malignant            the University of Colorado obtained           ongoing, but it is likely to be at least a
 changes in an        screening sputum cytology results in          few years before this test is commercially
 effort to identify   smokers with mild or greater degrees of       available.
 individuals at       obstructive lung disease and identified           In January, 1999, Mayo Clinic physi-
 very high risk for   carcinoma cells or severe dysplasia in        cians launched a lung cancer screening
 developing lung      2.5% of screened subjects (Kennedy TC         trial that is being supported by a grant
 cancer.”             et al. Cancer Res 1996;56:4,673-4,678).       from the NCI. Eligibility criteria for the
                      Another 25% had moderate dysplasia of         study are as follows: 50 years of age or
                      the sputum, which is believed to be a pre-    greater; current or former smoker (quit <
                      cursor of lung cancer. Patients with mod-     10 years ago) of 20 pack-years or more;
                      erate dysplasia were further evaluated        not on supplemental oxygen; life
                      with standard white light bronchoscopy        expectancy of 5-years; and no prior can-
                      and the new autofluorescent broncho-           cer within the last 5 years (except skin,
                      scope (LIFE-Lung System; Xillix               localized prostate cancer, or cervical car-
                      Technologies Corporation; Richmond,           cinoma in situ). The enrollment target of
                      British Columbia, Canada) capable of          1,500 individuals has been reached. All
                      detecting dysplasia and carcinoma in situ     patients will have a low-dose fast spiral
                      that may not be visible with standard         CT scan of the chest performed at the
                      bronchoscopy. The autofluorescent bron-        time of enrollment and yearly for 3 years
                      choscope is another new tool that may         and a sputum cytology performed on a
                      have a role in screening trials when the      yearly basis. All study tests will be per-
                      sputum cytology shows moderate or             formed free of charge to the patient. The
                      severe dysplasia (Lam S et al. Chest          dose of radiation associated with the low-
                      1998;113:696-702).                            dose spiral CT scan is equivalent to or
                         In addition to standard sputum cytol-      less than that associated with mammog-
                      ogy, investigators are evaluating sputum,     raphy. The goal of the study during the
                      bronchoalveolar lavage fluid, and              incidence screen (after the baseline scan)
                      bronchial biopsy specimens for DNA bio-       is to determine if we can detect 75% or
                      markers indicative of premalignant            more lung cancers while they are stage I
                      changes in an effort to identify individu-    and likely to be associated with excellent
                      als at very high risk for developing lung     long-term survival.
                      cancer (Belinsky SA et al. Proc Natl Acad     (Henschke CI et al. Am J Respir Crit
                      Sci 1998;95:11,891-11,896; Sozzi G et al.     Care Med 1999;159:A60).
                      Cancer Res 1998;58:5,032-5,037;                  Reprinted with permission: Pulmonary
                      Ahrendt SA et al. J Natl Cancer Inst          Perspectives 1999;16:1-3.
10
 Lung
 Cancer
          Frontiers
A Breath Test for Lung Cancer?               only for the surgeon and the otolaryngol-
                                             ogist, but most notably, the pulmonol-
           number of volatile organic        ogist. Lam’s, (Deputy Editor of


A          compounds, (VOCs), which are
           mainly alkanes and benzene
           derivatives have been identified
in the exhaled air from patients with lung
cancer. In a study of 108 patients who
                                             Frontiers), development of the light inten-
                                             sified fluorescent endoscope, (LIFE), is
                                             discussed in further detail in the contribu-
                                             tion he makes to this issue of LCF.

had abnormal chest radiographs and who
were scheduled for bronchoscopy, sam-        Historical Vignette
ples were collected with a portable appa-
ratus and assayed by gas chromatography           n his paper “On Direct
or mass spectroscopy. Lung cancer was
confirmed in 60 patients. A combination
of 22 breath VOCs, predominantly alka-
nes, alkane derivatives, and benzene
derivatives, discriminated between
                                             I    Bronchoscopy” at the sixth meeting
                                                  of the South German Society of
                                                  Laryngologists on May 29, 1898,
                                             Gustav Killian described the extraction of
                                             tracheobronchial foreign bodies from
patients with and without lung cancer,       three patients using a modified esophago- “Ikeda’s dream of
regardless of stage (all p < 0.0003), for    scope in topical cocaine anesthesia.        improved diagno-
stage 1 lung cancer. The 22 VOCs had         Others had previously inspected the tra-    sis of early lung
100% sensitivity and 81% specificity.         chea through a rigid tube, but, as Kirstein cancer with the
This study suggests that prospective stud-   had noted in 1894, manipulation may         flexible instrument
ies are needed to confirm the usefulness      have perforated the trachea where aortic    could not be ful-
of breath VOCs in detecting lung cancer      pulsation could be seen, causing fulminat- filled, however,
in the general population.                   ing hemorrhage. However, Killian knew       until this instru-
   Comment: This test might be most use-     of work done by another investigator,       ment could be
ful in high risk populations who have        Pieniazek, who had done direct lower tra- combined with
smoked 30 or more pack-years in the          cheoscopy through a tracheostoma with-      more sensitive
presence of airflow obstruction. It would     out complications. He spent the period      imaging tech-
be interesting to compare the yield of       between 1887 and 1894 intensively           niques.”
breath testing with sputum cytology.         studying direct visualization of the tra-
   Adapted from: Phillips M, et al.          cheobronchial tree.
Volatile organic compounds in breath as        First, he introduced bronchoscopes
markers of lung cancer: A cross-sectional    through tracheostomas, noticing that
study. Lancet 1999;353:1,930-1,933.          both trachea and bronchi were pliable
                                             and elastic; only the diameter of the
                                             bronchus limited deeper advancement of
The Bronchoscope in Historical               the instrument. Concurrently, he intu-
Perspective                                  bated many cadavers orotracheally. Once
                                             he felt confident enough, he performed
         ohn A. Nakhosteen, member of        bronchoscopies on a janitor working at


J        the Editorial Board of LCF, and
         a renowned bronchologist who
         teaches, does research, and prac-
tices in Bochum, Germany, offers the fol-
lowing historical vignette on the begin-
                                             Freiburg University, who readily volun-
                                             teered for repeat bronchoscopies in return
                                             for some pocket money (and, perhaps
                                             with time, the cocaine anesthesia). Then,
                                             on March 31, 1897, came the dramatic
nings of bronchoscopy and the landmark       case, the first of the three presented the
development of Ikeda’s fiberoptic bron-       year after, of the Black Forest farmer who
choscope, which has transformed modern       had aspirated a bone fragment - and rigid
bronchology. The fiberoptic broncho-          bronchoscopy was born! (continued)
scope has provided a major new tool, not
                                                                                                       11
The Forum for Early Diagnosis and Treatment of Lung Cancer




   Killian’s emulators included Chevallier   could not be fulfilled, however, until this
Jackson Sr., Chevallier Jackson, Jr.,        instrument could be combined with more
Lundy, Foregger, and Gillespie, who all      sensitive imaging techniques. Perhaps,
contributed to the development of the        with innovations such as Lam’s autofluo-
rigid bronchoscope. But the fundamental      rescent bronchoscope, we are now at the
device conceived by Killian remained         threshold of reaching this elusive goal of
unchanged until Ikeda developed the          early lung cancer detection approxi-
fiberoptic bronchoscope in 1964. Ikeda’s      mately one-hundred years after Killian’s
dream of improved diagnosis of early         discovery of open tube bronchoscopy!
lung cancer with the flexible instrument




Lung Cancer

Frontiers
January 2000

Lung Cancer Frontiers
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