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									Non-small Cell Lung Cancer

          Eva Szabo, MD
Division of Cancer Prevention, NCI
US Lung Cancer Statistics, 2003

• 171,900 estimated new cases
• 157,200 estimated deaths
  – 88,400 men and 68,800 women
• leading cause of cancer deaths
  – greater than breast+prostate+colon
• 15% five year survival
  – 5% in 1950’s, 13% in 1970’s
 Age-adjusted lung cancer death rates, USA
Rate per 80
100,000                Lung and bronchus (male)
                       Lung and bronchus (female)



               1930   1940    1950      1960        1970   1980   1990
Five-year survival by TNM status in
  Stage    TNM classification     5-year survival
  IA            T1N0M0                  61
  IB            T2N0M0                  38
  IIA           T1N1M0                  34
  IIB      T2N1M0 or T3N0M0             24
  IIIA    T1-3N2M0 orT3N1M0             13
  IIIB    T4NanyM0 or Tany N3M0          5
  IV           Tany NanyM1               1

                                          Mountain 1997
               Risk Factors
• Tobacco, tobacco, tobacco (85% lung ca.)
• Other exposures
  – Asbestos, radon, polycyclic aromatic
    hydrocarbons, chromium, nickel, inorganic
  – Passive smoking

• Non-small cell lung cancer
  –   Adenocarcinoma, inc bronchoalveolar 40%
  –   Squamous cell carcinoma 20%
  –   Large cell carcinoma 15%
  –   Others (carcinoid, etc.)
• Small cell lung cancer 20%
Sequential changes during lung cancer pathogenesis
               Early              Intermediate              Late

   Normal                                                             Invasive
                  Hyperplasia      Dysplasia          CIS
  epithelium                                                         carcinoma

3p LOH/small telomeric deletions         3p LOH/contiguous deletions
Microsatellite alterations
        9p21 LOH
        Telomerase dysregulation               Telomerase upregulation
        myc overexpression
                                8p21-23 LOH
                                   Loss of Fhit immunostaining
                                   p53 LOH              p53 mutations
                                                   5q21 APC-MCC LOH
                                                   K-ras mutation
                                                                   Hirsch et al 2001
      Treatment Strategies for
           Lung Cancer
• NSCLC: Treatment based on stage:
  – Early stage (Stage I/II) – surgery
  – Regional spread –combined modality
  – Metastatic – chemotherapy, radiation as needed
    for local control
• Small cell lung cancer: chemotherapy
  (+radiation for limited stage)
Controversies in NSCLC Treatment
• Adjuvant therapy
   – IALT study – small, but real (4.1%) improvement in
     survival with 3-4 cycles cisplatin (ASCO 2003)
   – UFT x 2 yrs in stage I adenoca – 2.5% improvement in
     survival (ASCO 2003)
• Neoadjuvant therapy
   – BLOT-phase II study, stage Ib-IIIA, induction taxol/carbo
     followed by surgery post-op chemo, 3 yr survival 63%
     superior to historical control (J Thor Cardio Surg 119:429,
• Adjuvant radiation
   – PORT meta-analysis – not for early stage, probably not for
     regional disease (Lancet 352:257, 1998)
 Controversies in NSCLC Treatment
• Choice of agents?
  – Platinum vs. not (probably yes)
  – Single vs. two vs. three agents (probably 2)
• Treatment of elderly – Yes if good performance
• Length of treatment – probably no more than 6
  cycles of cytotoxic conventional chemo
• Second line treatment – yes
  – Taxotere better than supportive care
  – Iressa (EGFR inhibitor) approved after
    cisplatin/taxotere failure
  Approaches to reducing cancer
    morbidity and mortality

• Prevention (primary, secondary, tertiary)
• Early detection

• Better therapeutics-novel targeted agents
          Primary Prevention

• Smoking cessation
  – Decline in California lung cancer rates 1988-
    1997 declined 14%, compared with 2.7% in
    non-California SEER sites, coincident with
    declining smoking rates probably due to
    California tobacco control initiatives

     • Cowling DW et al., MMWR 49:1066-9, 2000
Lung Cancer Risk After Smoking

                      -modified from
                      Peto et al.,
                      BMJ 321:323, 2000
   Cancer Chemoprevention

The use of natural or synthetic agents to
suppress or reverse carcinogenesis
– Regress existing neoplastic lesions (treat
  intraepithelial neoplasia)
– Prevent development of new neoplastic
  lesions (preneoplastic and cancer)
– Suppress recurrence of neoplastic lesions
    Cancer Prevention vs. Treatment
        Chemoprevention           Chemotherapy
Target • Cured cancer patient   • Cancer patient
       • Pre-cancer patient
       • Genetically

End- • Cancer development       • Eradicate cancer
point • Phenotype reversal      • Control/palliate

Agent • Minimal toxicity        • Moderate toxicity
      • Potentially long term   • Usually short term
            Field Cancerization
Multifocal Clonal Expansions    Second primary tumors

                                 First       Second
                    Carcinoma   Primary

  Evolution of Intraepithelial Neoplasia

Normal   Hyperplasia/Metaplasia   Dysplasia       Cancer



   Natural History of Bronchial Atypia
• Progression to cancer based on sputum analysis
  – Moderate dysplasia: 11%
  – Severe dysplasia: 19-46%

• Progression to cancer based on bronchoscopic dx, 2-3
  yr f/u (Bota et al., 2001; Venmans et al., 2000)
  – Normal/inflammatory: 16% became dysplastic
  – Hyperplasia/metaplasia: 37% regress, 2% cancer at 2 yrs
  – Low or moderate dysplasia: 37% regress, 3.5% severe
  – Severe dysplasia: 41% regress to normal, 37% remain or
  – Carcinoma in situ: 56% progress at site (44% also had
    severe dysplasia or CIS elsewhere)
Natural History of Atypical Alveolar

• Unknown at the current time

• Localized ground glass opacities on CT:
  – Fibrosis 15%; AAH 25%; bronchoalveolar ca
    50%; invasive adenoca 10% (Nakajima et al., J
    Comput Assist Tomogr 2002)
             Oral Leukoplakia
           (Hong et al., NEJM 1986)

• 44 pts., 3 mths high dose 13cRA vs. placebo
  – Response: decreased size in 67% vs. 10% placebo
  – Response: reversed dysplasia 54% vs. 10%
  – Relapse in >50% pts; toxicity high
• F/U study (Lippman et al., NEJM 1993)
  – 3 months high dose 13cRA followed by low dose
    maintenance is better than -carotene
    Prevention of Second Primary Cancers
                     Head & Neck
• Hong et al., 1990 NEJM: 103 pts., 12 months of
  isotretinoin (13cRA) high dose after curative therapy
  for H & N ca.
• Results:
   –  second primary tumors (4% vs. 24%, 32 mths)
   – no survival advantage; toxicity

• Khuri et al., Proc ASCO 2003: 1190 stage I/II H & N
  ca pts., low dose 13cRA for 3 yrs
   – No effect on second primaries or overall survival
Phase III Lung Chemoprevention Trials

ATBC         29,133       -carotene    18% risk
1994         smokers      +/- vit E     lung ca.
CARET        18,314       -carotene + Inc risk lung
1996         Smokers or   retinol      ca RR=1.36
EUROSCAN     2592 lung,   Retinyl palm No benefit
2000         H&N ca       +/- NAC
Intergroup   1265 lung    13-cRA        No benefit
2001         ca
Phase II Lung Chemoprevention Trials

Investigator Agents           Endpoint        Outcome
Arnold      Etretinate        Sputum Atypia   Negative
Lee         13cRA             Metaplasia      Negative
Kurie       4-HPR             Metaplasia      Negative
McLarty     -carot/Retinol   Sputum Atypia   Negative
Pastorino   Retinol Palmit    Lung Cancer     Positive
Kurie       9cRA vs. 13cRA+ RAR-beta          RAR- 
            Vit E                             with 9cRA
Lam         Anethole dithiole Bronchial        New
              thione            dysplasia       lesions
Critical Components of Clinical Trials

     Cohorts:               Endpoints:
     High risk              Cancer-related
     Likely to respond      Drug effect markers


          Dose, schedule, route, duration
          Efficacy vs. side effects

• Heavy smokers (current vs. former)
  – Lifetime risk lung cancer: 1% for 20 pack-yrs;
    5% for 60-pack yrs.; 13% for 100 pack-yrs.
• Curatively treated early stage tobacco-
  related cancer patients
  – Stage I NSCLC (5 yr surv: >70% for T1; 60%
  – Stage I/II H & N ca (80% 5 yr survival)
  – High rate of second primaries (1-3%/yr)
         Emerging Concepts
 Target Population: Former Smokers
• 50% of lung cancers are in former smokers
• Biologic differences between current and
  former smokers
  – extent of DNA damage, histologic abnormalities
• Adverse outcome in current, but not former,
  smokers in prior phase III studies
  – -carotene in ATBC/CARET
  – 13-cis retinoic acid in Intergroup Study
• Positive outcome more likely in former smokers
  without ongoing DNA damage
              Potential Endpoints

   • Histologic preneoplastic lesions
   • Proliferative indices
   • Apoptotic indices
   • Differentiation markers
   • Other carcinogenesis-related
     markers/processes (e.g., oxidative stress,
     oncogenes, methylated genes)
   • Drug effect biomarkers
Question: How can these help us determine whether to
          continue with drug development?

• Dose, route, schedule
• Approved vs. experimental
• Risk/benefit ratio
  – Importance of cohort risk
        New Agent Identification

• Mechanism
• Preclinical supportive data
  – Cell line studies
  – Animal carcinogenesis models
• Epidemiologic data (case-control, cohort)
• Secondary endpoints from clinical trials
     Mechanisms of Action of
     Chemopreventive Agents


Normal   Preneoplastic          Differentiation
 cell         cell

           Arachidonic Acid Metabolism
 A Novel Target for Aerodigestive Chemoprevention
                 Membrane Phospholipids
      Steroids           PLA2
                      Arachidonic Acid
     5-LO Inh       LO               COX      NSAIDs

                 HPETEs             PGG2
Zileuton    LO
            HETEs     LTs          PGH2

Effect of Budesonide on Mouse
     Lung Tumorigenesis

                     -82% inhibition

                    -Pereira et al.
                    Carcinogenesis 2002
Shift from Carcinoma to Adenoma
          by Budesonide

                           Pereira et al.,
Potential Mechanism of Action of
 Budesonide: Induction of CDK

                             Pereira et al.,
            DCP Phase IIb Trial of
                      S. Lam, BCCA
 115 smokers with dysplasia

              (Spiral CT)           # Screened (sputum): 1043
                                    # Dropped out (Rx): 15
Budesonide vs. Placebo x 6mths      Cancers detected: 13
               Spiral CT)
 1o Endpoint: bronchial dysplasia (#sites/grade)
 2o Endpoints: multiple biomarkers
    Effect of Budesonide on Bronchial


%   30                       Placebo
         CR   PR   SD   PD
     Effect of Budesonide on Spiral CT-
        Detected Peripheral Nodules

 Outcome        Placebo       Budesonide
               # Nodules       # Nodules
                (% total)       (% total)
 Unchanged     102 (87%)       43 (72%)

 Resolved       14 (12%)       16 (27%)*
 or smaller
 Follow-up       1 (1%)          1 (1%)

* P=0.024
          Arachidonic Acid Pathway:
            Lipoxygenase Branch
                                   Catalyzed by 5-Lipoxygenase:
              Arachidonic Acid
                                         O2             arachidonate

5,12,15 LOs
               12-HPETE 15-HPETE                               COOH

    5-HPETE                             H2O

    LTs       5-HETE                                   leukotriene-A4
       Decrease in Tumor # and Size by
           Leukotriene Inhibitors
      -Gunning et al., Cancer Res 62:4199, 2002

Inhibition of
Tumor #
Accolate (LTD4
inhibitor): 29.5%
Zileuton (5-LO
inhibitor): 28.1%
inhibitor): 37.8%
  Decrease in Carcinoma # by Leukotriene
       -Gunning et al., Cancer Res 62:4199, 2002

                                          Carcinomas by
                                               50 %

Inhibits:          5-LO   FLAP     LTD4
   DCP Phase IIb Trial of Zileuton
                O. Kucuk, Wayne State

134 smokers with dysplasia

Zileuton vs. Placebo x 6
mths (Bronch)                        1o Endpoint:
                                  bronchial dysplasia
                                (#sites/grade at 6 mths)
                                     2o Endpoints:
Cross-over x 6 mths (Bronch)     multiple biomarkers
    Agents currently under development

•   Inhaled budesonide
•   Zileuton (5-lipoxygenase inhibitor)
•   Celecoxib, rofecoxib (COX-2 inhibitor)
•   Pioglitazone (PPAR agonist)
•   Green tea polyphenols
•   ACAPHA (herbal extract)
•   Myo-inositol (dietary supplement)
•   Selenium
•   Sulindac sulfone (Exisulind)
         Emerging Concepts:
Regional Drug Delivery, Combinations

                             -Increase efficacy
                             -Reduce toxicity
                              (lower doses)

 Aerosolized delivery to
minimize systemic toxicity
 “For it happens…that in the beginning of
the malady it is easy to cure but difficult to
detect, but in the course of time, not having
   been either detected or treated in the
  beginning, it becomes easy to detect but
              difficult to cure.”
         -N. Machiavelli, The Prince
  Issues in Lung Cancer Screening
• Lead-time bias=earlier diagnosis but no
  postponement of death (survival appears longer)
• Length bias=diagnosis of more indolent disease
  with longer preclinical phase (better prognosis,
  better outcome)
• Overdiagnosis=identification of clinically
  unimportant lesions that would not be diagnosed

• Morbidity/mortality/cost of screening and
  subsequent work-up
Lung Cancer Screening Trials
    X-ray, Sputum Cytology
   Spiral CT for Early Lung Cancer
• ELCAP (Henschke et al., Lancet, 1999)
  – low dose spiral CT in 1000 asymptomatic smokers
  – results:
    • 2.7% lung cancers diagnosed by CT vs. 0.7% by CXR
    • 85% cancers were stage I vs. 22% expected
    • 96% were resectable
         Spiral CT Screening Trials
 Study              #Subjects %Positive     # Cancers   Stage I

ELCAP                1,000    23%         27 (prev)     85%
(Henschke et al.,
Mayo                 1,520    66%         23 (prev      57%
(Swensen et al.,                          & inc)
Japan                1,611    11.5%       14 (prev)     71%
(Sobue et al.,                            22 (inc)      82%
Ongoing NCI-Sponsored Lung Cancer
         Screening Studies
 – 74,000 men/women
 – Age 55-74
 – CXR vs. none (prevalence, then x3)
 – 50,000 smokers (current and former)
 – Age 55-74
 – Spiral CT vs. chest –Xray (prevalence, then x2)
“An ounce of prevention
is worth a pound of cure”
        -Benjamin Franklin

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