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non small cell lung cancer

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									Non-small Cell Lung Cancer

          Eva Szabo, MD
Division of Cancer Prevention, NCI



                   TRACO 11-26-07
 US Lung Cancer Statistics, 2007
• 213,380 estimated new cases
• 160,390 estimated deaths
• leading cause of cancer deaths
  – greater than breast+prostate+colon
• 15% five year survival
  – 5% in 1950’s, 13% in 1970’s
  – 32% of all male cancer deaths, 25% of all
    female cancer deaths
  – Lifetime risk: 1:12 men, 1:16 women
   Tobacco Use in the US, 1900-2003
                                       5000                                                                                                                                                      100

                                       4500                                                                                                                                                      90
    Per Capita Cigarette Consumption




                                                                                                                                                                                                       Age-Adjusted Lung Cancer Death
                                       4000                                                                                                                                                      80

                                       3500                                                                                                                                                      70
                                                                          Per capita cigarette
                                       3000                                     consumption                                                                                                      60




                                                                                                                                                                                                                    Rates*
                                       2500                                                                                              Male lung cancer                                        50
                                                                                                                                         death rate
                                       2000                                                                                                                                                      40

                                       1500                                                                                                                                                      30

                                       1000                                                                                                                                                      20
                                                                                                                                                       Female lung cancer
                                       500                                                                                                             death rate                                10

                                         0                                                                                                                                                       0
                                              1900
                                                     1905
                                                            1910
                                                                   1915
                                                                          1920
                                                                                 1925
                                                                                        1930
                                                                                               1935
                                                                                                      1940
                                                                                                             1945
                                                                                                                    1950
                                                                                                                           1955
                                                                                                                                  1960
                                                                                                                                         1965
                                                                                                                                                1970
                                                                                                                                                       1975
                                                                                                                                                              1980
                                                                                                                                                                     1985
                                                                                                                                                                            1990
                                                                                                                                                                                   1995
                                                                                                                                                                                          2000
                                                                                                                    Year
*Age-adjusted to 2000 US standard population.
Source: Death rates: US Mortality Public Use Tapes, 1960-2003, US Mortality Volumes, 1930-1959, National
Center for Health Statistics, Centers for Disease Control and Prevention, 2005. Cigarette consumption: US
Department of Agriculture, 1900-2003.
Radiographic Evidence Linking
 Tobacco Use to Lung Cancer




 -McMullen, DM & Cohen GA, NEJM 354:397, 2006
                      Risk Factors
• Tobacco, tobacco, tobacco (85% lung ca.)
   – Including passive smoking
   – Prior aerodigestive malignancy
   – COPD
• Other exposures
   – Asbestos, radon, polycyclic aromatic hydrocarbons, chromium,
     nickel, inorganic arsenic – mining, ship building, oil refining
• Genetic predisposition
   – Familial lung cancer – 6q23-25 (Am J Hum Gen, 9/04)
Five-year survival by TNM status in
              NSCLC
  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 TanyN3M0          5
  IV           TanyNanyM1               1


                                         Mountain 1997
  Pathology: Non-small Cell Lung Cancer

• Adenocarcinoma, inc bronchoalveolar
  – 40%

• Squamous cell carcinoma
   – 20%

• Large cell carcinoma
   – 15%

• Others (carcinoid, etc.)
Pathology: Small Cell Lung Cancer

• 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
                                                                             ~80%
Microsatellite alterations
                                                                             ~50%
        9p21 LOH
                                                                             ~70%
        Telomerase dysregulation               Telomerase upregulation
                                                                             ~80%
        myc overexpression
                                                                             ~60%
                                8p21-23 LOH
                                                                             ~80%
                                   Neoangiogenesis
                                                                             ~40%
                                   Loss of Fhit immunostaining
                                                                             ~40%
                                   p53 LOH              p53 mutations
                                                                             ~70%
                                   Aneuploidy
                                                                             ~80%
                                   Methylation
                                                                            ~100%
                                                   5q21 APC-MCC LOH
                                                                             ~30%
                                                   K-ras mutation
                                                                             ~20%
                                                                   Hirsch et al 2001
Treatment Strategies for Lung Cancer
• Treatment based on stage:
  – Early stage (Stage I) – surgery
  – Early stage (Stage II, IIIA)-surgery + adjuvant chemo
  – Regional spread – combined modality
    (chemoradiation, +/- surgery)
  – Metastatic – chemotherapy, radiation as needed for
    local control, occasional resection of isolated mets
• Small cell lung cancer: chemotherapy (+thoracic
  radiation for limited stage; prophylactic cranial
  radiation to prevent brain mets)
 Controversies in NSCLC Treatment
• Choice of agents?
  – Platinum vs. not (probably yes)
  – Single vs. two vs. three agents (2 conventional
    chemos)
• Treatment of elderly – Yes if good performance
• Length of treatment – probably no more than 4-
  6 cycles of cytotoxic conventional chemo
• Second line treatment – yes
  – Taxotere and pemetrexed better than supportive care
  – Erlotinib (EGFR inhibitor) for 2nd or 3rd line
     What is the state of the art for
      NSCLC treatment in 2007?
• Adjuvant chemotherapy after resection
  – 4-15% absolute increase in 5-year survival,
    standard of care for stage IIA-IIIA resected
    NSCLC
  – Cisplatin and vinorelbine appear best
     • NEJM 2004;350:351
     • NEJM 2005;352:2589
     • Lancet Oncol 2006;7:719
      What is the state of the art for
       NSCLC treatment in 2007?
• Bevacizumab (anti-VEGF antibody) in
  advanced NSCLC – frontline treatment in
  combination with chemotherapy (taxol/carbo) –
  E4599 (Sandler et al. NEJM 2006;355:2542)
  –   Median survival 12.3 vs. 10.3 mths
  –   Response rate 27% vs. 10%
  –   Time to progression 6.4 vs. 4.5 mths
  –   In non-squamous cancers only (life-threatening
      bleeding higher in squamous cancers)
      What is the state of the art for
       NSCLC treatment in 2007?
• Epidermal growth factor receptor (EGFR) inhibition in
  advanced NSCLC
   – 10% response rate in advanced disease, 30% prolonged stabilization
   – Survival advantage (erlotinib)
       • Shepherd, F. A. et al. N Engl J Med 2005;353:123-132
   – Mutually exclusive with K-ras
   – Most benefit for non-smoking related NSCLC, with EGFR mutations
     (females, adenocarcinomas), but benefit in non-mutated as well
       • Lynch et al., NEJM 350:2129, 2004; Paez et al., Science 304:1497, 2004;
         Pao et al., PNAS 101:13306, 2004
   – Mechanisms of secondary resistance to EGFR inhibitors being identified
     (T790M mutation-50%, Met amplification-20%)
       • Pao et al., PLoS Med 2:e17, 2005; Engelman et al., Science 316:1039, 2007
  Approaches to reducing cancer
    morbidity and mortality

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

• Better therapeutics
          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
Effect of Smoking Cessation on Lung
           Cancer Deaths
     Lung Health Study, 14.5 yr F/U



                                 -Anthonisen
                                 et al., Ann
                                 Intern Med
                                 142:233, 2005
   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 predisposed

        • Cancer development        • Eradicate cancer
End-
        • Phenotype reversal        • Control/palliate
point
                                    • Moderate toxicity
Agent • Minimal toxicity
      • Potentially long term       • Usually short term
                Field Cancerization
Multifocal Clonal Expansions    Second primary tumors

   Metaplasia
                                 First       Second
                    Carcinoma   Primary      Primary
Dysplasia
            Hyperplasia



                                              Third
                                             Primary
  Evolution of Intraepithelial Neoplasia

Normal   Hyperplasia/Metaplasia   Dysplasia       Cancer

                              Mild/Moderate/Severe/CIS



Squamous



Adenomatous
 When is the best time to intervene
   during lung carcinogenesis?
• Efficacy of intervention
   – Early stage cancer is more curable than late
   – Are precursor lesions more curable than invasive
     cancer?
   – Can carcinogen-induced DNA damage be prevented?
• Toxicity of intervention
   – High toxicity acceptable short-term, in setting of cancer
• Size of target population
   – Many at risk (smokers), relatively few get cancer/yr
• Cost (resources, psychological impact, etc.)
Upper Aerodigestive Tract
   Chemoprevention:
     Historical Perspective

-Oral premalignancy (leukoplakia)
-2nd Primary Head and neck cancer
-Lung cancer
             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%
    placebo
  – Relapse in >50% pts; toxicity high
    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
             asbestos
EUROSCAN     2592 lung,   Retinyl palm No benefit
2000         H&N ca       +/- NAC
Intergroup   1265 lung    13-cRA        No benefit
2001         ca
Critical Issues in Chemoprevention

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



           Design/Execution

        Agents:
        Target
        Dose, schedule, route, duration
        Efficacy vs. side effects
                    Cohorts

• 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%
    T2)
  – Stage I/II H & N ca (80% 5 yr survival)
  – High rate of second primaries (1-3%/yr)
Persistent Lung Cancer Risk After
        Smoking Cessation
      Peto et al., BMJ 321:323, 2000




                                   -50% of lung
                                  cancer occurs
                                    in former
                                     smokers
Lung Cancer Risk Assessment Tool
        -Bach et al., JNCI 2003;95:470
http://www.mskcc.org/mskcc/html/12463.cfm




 -age 50-75; 10-60 cigs/d for 25-55 yrs; current or former
 smoker who quit less <20 yrs ago
         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 and
  pharmacologic interactions
 Differences between current and former
smokers: Response rate in placebo group
at 6 months (Lam et al. Budesonide Trial)
    70
    60
    50
                                     Current
    40
                                     Smoker
    30
                                     Former
    20                               Smoker
    10
     0
          CR      PR   SD    PD

         P=0.01             P=0.13
Differences between current and former smokers:
      Bcl2 expression in bronchial dysplasia

                           24
                           22
        Percent Positive


                                            P=0.0017
                           20
                           18
                           16
                           14
                           12
                           10
                           8
                                CURRENT FORMER
                                 N = 200 N = 39
             Endpoints

• Phase III: cancer incidence
• Phase II: surrogates for incidence
  – Typically, intraepithelial neoplasia
• Phase I: safety/tolerability, PKs,
  surrogate endpoints
                   Agents

• 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
           Arachidonic Acid Metabolism
    As a Target for Aerodigestive Chemoprevention
                 Membrane Phospholipids
      Steroids           PLA2
                      Arachidonic Acid
     5-LO Inh       LO               COX      NSAIDs
     Zileuton

                 HPETEs             PGG2
Zileuton    LO
            HETEs     LTs          PGH2

                                 Prostaglandins
     Effect of Budesonide on Mouse
          Lung Tumorigenesis
             Pereira et al., Carcinogenesis 2002




-82% decrease in tumors       -Shift from adenoma to carcinoma
    DCP Phase IIb Trial of Budesonide
       Lam et al. Clin Cancer Res 10:6502, 2004

 115 smokers with dysplasia
       (Bronch)

              (Spiral CT)          # Screened (sputum): 1043
                                   # Dropped out (Rx): 15
Budesonide vs. Placebo x 6mths     Cancers detected: 13
                                   (3.1%)
               (Bronch,
               Spiral CT)
 1o Endpoint: bronchial dysplasia (#sites/grade)
 2o Endpoints: multiple biomarkers
    Effect of Budesonide on Bronchial
                Histology

    60
    50
    40

%   30                       Placebo
                             Budesonide
    20
    10
     0
         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%)
 pending


* P=0.024
       Ongoing Phase IIb Budesonide
         Chemoprevention Trial
       PI: Giulia Veronesi, EIO, Milan, IT

202 participants with persistent spiral CT-detected
  peripheral nodules
                         Randomize
  inhaled budesonide vs. placebo x 1 year

             repeat spiral CT

  Primary endpoint: shrinkage of lung nodules
          Arachidonic Acid Pathway:
            Lipoxygenase Branch
                                   Catalyzed by 5-Lipoxygenase:
                                                               COOH
              Arachidonic Acid
                                         O2             arachidonate

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



                                                          5-HPETE
    5-HPETE                             H2O
                                                O
                                                               COOH


    LTs       5-HETE                                   leukotriene-A4
Effect of Leukotriene Inhibitors on Mouse
           Lung Tumorigenesis
    -Gunning et al., Cancer Res 62:4199, 2002

Tumor # by 30%
                                  Carcinomas by 50%
Tumor size




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

134 smokers with dysplasia
      (Bronch)



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
              COX-2 as a Target

Membrane Phospholipids
          PLA2
                              Rationale
     Arachidonic Acid
                              •Epidemiology
          COX        NSAIDs
                              suggestive
                              •Animal models
     PGG2                     •Mechanistic data
                              •Expression in
     PGH2                     precursors (AAH)

    Prostaglandins
    Agents currently under development

• Arachidonic acid metabolism:
     – Zileuton (5-lipoxygenase inhibitor)
     – COX-2 inhibitors- celecoxib, sulindac (COX-
       1/COX-2)
     – Iloprost (prostacyclin analogue)
     – Budesonide for adenocarcinoma prevention
•   Green tea polyphenols
•   ACAPHA (herbal extract)
•   Myo-inositol (dietary supplement)
•   Selenium
         Emerging Concepts:
Regional Drug Delivery, Combinations


                               Combination
                             Chemoprevention
                             -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
  otherwise

• Morbidity/mortality/cost of screening and
  subsequent work-up
Lung Cancer Screening Trials
    X-ray, Sputum Cytology
   Spiral CT for Early Lung Cancer
               Detection
• ELCAP (Lancet 1999;354:99)
  – 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
• I-ELCAP (NEJM 2006;355:1763-71)
  – Low dose spiral CT 31,567 asymptomatic screened “at-risk”
    individuals (inc. second hand smoke exposed)
  – Results
     • 85% stage I, estimated 10-yr survival 88%
             Spiral CT Screening Trials
 Study               #Subjects %Positive   # Cancers   Stage I

ELCAP 1999 1,000                 23%       27 (prev) 85%
(Henschke et al.)
Mayo 2002             1,520      66%       23 (prev    57%
(Swensen et al.)                           & inc)
Japan 2002            1,611      11.5%     14 (prev)   71%
(Sobue et al.,)                            22 (inc)    82%
Milan 2003            1035       29%       11 (prev)   55%
(Pastorino et al.)                         11 (inc)    100%
NCI LSS 2004 1,660 CT            20.5%     30 (CT)     53%
(Gohagan et al.) 1,658 CXR       9.8%      7 (CXR)     86%
 Ongoing NCI-Sponsored Lung Cancer
          Screening Studies

• PLCO
 – 74,000 men/women
 – Age 55-74
 – CXR vs. none (prevalence, then x3)
• NLST
 – 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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