Non-small Cell Lung Cancer

1
Non-small Cell Lung Cancer

• Eva Szabo, MD
• Division of Cancer Prevention, NCI

2
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 breastprostatecolon
• 15 five year survival
• 5 in 1950s, 13 in 1970s

3
Age-adjusted lung cancer death rates, USA
(1930-1998)
80
Rate per 100,000 male/female population
Lung and bronchus (male) Lung and bronchus
(female)
60
40
20
0
1930
1940
1950
1960
1970
1980
1990
4
Five-year survival by TNM status in NSCLC
Stage IA IB IIA IIB IIIA IIIB IV
TNM classification T1N0M0 T2N0M0 T1N1M0 T2N1M0
or T3N0M0 T1-3N2M0 orT3N1M0 T4NanyM0 or
TanyN3M0 TanyNanyM1
5-year survival () 61 38 34 24 13 5 1
Mountain 1997
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Risk Factors

• Tobacco, tobacco, tobacco (85 lung ca.)
• Other exposures
• Asbestos, radon, polycyclic aromatic
  hydrocarbons, chromium, nickel, inorganic arsenic
  
• Passive smoking

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Pathology

• 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

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Sequential changes during lung cancer pathogenesis
Early Intermediate
Late
Normal epithelium
Invasive carcinoma
Hyperplasia
Dysplasia
CIS
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
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Treatment Strategies for Lung Cancer

• NSCLC Treatment based on stage
• Early stage (Stage I/II) surgery
• Regional spread combined modality
  (chemoradiation)
• Metastatic chemotherapy, radiation as needed
  for local control
• Small cell lung cancer chemotherapy (radiation
  for limited stage)

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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 119429, 2000)
• Adjuvant radiation
• PORT meta-analysis not for early stage,
  probably not for regional disease (Lancet
  352257, 1998)

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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

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Approaches to reducing cancer morbidity and
mortality

• Prevention (primary, secondary, tertiary)
• Early detection
• Better therapeutics-novel targeted agents

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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 491066-9, 2000

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Lung Cancer Risk After Smoking Cessation
-modified from Peto et al., BMJ 321323, 2000
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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

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Cancer Prevention vs. Treatment
Chemoprevention Chemotherapy

• Cancer patient
• Eradicate cancer
• Control/palliate
• Moderate toxicity
• Usually short term

Target End- point Agent

• Cured cancer patient
• Pre-cancer patient
• Genetically predisposed
• Cancer development
• Phenotype reversal
• Minimal toxicity
• Potentially long term

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Field Cancerization
Second primary tumors
Multifocal Clonal Expansions
Metaplasia
First Primary
Second Primary
Carcinoma
Dysplasia
Hyperplasia
Third Primary
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Evolution of Intraepithelial Neoplasia
Normal Hyperplasia/Metaplasia
Dysplasia Cancer
Mild/Moderate/Severe/CIS
Squamous Adenomatous
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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 dysplasia
• Severe dysplasia 41 regress to normal, 37
  remain or progress
• Carcinoma in situ 56 progress at site (44
  also had severe dysplasia or CIS elsewhere)

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Natural History of Atypical Alveolar Hyperplasia

• 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)

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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 gt50 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 maintenance

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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

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Phase III Lung Chemoprevention Trials
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Phase II Lung Chemoprevention Trials

• Investigator
• Arnold
• Lee
• Kurie
• McLarty
• Pastorino
• Kurie
• Lam

Agents Etretinate 13cRA 4-HPR ?-carot/Retinol Reti
nol Palmit 9cRA vs. 13cRA Vit E Anethole
dithiole thione
Outcome Negative Negative Negative Negative Positi
ve RAR-? ? with 9cRA ? New lesions
Endpoint Sputum Atypia Metaplasia Metaplasia Sputu
m Atypia Lung Cancer RAR-beta Bronchial dysplasia
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Critical Components of Clinical Trials
Cohorts High risk Likely to respond
Endpoints Cancer-related Drug effect markers
Design/Execution
Agents Target Dose, schedule, route,
duration Efficacy vs. side effects
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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 gt70 for T1 60 T2)
• Stage I/II H N ca (80 5 yr survival)
• High rate of second primaries (1-3/yr)

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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

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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?
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Agents

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

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New Agent Identification

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

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Mechanisms of Action of Chemopreventive Agents
Apoptosis
Normal cell
Preneoplastic cell
Differentiation
Growth
Angiogenesis
Invasion
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Arachidonic Acid MetabolismA Novel Target for
Aerodigestive Chemoprevention
Membrane Phospholipids PLA2 Arachidonic
Acid LO COX
HPETEs PGG2 LO HETEs
LTs PGH2 Prostaglandins

Steroids
5-LO Inh Zileuton
NSAIDs
Zileuton
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Effect of Budesonide on Mouse Lung Tumorigenesis
-82 inhibition
-Pereira et al. Carcinogenesis 2002
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Shift from Carcinoma to Adenoma by Budesonide
Pereira et al., Carcinogenesis 2002
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Potential Mechanism of Action of Budesonide
Induction of CDK Inhibitors
Pereira et al., Carcinogenesis 2002
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DCP Phase IIb Trial of Budesonide S. Lam, BCCA
115 smokers with dysplasia (Bronch)
Screened (sputum) 1043 Dropped out (Rx)
15 Cancers detected 13 (3.1)
(Spiral CT)
Budesonide vs. Placebo x 6mths
(Bronch, Spiral CT)
1o Endpoint bronchial dysplasia
(sites/grade) 2o Endpoints multiple biomarkers

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Effect of Budesonide on Bronchial Histology

37
Effect of Budesonide on Spiral CT-Detected
Peripheral Nodules
P0.024
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Arachidonic Acid Pathway Lipoxygenase Branch
Arachidonic Acid 5-HPETE LTs
5-HETE
5,12,15 LOs
12-HPETE 15-HPETE
39
Decrease in Tumor and Size by Leukotriene
Inhibitors-Gunning et al., Cancer Res 624199,
2002
Inhibition of Tumor Accolate (LTD4 inhibitor)
29.5 Zileuton (5-LO inhibitor) 28.1 MK866
(FLAP inhibitor) 37.8
40
Decrease in Carcinoma by Leukotriene
Inhibitors-Gunning et al., Cancer Res 624199,
2002

• Carcinomas by
• 50

Inhibits 5-LO FLAP LTD4
41
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
multiple biomarkers
Cross-over x 6 mths (Bronch)
42
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)

43
Emerging ConceptsRegional Drug Delivery,
Combinations
Combination Chemoprevention
-Increase efficacy -Reduce toxicity (lower
doses)
Aerosolized delivery to minimize systemic toxicity
44
For it happensthat 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
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Issues in Lung Cancer Screening

• Lead-time biasearlier diagnosis but no
  postponement of death (survival appears longer)
• Length biasdiagnosis of more indolent disease
  with longer preclinical phase (better prognosis,
  better outcome)
• Overdiagnosisidentification of clinically
  unimportant lesions that would not be diagnosed
  otherwise
• Morbidity/mortality/cost of screening and
  subsequent work-up

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Lung Cancer Screening TrialsX-ray, Sputum
Cytology
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Spiral CT for Early Lung Cancer Detection

• 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

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Spiral CT Screening Trials
Study Subjects Positive
Cancers Stage I
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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)

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An ounce of prevention is worth a pound of
cure -Benjamin Franklin