Chemoprevention of Lung Cancer PowerPoint Presentation

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Non-small Cell Lung Cancer Eva Szabo, MD Division of Cancer Prevention, NCI

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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

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Age-adjusted lung cancer death rates, USA (1930-1998) 80 60 40 20 0 1930 1940 1950 1960 1970 1980 1990 Rate per 100,000 male/female population Lung and bronchus (male) Lung and bronchus (female)

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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 Hyperplasia Dysplasia CIS Invasive carcinoma ~80% 3p LOH/small telomeric deletions 3p LOH/contiguous deletions ~50% Microsatellite alterations ~70% 9p21 LOH ~80% Telomerase dysregulation Telomerase upregulation ~60% myc overexpression ~80% 8p21-23 LOH ~40% Neoangiogenesis ~40% Loss of Fhit immunostaining ~70% p53 LOH p53 mutations ~80% Aneuploidy ~100% Methylation ~30% 5q21 APC-MCC LOH ~20% K-ras mutation 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 119:429, 2000) Adjuvant radiation PORT meta-analysis – not for early stage, probably not for regional disease (Lancet 352:257, 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 49:1066-9, 2000

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Lung Cancer Risk After Smoking Cessation -modified from Peto et al., BMJ 321:323, 2000

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The use of natural or synthetic agents to suppress or reverse carcinogenesis Cancer Chemoprevention 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 Cured cancer patient Pre-cancer patient Genetically predisposed Cancer development Phenotype reversal Minimal toxicity Potentially long term Cancer patient Eradicate cancer Control/palliate Moderate toxicity Usually short term Chemoprevention Chemotherapy Target End- point Agent

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Field Cancerization Carcinoma Hyperplasia Metaplasia Dysplasia First Primary Second Primary Third Primary Second primary tumors Multifocal Clonal Expansions

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Evolution of Intraepithelial Neoplasia Mild/Moderate/Severe/CIS Squamous Adenomatous Normal Hyperplasia/Metaplasia Dysplasia Cancer

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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 >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 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 Retinol Palmit 9cRA vs. 13cRA+ Vit E Anethole dithiole thione Outcome Negative Negative Negative Negative Positive RAR-  with 9cRA  New lesions Endpoint Sputum Atypia Metaplasia Metaplasia Sputum Atypia Lung Cancer RAR-beta Bronchial dysplasia

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Critical Components of Clinical Trials Agents: Target Dose, schedule, route, duration Efficacy vs. side effects Cohorts: High risk Likely to respond Endpoints: Cancer-related Drug effect markers Design/Execution

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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: >70% 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 Normal cell Preneoplastic cell Differentiation Growth Angiogenesis Apoptosis Invasion

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Arachidonic Acid Metabolism A Novel Target for Aerodigestive Chemoprevention Membrane Phospholipids PLA2 Arachidonic Acid LO COX HPETEs PGG2 LO HETEs LTs PGH2 Prostaglandins NSAIDs 5-LO Inh Zileuton Zileuton Steroids

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

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Effect of Budesonide on Bronchial Histology %

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Effect of Budesonide on Spiral CT-Detected Peripheral Nodules * P=0.024

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Arachidonic Acid Pathway: Lipoxygenase Branch Arachidonic Acid 5-HPETE LTs 5-HETE 5,12,15 LOs 12-HPETE 15-HPETE

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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% MK866 (FLAP inhibitor): 37.8%

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Decrease in Carcinoma # by Leukotriene Inhibitors -Gunning et al., Cancer Res 62:4199, 2002 Carcinomas by 50 % Inhibits: 5-LO FLAP LTD4

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DCP Phase IIb Trial of Zileuton O. Kucuk, Wayne State 134 smokers with dysplasia (Bronch) Zileuton vs. Placebo x 6 mths (Bronch) Cross-over x 6 mths (Bronch) 1o Endpoint: bronchial dysplasia (#sites/grade at 6 mths) 2o Endpoints: multiple biomarkers

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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)

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Emerging Concepts: Regional Drug Delivery, Combinations Aerosolized delivery to minimize systemic toxicity Combination Chemoprevention -Increase efficacy -Reduce toxicity (lower doses)

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“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

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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

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Lung Cancer Screening Trials X-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