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Non-small Cell Lung Cancer

Small cell lung cancer: chemotherapy (+radiation for limited stage) ... Decline in California lung cancer rates 1988-1997 declined 14%, compared with ...

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Non-small Cell Lung Cancer

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  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 breast+prostate+colon • 15% five year survival • 5% in 1950’s, 13% in 1970’s

  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

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

  6. 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%

  7. 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

  8. 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)

  9. 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)

  10. 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

  11. Approaches to reducing cancer morbidity and mortality • Prevention (primary, secondary, tertiary) • Early detection • Better therapeutics-novel targeted agents

  12. 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

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

  14. 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

  15. 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 Cancer Prevention vs. Treatment ChemopreventionChemotherapy Target End- point Agent

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

  17. Evolution of Intraepithelial Neoplasia Normal Hyperplasia/Metaplasia DysplasiaCancer Mild/Moderate/Severe/CIS Squamous Adenomatous

  18. 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)

  19. 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)

  20. 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

  21. Prevention of Second Primary CancersHead & 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

  22. Phase III Lung Chemoprevention Trials

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

  24. 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

  25. 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)

  26. 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

  27. 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?

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

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

  30. Mechanisms of Action of Chemopreventive Agents Apoptosis Normal cell Preneoplastic cell Differentiation Growth Angiogenesis Invasion

  31. Arachidonic Acid MetabolismA Novel Target for Aerodigestive Chemoprevention Membrane Phospholipids PLA2 Arachidonic Acid LOCOX HPETEsPGG2 LO HETEsLTsPGH2 Prostaglandins Steroids 5-LO Inh Zileuton NSAIDs Zileuton

  32. Effect of Budesonide on Mouse Lung Tumorigenesis -82% inhibition -Pereira et al. Carcinogenesis 2002

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

  34. Potential Mechanism of Action of Budesonide: Induction of CDK Inhibitors Pereira et al., Carcinogenesis 2002

  35. 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

  36. Effect of Budesonide on Bronchial Histology %

  37. Outcome Placebo # Nodules (% total) Budesonide # Nodules (% total) Unchanged 102 (87%) 43 (72%) Resolved or smaller 14 (12%) 16 (27%)* Follow-up pending 1 (1%) 1 (1%) Effect of Budesonide on Spiral CT-Detected Peripheral Nodules * P=0.024

  38. 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 62:4199, 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 62:4199, 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 Concepts:Regional Drug Delivery, Combinations Combination Chemoprevention -Increase efficacy -Reduce toxicity (lower doses) Aerosolized delivery to minimize systemic toxicity

  44. “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

  45. 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

  46. Lung Cancer Screening TrialsX-ray, Sputum Cytology

  47. 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

  48. Spiral CT Screening Trials Study #Subjects %Positive # Cancers Stage I

  49. 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)

  50. “An ounce of prevention is worth a pound of cure” -Benjamin Franklin

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