Thoracic Committee Corey Langer Director of Thoracic Oncology - PowerPoint PPT Presentation

ECOG Thoracic Committee Corey Langer Director of Thoracic Oncology Abramson Cancer Center University of Pennsylvania Philadelphia, PA 19104 On behalf of Joan Schiller eastern cooperative oncolo logy gro roup

Specific Aims  Investigate novel therapeutic agents for lung cancer and other thoracic malignancies [treatment and prevention]  Develop and incorporate novel chemotherapy regimens and combined modality approaches into the treatment of lung cancer and other thoracic malignancies  Identify hypothesis-driven, prognostic and predictive biomarkers, so as to identify groups of patients most likely to benefit from novel, molecularly targeted agents . easte stern rn coopera rati tive oncolo logy gro roup

Specific Aims  Investigate novel therapeutic agents for lung cancer and other thoracic malignancies [treatment and prevention]  Develop and incorporate novel chemotherapy regimens and combined modality approaches into the treatment of lung cancer and other thoracic malignancies  Identify hypothesis-driven, prognostic and predictive biomarkers, so as to identify groups of patients most likely to benefit from novel, molecularly targeted agents. easte stern rn coopera rati tive oncolo logy gro roup

Specific Aims  Investigate novel therapeutic agents for lung cancer and other thoracic malignancies  Selenium: Trace Mineral as Chemoprevention  Angiogenesis • Hypothesis: anti-angiogenic drugs have activity in lung cancer, and can improve the outcome of patients, either as single agents, or in combination with chemotherapy easte stern rn coopera rati tive oncolo logy gro roup

Stage I NSCLC: Chemoprevention  E-91025: phase III randomized, placebo-controlled evaluation of cRA in pathologically proven T 1 N 0 , T 2 N 0 NSCLC; accrual (n=1482) completed ~ 4/97; no benefit (except in never smokers)… Lippman SM, Journal of the National Cancer Institute, Vol. 93, No. 8, 605-618, April 18, 2001  E5597: Placebo controlled trial evaluating selenium in stage I disease (featured at ASCO ‘10) easte stern rn coopera rati tive oncolo logy gro roup

E5597: Phase III Chemoprevention Trial of Selenium Supplementation in Persons with Resected Stage I Non-Small Cell Lung Cancer Daniel D. Karp, Sandra Lee, Gail Shaw Wright, David Johnson, Michael Johnston, Gary Goodman, Gerald Clayman, Gordon Okawara, Randolph Marks, Jack Ruckdeschel Eastern Cooperative Oncology Group Together with Cancer and Acute Leukemia Group B NCI Canada Treatment Group North Central Cancer Treatment Group Radiation Therapy Oncology Group Southwest Oncology Group Enrollment from Oct. 2000 – Nov. 2009 ASCO 2010 easte stern rn coopera rati tive oncolo logy gro roup

Selenium Intergroup Prevention Study in Resected Stage I NSCLC  Objectives  Reduce incidence of second primary tumors (SPTs)  Evaluate safety and toxicity of L-Seleno-methionine  Compare overall and organ specific cancer mortality • Selenium 200 microgms/day for ELIGIBILITY** 48 months 1. Stage pT1N0 and pT2N0 • Monitor for safety, SPTs and 6 – 36mo. post-op 2. recurrence 3. Adjuvant Chemo allowed^ 4. Normal organ function 5. ECOG PS 0 or 1 • Placebo daily for 48 months Compliance with 4 wk “run - in” 6. • Monitor for safety, SPTs, and 7. No dietary supplements recurrence 8. No synchronous cancers **Stratify by smoking status and gender ^ Based on subsequent amendment easte stern rn coopera rati tive oncolo logy gro roup

Stratification s 1. Smoking Status  Active (within 1 yr)  Former (> 1 year)  Never smoked (< 100 cigarettes) 2. Gender  Male  Female 3. Stage /Previous Therapy Ia  Ib no chemotherapy  Ib prior chemotherapy  easte stern rn coopera rati tive oncolo logy gro roup

Selenium and Lung Cancer: A Quantitative Analysis of the Current Epidemiological Literature Hanjing Zhuo, Allan H. Smith, and Craig Steinmaus. Cancer Epidemiology, Biomarkers & Prevention 2004; 13(5). May 2004  Clark et al: 30% reduction in prostate and lung cancer with Se enrichment  Meta-analysis of 16 studies  5 as Relative Risk (RR)  3 as Mean Differences (MD)  8 both RR & MD  Overall pooled RR is 0.74 (95% CI 0.57-0.97) c2 = 28.9 p<0.01)  Protective effects greater in low Se areas  Hypothesis: Threshold effect easte stern rn coopera rati tive oncolo logy gro roup

Selenium: Proposed MOAs  Stimulation of glutathione peroxidase thereby lowering tissue peroxides.  Alterations in carcinogen metabolism.  Production of cytotoxic selenium metabolites.  Inhibition of protein synthesis.  Inhibition of specific enzymes.  Stimulation of apoptosis. easte stern rn coopera rati tive oncolo logy gro roup

Objects of E5597  Evaluate the efficacy of Selenium in  Preventing second primary cancers in patients who have had a curative resection for Stage I NSCLC  Assess Toxicity  Lab Correlates  Steve Belinsky, Lovelace Institute, Albuquerque, NM  Determine prevalence of • methylation of p16 • O6-methylguanine-DNA methyltransferase (MGMT)  Longitundinal determination of methylation profile.  Assessment of DNA Oxidation Products • 5- Hydroxymethyldeoxyuridine (5-HETE) • Lipoxygenase (LTB4) easte stern rn coopera rati tive oncolo logy gro roup

Selenium Intergroup Prevention Study in Resected Stage I NSCLC  Objectives  Reduce incidence of second primary tumors (SPTs)  Evaluate safety and toxicity of L-Seleno-methionine  Compare overall and organ specific cancer mortality • Selenium 200 microgms/day for ELIGIBILITY** 48 months 1. Stage pT1N0 and pT2N0 • Monitor for safety, SPTs and 6 – 36mo. post-op 2. recurrence 3. Adjuvant Chemo allowed 4. Normal organ function 5. ECOG PS => 0 or 1 • Placebo daily for 48 months Compliance with “run - in” 6. • Monitor for safety, SPTs, and 7. No dietary supplements recurrence 8. No synchronous cancers **Stratify by smoking status and gender easte stern rn coopera rati tive oncolo logy gro roup

Results 1. E5597 Selenium Prevention of Second Primary Lung Cancers in Resected Stage I Non Small Cell Lung Cancer  STUDY DURATION  Opened Oct 6, 2000 – Closed Nov 5, 2009  1772 pts enrolled 1561 randomized Step 2 (211 too early)  Planned: 1960 participants to detect a 40% decrease in SPTs [80% power]  SECOND PRIMARY TUMOR INCIDENCE (as of 26 Aug ’09)  216 second primary tumors (from 190 cases). 84 lung cancers in 83 patients ( 46.7% of anticipated 180)   Placebo: 1.36 per 100 person yrs  Selenium: 1.91 (2-sided p-value=.150, NS)  FUTILITY ANALYSIS  Ratio (Selenium/Placebo): 1.40, 95% CI (.65, 3.04)  Conditional power calculation made a positive effect extremely unlikely.  OVERALL SECOND PRIMARY TUMORS  Placebo: 3.66 per 100 person yrs followed  Selenium: 4.11 per 100 person yrs followed Daniel Karp, MD UT M. D. Anderson Cancer Center easte stern rn coopera rati tive oncolo logy gro roup

Results 2. E5597 Selenium Prevention Study: Progression Free Survival (PFS) Better for The Control Group Control Group: 78% PFS at 5 yrs Divergence at approx. 28 months Selenium Group: 72% PFS at 5 yrs p = 0.15) Daniel Karp, MD UT M. D. Anderson Cancer Center easte stern rn coopera rati tive oncolo logy gro roup

Results 3. ECOG 5597 Selenium in Resected Stage I NSCLC. Overall Survival. 90% 80% 85% 75% The selenium group had approximately 5% lower survival at 3 and 5 years. (p = 0.15, NS) Daniel Karp, MD UT M. D. Anderson Cancer Center easte stern rn coopera rati tive oncolo logy gro roup

E5597: Results  Stopped b/o futility:  Interim analysis occurred in Oct ’09 after 1561/1772 pts reached step 2 (completion of the 4 week (step 1) run-in period requiring at least 75% of the study drug to be taken).  216 SPTs developed of which 84 (38.9%) were lung cancer. SPTs/ 100 person years Placebo Selenium P values Lung 1.36 1.91 Overall 3.66 4.11 5 yr PFS 78% 72% 0.15 5 yr OS 80% 75% 0.15 Gr 3 toxicity 3% 1% Compliance at 2 yrs > 95% > 95% easte stern rn coopera rati tive oncolo logy gro roup

E5597: Conclusions  No benefit for Selenium wrt to SPTs, recurrence, or Overall Survival  No increase in diabetes or skin cancer detected.  Never smokers: slight benefit [NSS]  Selenium was safe, but conferred no benefit over placebo. easte stern rn coopera rati tive oncolo logy gro roup

ECOG 5597: Is there anything salvageable? easte stern rn coopera rati tive oncolo logy gro roup

ECOG 5597: Is there anything salvageable?  Vital data on natural history of stage IA and IB pts in the post PET era  Will ultimately “mine” patterns of recurrence  Crucial bio-correlates regarding methylation, etc easte stern rn coopera rati tive oncolo logy gro roup

ECOG 5597: Is there anything salvageable?  Vital data on natural history of stage IA and IB pts in the post PET era  Will ultimately “mine” patterns of recurrence  Crucial bio-correlates regarding methylation, etc  Should give us and our patients pause when they graft supplements and nutriceuticals onto standard Tx  Future studies will need to focus on molecular signaling pathways, not epidemiologic extrapolation easte stern rn coopera rati tive oncolo logy gro roup