P. J. Loehrer Sr., M. Powell, H. Cardenes, L.Wagner, J. Brell, R. Ramanathan,

1. A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized unresectable pancreatic cancer: E4201 P. J. Loehrer Sr., M. Powell, H. Cardenes, L.Wagner, J. Brell, R. Ramanathan, C. Crane, S. Alberts, A. B. Benson On behalf of The Eastern Cooperative Oncology Group

2. Faculty Disclosure Research Funding: - Eli Lilly - Novartis - AstraZeneca - Imclone

3. Background:Radiation in Pancreatic Cancer In locally advanced pancreatic cancer, radiation plus FU has been a standard of therapy (GITSG: Moertel,1981) Trials in the US and Europe have questioned the role of radiation in pancreatic cancer: ESPAC (Neoptolemos JP,2001) ECOG: 5-FU vs. 5-FU plus XRT (Klaassen,1985)

4. J Clin Oncol 3: 373-78, 1985

5. Background: Gemcitabine plus Radiation Gemcitabine in pancreatic cancer Superior to 5-FU (Burris, 1997) Potent radiation sensitizer in vitro(Lawrence, 1996). Numerous phase I/II trials with once or twice weekly gemcitabine plus radiation Phase I trial (Fox Chase, Michigan, Indiana): 50.4 Gy plus GEM (DLT- 600 mg/m2) (McGinn, ASCO 1997). Phase II trial (HOG): Six PR/28 pts (21%), MST 7.9 mos and 31% one year survival (Moore, ASCO 2004)

6. E4201: Schema RANDOMIZE ARM A: CONSOLIDATION GEMCITABINE 1000mg/M2 Once weekly x 3 weeks Followed by 1 week rest x 5 cycles 1 cycle = 4 weeks ARM A: INDUCTION GEMCITABINE 1000mg/M2 Once weekly x 6 weeks 1 week rest • Stratify: • PS (0 vs 1) • Weight loss • ( >10% vs <10%) ARM B: INDUCTION GEMCITABINE 600 mg/M2 Once weekly x 6 weeks CONCURRENT RT 180 cGy/day 5 days week x 6 weeks Total dose 50.40 Gy ARM B: CONSOLIDATION GEMCITABINE 1000mg/M2 Once weekly x 3 weeks Followed by 1 week rest x 5 cycles 1 cycle = 4 weeks 4 weeks rest

7. 3D-conformal Therapy PTV1: 3960 cGy GTV (primary + gross nodal disease) + 2-3 cm margin Immediately adjacent lymph node regions + 1.5 cm margin Adjust margins to accommodate normal tissue tolerance requirements PTV2: 5040 cGy GTV + 1.5-2 cm margin Treatment dose-volume were centrally reviewed (submitted within 3 days) Radiation Therapy

8. Endpoints • Primary: • Overall Survival • Secondary: • Response Rates • Progression Free Survival • Quality of Life (not presented today)

9. Inclusion Criteria • Histological confirmation of adenocarcinoma or adenosquamous carcinoma of the pancreas • Loco-regionally advanced disease • Unresectable disease without evidence of metastasis • No prior therapy • Measurable or evaluable disease • Adequate hematological, renal and hepatic functions • ECOG performance status of 0 or 1

10. Statistics • Primary Endpoint: Overall Survival • 88% Power to detect a 50% difference in median survival (8 months vs. 12 months) • Two-sided log-rank test (alpha = 0.05) • Accrual goal: 316 patients • Activated April 2003; terminated December 2005 • Reason: “poor accrual” (i.e. <10 entries per month) • Final accrual was 74 patients • All patients have expired • Data updated May, 2008

11. Patient Population GEMGEM/XRT No. eligible patients 38 36 Ineligible (metastases) 1 2 Total evaluable for survival 37 34 Total evaluable for toxicity 35 34

12. Patient characteristics

13. Grade 3/4 Toxicities Two grade 5 toxicities: Cardiac (GEM) and ARDS (GEM/XRT) * Two sided Fisher’s exact test

14. Response * Clinical “progression’ without confirmation scans or scans performed outside of scheduled times

15. GEM Overall Survival p-value = 0.034 Two-Sided, stratified Log rank GEM plus XRT GEM GEM: Median Survival 9.2 Months (95% CI [7.8, 11.4]) ----------------------- GEM + Radiation: Median Survival 11.0 Months (95% CI [8.4, 15.5])-----------------------

16. Survival

17. Progression-Free Survival p-value = 0.50 Two-Sided, stratified Log rank GEM plus XRT GEM GEM: Median PFS 6.7 Months (95% CI [4.6, 8.7]) ----------------------- GEM + Radiation: Median PFS 6.0 Months (95% CI [5.6, 8.4])-----------------------

18. Sites of Relapse * Clinical “progression’ without confirmation scans or scans performed outside of scheduled times

19. Progression-Free Survival in Pancreatic cancer: Problems • Definition of PFS: “The shorter of: • The time from registration to progression. • The time from registration to death from any cause without documentation of progression” • Difficulty measuring objective response • Surrogate markers of progression (e.g. pain, anorexia, performance status)

20. “Explanations” for poor accrual • Competing trials in metastatic disease include locally advanced disease • Dosages of gemcitabine not equal • “Unethical” not to use radiation therapy • “Unethical” to use radiation therapy

21. E4201: Limitations • Survival only modestly prolonged • Response Rate and PFS not different • Toxicity: Treatment or disease related? • Single study • Small sample size

22. Conclusions • Gemcitabine plus radiation therapy has superior survival compared to gemcitabine alone (11.0 mos vs. 9.2 mos; p=0.034) • Similar PFS and overall response rates • Toxicity is very common, but manageable in both arms (QOL to be reported later) • Locally advanced and stage IV pancreatic cancers should be treated as separate entities

23. Final Personal Comments • Clinical significance: • Some: an affirmation for radiation • Others: an underpowered trial • If combined modality therapy is considered for locally advanced pancreatic cancer, gemcitabine is more attractive than 5-FU • It remains a sobering reality that in nearly three decades of research, the true impact of radiation therapy in pancreatic cancer is still controversial

24. Acknowledgments • The patients who participated in this study • Those investigators and nurses within ECOG and the CTSU who continue to work hard for their patients and to seek knowledge on their behalf