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

3. Background: Gemcitabine plus Radiation Gemcitabine in pancreatic cancer Burris, 1997 –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)

4. E4201: Schema ARM A: INDUCTION GEMCITABINE 1000mg/M2 Once weekly x 6 weeks 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 A: CONSOLIDATION GEMCITABINE 1000mg/M2 Once weekly x 3 weeks Followed by 1 week rest x 5 cycles 1 cycle = 4 weeks ARM B: CONSOLIDATION GEMCITABINE 1000mg/M2 Once weekly x 3 weeks Followed by 1 week rest x 5 cycles 1 cycle = 4 weeks 1 week rest 4 weeks rest Stratify: PS (0 vs 1) Weight loss ( >10% vs <10%) RANDOMIZERANDOMIZE

5. Radiation Therapy 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)

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

7. 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

8. 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

9. Accrual sites GroupNo of Patients ECOG52 SWOG12 NCCTG 5 CALGB 1 RTOG 1 NSABP 1 CTSU 1 Total 74

10. 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

11. Patient characteristics GEM alone (n=37) GEM plus XRT (n=34) Median Age (yrs.)68.765.7 % Female51%44% PS = 176%82% >10% Weight Loss43%47%

12. Grade 3/4 Toxicities GEM alone (n=35) GEM plus XRT (n=34) p value* Neutropenia3%12%ns Thrombocytopenia6%21%ns Hemorrhage0%3%ns Gastrointestinal14%38%0.03 Fatigue6%32%0.006 Overall Grade 3/482%93%ns * Two sided Fisher’s exact test Two grade 5 toxicities: Cardiac (GEM) and ARDS (GEM/XRT)

13. Response GEM aloneGEM plus XRT Partial Resp.5%6% Stable Disease35%68% Progression16%6% Inevaluable*46%21% * Clinical “progression’ without confirmation scans or scans performed outside of scheduled times

14. Overall Survival GEM GEM plus XRT 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]) ----------------------- GEM p-value = 0.034 two-sided, stratified Log rank HR = 0.574 (95% CI- 0.342, 0.963)

15. Survival 6 mos12 mos18 mos24 mos GEM alone76%32%11%4% GEM plus XRT74%50%29%12%

16. Progression-Free Survival p-value = 0.50 two-sided, stratified Log rank HR= 0.821 (95%CI- 0.463,1.463) 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]) ----------------------- GEM plus XRT GEM

17. Sites of Relapse GEM aloneGEM plus XRT Local41%23% Distant14%23% Local and Distant5%9% Not documented*41%44% * Clinical “progression’ without confirmation scans or scans performed outside of scheduled times

18. 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)

19. “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

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

21. 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

22. 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

23. 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

24. My Comments Small trial Response rates are superior with CTRT if we count those with stable disease (74% vs 40%) Dose of concomitant Gem (600 mg/m2) is rather high with no significant excessive Gr 3,4 toxicity Mandatory use of 3D conformal RT is maybe a reason These data are different from the French trial using PF/RT-Gem vs Gem alone (B. Chauffert; ASCO 2006 )