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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
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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
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) ESPAC (Neoptolemos JP,2001)
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)
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
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
Endpoints • Primary: • Overall Survival • Secondary: • Response Rates • Progression Free Survival • Quality of Life (not presented today)
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
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
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
Grade 3/4 Toxicities Two grade 5 toxicities: Cardiac (GEM) and ARDS (GEM/XRT) * Two sided Fisher’s exact test
Response * Clinical “progression’ without confirmation scans or scans performed outside of scheduled times
GEM Overall Survival p-value = 0.034 two-sided, stratified Log rank HR = 0.574 (95% CI- 0.342, 0.963) 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])-----------------------
Progression-Free Survival p-value = 0.50 two-sided, stratified Log rank HR= 0.821 (95%CI- 0.463,1.463) 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])-----------------------
Sites of Relapse * Clinical “progression’ without confirmation scans or scans performed outside of scheduled times
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)
“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
E4201: Limitations • Survival only modestly prolonged • Response Rate and PFS not different • Toxicity: Treatment or disease related? • Single study • Small sample size
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
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
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
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 )