Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma

TY - JOUR

T1 - Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma

T2 - the ESPAC-3 periampullary cancer randomized trial

AU - Neoptolemos, John P

AU - Moore, Malcolm J

AU - Cox, Trevor F

AU - Valle, Juan W

AU - Palmer, Daniel H

AU - McDonald, Alexander C

AU - Carter, Ross

AU - Tebbutt, Niall C

AU - Dervenis, Christos

AU - Smith, David

AU - Glimelius, Bengt

AU - Charnley, Richard M

AU - Lacaine, François

AU - Scarfe, Andrew G

AU - Middleton, Mark R

AU - Anthoney, Alan

AU - Ghaneh, Paula

AU - Halloran, Christopher M

AU - Lerch, Markus M

AU - Oláh, Attila

AU - Rawcliffe, Charlotte L

AU - Verbeke, Caroline S

AU - Campbell, Fiona

AU - Büchler, Markus W

AU - European Study Group for Pancreatic Cancer

AU - Schafhausen, Philippe

PY - 2012/7/11

Y1 - 2012/7/11

N2 - CONTEXT: Patients with periampullary adenocarcinomas undergo the same resectional surgery as that of patients with pancreatic ductal adenocarcinoma. Although adjuvant chemotherapy has been shown to have a survival benefit for pancreatic cancer, there have been no randomized trials for periampullary adenocarcinomas.OBJECTIVE: To determine whether adjuvant chemotherapy (fluorouracil or gemcitabine) provides improved overall survival following resection.DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary trial, an open-label, phase 3, randomized controlled trial (July 2000-May 2008) in 100 centers in Europe, Australia, Japan, and Canada. Of the 428 patients included in the primary analysis, 297 had ampullary, 96 had bile duct, and 35 had other cancers.INTERVENTIONS: One hundred forty-four patients were assigned to the observation group, 143 patients to receive 20 mg/m2 of folinic acid via intravenous bolus injection followed by 425 mg/m2 of fluorouracil via intravenous bolus injection administered 1 to 5 days every 28 days, and 141 patients to receive 1000 mg/m2 of intravenous infusion of gemcitabine once a week for 3 of every 4 weeks for 6 months.MAIN OUTCOME MEASURES: The primary outcome measure was overall survival with chemotherapy vs no chemotherapy; secondary measures were chemotherapy type, toxic effects, progression-free survival, and quality of life.RESULTS: Eighty-eight patients (61%) in the observation group, 83 (58%) in the fluorouracil plus folinic acid group, and 73 (52%) in the gemcitabine group died. In the observation group, the median survival was 35.2 months (95%% CI, 27.2-43.0 months) and was 43.1 (95%, CI, 34.0-56.0) in the 2 chemotherapy groups (hazard ratio, 0.86; (95% CI, 0.66-1.11; χ2 = 1.33; P = .25). After adjusting for independent prognostic variables of age, bile duct cancer, poor tumor differentiation, and positive lymph nodes and after conducting multiple regression analysis, the hazard ratio for chemotherapy compared with observation was 0.75 (95% CI, 0.57-0.98; Wald χ2 = 4.53, P = .03).CONCLUSIONS: Among patients with resected periampullary adenocarcinoma, adjuvant chemotherapy, compared with observation, was not associated with a significant survival benefit in the primary analysis; however, multivariable analysis adjusting for prognostic variables demonstrated a statistically significant survival benefit associated with adjuvant chemotherapy.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

AB - CONTEXT: Patients with periampullary adenocarcinomas undergo the same resectional surgery as that of patients with pancreatic ductal adenocarcinoma. Although adjuvant chemotherapy has been shown to have a survival benefit for pancreatic cancer, there have been no randomized trials for periampullary adenocarcinomas.OBJECTIVE: To determine whether adjuvant chemotherapy (fluorouracil or gemcitabine) provides improved overall survival following resection.DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary trial, an open-label, phase 3, randomized controlled trial (July 2000-May 2008) in 100 centers in Europe, Australia, Japan, and Canada. Of the 428 patients included in the primary analysis, 297 had ampullary, 96 had bile duct, and 35 had other cancers.INTERVENTIONS: One hundred forty-four patients were assigned to the observation group, 143 patients to receive 20 mg/m2 of folinic acid via intravenous bolus injection followed by 425 mg/m2 of fluorouracil via intravenous bolus injection administered 1 to 5 days every 28 days, and 141 patients to receive 1000 mg/m2 of intravenous infusion of gemcitabine once a week for 3 of every 4 weeks for 6 months.MAIN OUTCOME MEASURES: The primary outcome measure was overall survival with chemotherapy vs no chemotherapy; secondary measures were chemotherapy type, toxic effects, progression-free survival, and quality of life.RESULTS: Eighty-eight patients (61%) in the observation group, 83 (58%) in the fluorouracil plus folinic acid group, and 73 (52%) in the gemcitabine group died. In the observation group, the median survival was 35.2 months (95%% CI, 27.2-43.0 months) and was 43.1 (95%, CI, 34.0-56.0) in the 2 chemotherapy groups (hazard ratio, 0.86; (95% CI, 0.66-1.11; χ2 = 1.33; P = .25). After adjusting for independent prognostic variables of age, bile duct cancer, poor tumor differentiation, and positive lymph nodes and after conducting multiple regression analysis, the hazard ratio for chemotherapy compared with observation was 0.75 (95% CI, 0.57-0.98; Wald χ2 = 4.53, P = .03).CONCLUSIONS: Among patients with resected periampullary adenocarcinoma, adjuvant chemotherapy, compared with observation, was not associated with a significant survival benefit in the primary analysis; however, multivariable analysis adjusting for prognostic variables demonstrated a statistically significant survival benefit associated with adjuvant chemotherapy.TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

KW - Adenocarcinoma

KW - Aged

KW - Ampulla of Vater

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Chemotherapy, Adjuvant

KW - Common Bile Duct Neoplasms

KW - Deoxycytidine

KW - Female

KW - Fluorouracil

KW - Humans

KW - Leucovorin

KW - Male

KW - Middle Aged

KW - Prognosis

KW - Survival Analysis

KW - Watchful Waiting

U2 - 10.1001/jama.2012.7352

DO - 10.1001/jama.2012.7352

M3 - SCORING: Journal article

C2 - 22782416

VL - 308

SP - 147

EP - 156

JO - JAMA-J AM MED ASSOC

JF - JAMA-J AM MED ASSOC

SN - 0098-7484

IS - 2

ER -