Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial.
BACKGROUND
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.


METHODS
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.


METHODS
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.


METHODS
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00058201.
Institute of Translational Medicine, Liverpool Cancer Trials Unit, Liverpool Cancer Research United Kingdom Centre, University of Liverpool, Liverpool, England, United Kingdom. j.p.neoptolemos@liverpool.ac.uk
John P
JP
Neoptolemos
Malcolm J
MJ
Moore
Trevor F
TF
Cox
Juan W
JW
Valle
Daniel H
DH
Palmer
Alexander C
AC
McDonald
Ross
R
Carter
Niall C
NC
Tebbutt
Christos
C
Dervenis
David
D
Smith
Bengt
B
Glimelius
Richard M
RM
Charnley
François
F
Lacaine
Andrew G
AG
Scarfe
Mark R
MR
Middleton
Alan
A
Anthoney
Paula
P
Ghaneh
Christopher M
CM
Halloran
Markus M
MM
Lerch
Attila
A
Oláh
Charlotte L
CL
Rawcliffe
Caroline S
CS
Verbeke
Fiona
F
Campbell
Markus W
MW
Büchler
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000601:surgery; D000368:Aged; D014670:Ampulla of Vater; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D003138:Common Bile Duct Neoplasms / Q000188:drug therapy* / Q000601:surgery; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D057832:Watchful Waiting; D000093542:Gemcitabine
D003841:Deoxycytidine; D002955:Leucovorin; D005472:Fluorouracil; D000093542:Gemcitabine