Adjuvant Chemotherapy With Fluorouracil Plus Folinic Acid vs Gemcitabine Following Pancreatic Cancer Resection
A Randomized Controlled Trial
- John P. Neoptolemos, MD;
- Deborah D. Stocken, PhD;
- Claudio Bassi, MD;
- Paula Ghaneh, MD;
- David Cunningham, MD;
- David Goldstein, MD;
- Robert Padbury, MD;
- Malcolm J. Moore, MD;
- Steven Gallinger, MD;
- Christophe Mariette, MD;
- Moritz N. Wente, MD;
- Jakob R. Izbicki, MD;
- Helmut Friess, MD;
- Markus M. Lerch, MD;
- Christos Dervenis, MD;
- Attila Oláh, MD;
- Giovanni Butturini, MD;
- Ryuichiro Doi, MD;
- Pehr A. Lind, MD;
- David Smith, MD;
- Juan W. Valle, MD;
- Daniel H. Palmer, MD;
- John A. Buckels, MD;
- Joyce Thompson, MD;
- Colin J. McKay, MD;
- Charlotte L. Rawcliffe, MSc;
- Markus W. Büchler, MD
- for the European Study Group for Pancreatic Cancer
- Author Affiliations: Liverpool Cancer Research UK Cancer Trials Unit, Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, United Kingdom (Drs Neoptolemos and Ghaneh and Ms Rawcliffe); Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom (Dr Stocken); Department of Surgery, University of Verona, Verona, Italy (Drs Bassi and Butturini); the Royal Marsden National Health Service Foundation Trust, London and Surrey, United Kingdom (Dr Cunningham); Australasian Gastro-Intestinal Trials Group, Camperdown, New South Wales, Australia (Drs Goldstein and Padbury); Princess Margaret Hospital, Toronto, Ontario, Canada (Dr Moore); Department of Surgery, Faculty of Medicine, University of Toronto, University Health Network, Toronto (Dr Gallinger); Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille, France, and the French Federation of Surgical Research (Dr Mariette); Department of Surgery, University of Heidelberg, Heidelberg, Germany (Drs Wente and Büchler); Department of General, Visceral and Thoracic Surgery, University of Hamburg, Hamburg, Germany (Dr Izbicki); Department of Surgery, Technische Universität Munchen, Munich, Germany (Dr Friess); Department of Medicine A, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany (Dr Lerch); Agia Olga Hospital, Athens, Greece (Dr Dervenis); Petz Aladar Hospital, Gyor, Hungary (Dr Oláh); Department of Surgery, Kyoto University, Sakyo, Kyoto, Japan (Dr Doi); Department of Oncology, Karolinska-Stockholm Söder Hospital, Stockholm, Sweden (Dr Lind); Medical Oncology, Clatterbridge Centre for Oncology, Clatterbridge Road, Bebington, Merseyside, United Kingdom (Dr Smith); Christie National Health Service Foundation Trust, Manchester, United Kingdom (Dr Valle); Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom (Drs Palmer and Buckels); Birmingham Heartlands Hospital, Birmingham (Dr Thompson); and Lister Department of Surgery, Glasgow Royal Infirmary, Glasgow, Scotland, United Kingdom (Dr McKay).
Abstract
Context Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer.
Objective To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer.
Design, Setting, and Patients The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up.
Interventions Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m2, intravenous bolus injection, followed by fluorouracil, 425 mg/m2 intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m2 intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months.
Main Outcome Measures Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life.
Results Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (χ21 = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups.
Conclusion Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer.
Trial Registration clinicaltrials.gov Identifier: NCT00058201
