The new england journal of medicine original article A Randomized Trial of Chemoradiotherapy and Chemotherapy after Resection of Pancreatic Cancer John P. Neoptolemos, M.D., Deborah D. Stocken, M.Sc., Helmut Friess, M.D., Claudio Bassi, M.D., Janet A. Dunn, M.Sc., Helen Hickey, B.Sc., Hans Beger, M.D., Laureano Fernandez-Cruz, M.D., Christos Dervenis, M.D., François Lacaine, M.D., Massimo Falconi, M.D., Paolo Pederzoli, M.D., Akos Pap, M.D., David Spooner, M.D., David J. Kerr, M.D., and Markus W. Büchler, M.D., for the European Study Group for Pancreatic Cancer abstract background From the Department of Surgery, Liver- The effect of adjuvant treatment on survival in pancreatic cancer is unclear. We report the pool University, Liverpool, United King- final results of the European Study Group for Pancreatic Cancer 1 Trial and update the dom (J.P.N., H.H.); the Cancer Research U.K. Clinical Trials Unit, University of Bir- interim results. mingham, Birmingham, United Kingdom (D.D.S., J.A.D., D.J.K.); the University of methods Heidelberg, Heidelberg, Germany (H.F., M.W.B.); the Surgical Department, Univer- In a multicenter trial using a two-by-two factorial design, we randomly assigned 73 pa- sity of Verona, Verona, Italy (C.B., M.F., tients with resected pancreatic ductal adenocarcinoma to treatment with chemoradio- P.P.); University Hospital of Surgery, Ulm, therapy alone (20 Gy over a two-week period plus fluorouracil), 75 patients to chemo- Germany (H.B.); Barcelona University Hos- pital, Barcelona, Spain (L.F.-C.); the Depart- therapy alone (fluorouracil), 72 patients to both chemoradiotherapy and chemotherapy, ment of Surgery, Agia Olga Hospital, Ath- and 69 patients to observation. ens, Greece (C.D.); the Service de Chirurgie Digestive et Générale, Hôpital Tenon, Paris results (F.L.); the Department of Gastroenterology, Mav Hospital, Budapest, Hungary (A.P.); The analysis was based on 237 deaths among the 289 patients (82 percent) and a median and the Department of Radiotherapy, follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival Queen Elizabeth Hospital, Birmingham, United Kingdom (D.S.). rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 per- cent among patients who did not receive chemoradiotherapy (P=0.05). The five-year N Engl J Med 2004;350:1200-10. survival rate was 21 percent among patients who received chemotherapy and 8 percent Copyright © 2004 Massachusetts Medical Society. among patients who did not receive chemotherapy (P=0.009). The benefit of chemo- therapy persisted after adjustment for major prognostic factors. conclusions Adjuvant chemotherapy has a significant survival benefit in patients with resected pan- creatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival. 1200 n engl j med 350;12 www.nejm.org march 18, 2004 The New England Journal of Medicine Downloaded from www.nejm.org on September 12, 2010. For personal use only. No other uses without permission. Copyright © 2004 Massachusetts Medical Society. All rights reserved. chemoradiotherapy and chemotherapy after resection of pancreatic cancer ancreatic cancer, with an overall chemotherapy vs. no chemotherapy) and giving the five-year survival rate ranging from 0.4 per- study the ability to detect absolute differences in the p 1 2 cent to 4 percent, has a poor prognosis mortality rate at two years of more than 20 percent and is one of the top 10 causes of death from cancer at a significance level of 5 percent with 90 percent in the Western world.3,4 Surgical resection improves power. The trial was approved by the ethics commit- the outlook, although only about 10 percent of pa- tees at the national and local level according to the tients with pancreatic cancer are eligible for the pro- requirements of each country, and all participants cedure.5-9 Most treatment failures are due to local gave written informed consent. recurrence, hepatic metastases, or both and occur Patients who had undergone a complete macro- within one to two years after surgery.10-12 scopic resection22 of histologically proven pancre- Adjuvant (postoperative) therapy may improve atic ductal adenocarcinoma underwent randomiza- long-term survival,7-9,13-16 but its routine use is not tion with the use of a blocked method. They were universal8 because the results of randomized trials stratified according to the randomization center (the have been inconclusive.13 The Gastrointestinal Tu- United Kingdom, Switzerland, Germany, or France) mor Study Group (GITSG) randomly assigned 43 and the status of the resection margin (positive or patients to receive surgery alone or chemoradiother- negative). Patients were followed up at three-month apy followed by maintenance chemotherapy.14,15 intervals until death. A subgroup of patients com- The median survival was significantly longer in the pleted questionnaires about their quality of life.23 adjuvant-treatment group than in the surgery group (20 months vs. 11 months), with 5-year survival adjuvant therapy estimates of 18 percent and 8 percent, respective- Chemoradiotherapy consisted of a 20-Gy dose to the ly.14,15 Three subsequent randomized studies, how- tumor given in 10 daily fractions over a two-week ever, failed to confirm the benefit of adjuvant treat- period plus an intravenous bolus of fluorouracil ment.17-19 Moreover, it is unclear whether the (500 mg per square meter of body-surface area on survival advantage in the GITSG trial was due to the each of the first three days of radiotherapy and again combination of chemoradiotherapy and mainte- after a planned break of two weeks). Chemotherapy nance chemotherapy or to only one of these treat- consisted of an intravenous bolus of leucovorin (20 ments.13 mg per square meter), followed by an intravenous The European Study Group for Pancreatic Can- bolus of fluorouracil (425 mg per square meter) on cer (ESPAC) undertook a large, multicenter trial to each of 5 consecutive days every 28 days for six cy- investigate the possible benefits of adjuvant chemo- cles. Combination therapy consisted of chemora- radiotherapy and maintenance chemotherapy in pa- diotherapy followed by chemotherapy, both admin- tients with pancreatic cancer. Although preliminary istered as described above. data indicated a survival benefit for adjuvant chemo- Adverse effects were assessed with the use of the therapy, the results were inconclusive owing to the Common Toxicity Criteria24 and a clearly defined short follow-up of only 10 months.20,21 In this re- protocol for modifications and delays of treatment. port we summarize the results of this trial after it The study required each center to treat patients ac- reached the primary end point and a median follow- cording to its own quality-assurance standards for up of 47 months among surviving patients.20,21 radiotherapy. methods statistical analysis The primary outcome measure was the two-year sur- patients and trial design vival rate; secondary outcomes were the incidence The ESPAC-1 trial used a two-by-two factorial design of adverse effects and recurrence and measures of in which, after resection of the pancreatic ductal ad- the quality of life. Survival was calculated from the enocarcinoma, each patient was randomly assigned date of resection until the date of death from any to receive chemoradiotherapy or chemotherapy, nei- cause; for patients lost to follow-up, data were cen- ther treatment, or both treatments (Fig. 1). The goal sored on the date the patient was last seen alive. Sur- was to enroll 70 patients in each of the four groups, vival estimates were derived by the method of Kap- yielding combined data for 140 patients in each lan and Meier,25 and the log-rank test26 was used to group for the two main treatment comparisons assess differences in survival estimates among the (chemoradiotherapy vs. no chemoradiotherapy and groups. Stratified log-rank analyses and Cox pro- n engl j med 350;12 www.nejm.org march 18, 2004 1201 The New England Journal of Medicine Downloaded from www.nejm.org on September 12, 2010. For personal use only. No other uses without permission. Copyright © 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine ment was 46 days (interquartile range, 34 to 67) for 289 Patients with histologically proven the patients assigned to chemotherapy and 61 days adenocarcinoma of the pancreas who had (interquartile range, 47 to 80) for the patients as- undergone potentially curative resection signed to chemoradiotherapy. compliance and adverse effects A total of 145 patients were assigned to receive 73 Assigned to 72 Assigned to chemoradiotherapy (alone or with adjuvant chemo- 69 Assigned to 75 Assigned to chemoradio- chemoradiotherapy observation chemotherapy therapy), and 144 were assigned not to receive therapy and chemotherapy chemoradiotherapy — they received chemotherapy alone or were observed — according to the two-by- two design (Fig. 1). Treatment details were available for 128 of the 145 patients who received chemora- Treatment comparison diotherapy (88 percent), of whom 90 (70 percent) received a total of 40 Gy according to the protocol, 27 (21 percent) received either more or less than 40 Gy, and 11 (9 percent) did not receive any chemora- No chemoradiotherapy No chemotherapy diotherapy; most protocol violations were due to the vs. chemoradiotherapy vs. chemotherapy patient’s decision not to receive the randomly as- (144 vs. 145) (142 vs. 147) signed treatment (50 percent) or to progressive dis- ease (19 percent). Figure 1. The Two-by-Two Randomization Procedure Used for Both Chemora- A total of 147 patients were assigned to chemo- diotherapy and Chemotherapy. therapy (75 to chemotherapy alone and 72 to chemo- therapy in combination with chemoradiotherapy), and 142 did not receive chemotherapy alone (69 were assigned to the observation group and 73 to the portional-hazards modeling27 were used to inves- chemoradiotherapy group), according to the two- tigate and adjust for major prognostic and stratifica- by-two design (Fig.