ArticlesAdjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial
Introduction
Pancreatic ductal adenocarcinoma remains one of the most difficult cancers to treat, with overall 5-year survival of only 0·4%1 and 5-year relative survival of 4%.2 It causes around 28 000 deaths per year in the USA and 40 000 per year in Europe.3 Although 10–15% of patients undergo potentially curative pancreatic surgery, with a low postoperative mortality rate, the median survival is only 10–18 months with 5-year survival of 17–24%.4, 5, 6 The best predictors of survival after surgery are stage of disease, tumour grade, and resection-margin status, but even the most favourable characteristics do not guarantee a cure.7, 8 Most failures occur within 1–2 years of surgery, through local recurrence, hepatic metastases, or both.9, 10 Radical surgery does not substantially improve survival.11
There is therefore a need for adjuvant therapy. In the Gastrointestinal Tumor Study Group (GITSG) randomised controlled trial,12, 13 43 patients were assigned adjuvant therapy (40 Gy radiotherapy combined with fluorouracil and then weekly fluorouracil for 2 years) or no such therapy. Median, 2-year, and 5-year survivals were significantly higher in the treatment group. In a study of 61 patients in Norway (including 14 with ampullary cancer), a regimen of fluorouracil, doxorubicin, and mitomycin improved median but not 5-year survival.14 The European Organization for Research and Treatment of Cancer (EORTC) study of adjuvant chemoradiotherapy (as in the GITSG regimen but with no follow-on chemotherapy) of 114 patients with pancreatic cancer found no significant difference in median survival between adjuvant-treated patients and controls (no extra treatment).15 Adjuvant treatment seems to provide a survival benefit (5–12 months increase in median survival) but definitive conclusions are not possible from these three trials because they were all inadequately powered.
We report on behalf of the European Study Group for Pancreatic Cancer (ESPAC) the interim results of a randomised controlled trial (ESPAC-1) that aimed to address whether adjuvant chemoradiotherapy or adjuvant chemotherapy alone has a role in improving survival of patients with resectable pancreatic cancer. Survival estimates were compared by treatment to answer the two hypotheses, and Cox's proportional-hazards models were constructed to investigate treatment effects adjusted for important prognostic factors. This paper reports the first planned look at the data at the time the study closed to recruitment (314 events). The final analysis will be done when all patients have been followed up for at least 2 years.
Section snippets
Participants
83 clinicians in 61 cancer centres in 11 countries recruited patients with resected pancreatic cancer between February 1994 and April 2000. Each cancer centre obtained ethical approval before entering patients into the trial. Patients were eligible if they had histologically proven ductal adenocarcinoma of the pancreas, macroscopically resected, with no evidence of local spread or distant metastases. Patients had to be fully recovered from surgery, to have a life expectancy of more than 3
Patients
548 patients with ductal adenocarcinomas of the pancreas were randomised. After review, seven patients were deemed ineligible: one had not had resection, two had previously had breast cancer, one had metastases at entry, and three had duplicate records through being randomised twice in error. Exclusion of these seven patients from further analysis did not unbalance treatment allocation. Of the remaining 541 eligible patients, 285 were entered into the two-by-two factorial design, 68 into
Discussion
The main conclusions of this trial were that the adjuvant chemoradiotherapy regimen did not improve 2-year survival. There was a strong indication that adjuvant chemotherapy prolongs survival, and a confounding negative effect of chemoradiotherapy on the benefit of chemotherapy alone was apparent. Although observed in the overall analysis, the benefit of chemotherapy was not seen in patients randomised in the two-by-two factorial design. These latter observations raise doubts about the size of
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