Elsevier

The Lancet

Volume 358, Issue 9293, 10 November 2001, Pages 1576-1585
The Lancet

Articles
Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(01)06651-XGet rights and content

Summary

Background

The role of adjuvant treatment in pancreatic cancer remains uncertain. The European Study Group for Pancreatic Cancer (ESPAC) assessed the roles of chemoradiotherapy and chemotherapy in a randomised study.

Methods

After resection, patients were randomly assigned to adjuvant chemoradiotherapy (20 Gy in ten daily fractions over 2 weeks with 500 mg/m2 fluorouracil intravenously on days 1–3, repeated after 2 weeks) or chemotherapy (intravenous fluorouracil 425 mg/m2 and folinic acid 20 mg/m2 daily for 5 days, monthly for 6 months). Clinicians could randomise patients into a two-by-two factorial design (observation, chemoradiotherapy alone, chemotherapy alone, or both) or into one of the main treatment comparisons (chemoradiotherapy versus no chemoradiotherapy or chemotherapy versus no chemotherapy). The primary endpoint was death, and all analyses were by intention to treat.

Findings

541 eligible patients with pancreatic ductal adenocarcinoma were randomised: 285 in the two-by-two factorial design (70 chemoradiotherapy, 74 chemotherapy, 72 both, 69 observation); a further 68 patients were randomly assigned chemoradiotherapy or no chemoradiotherapy and 188 chemotherapy or no chemotherapy. Median follow-up of the 227 (42%) patients still alive was 10 months (range 0–62). Overall results showed no benefit for adjuvant chemoradiotherapy (median survival 15·5 months in 175 patients with chemoradiotherapy vs 16·1 months in 178 patients without; hazard ratio 1·18 [95% Cl 0·90–1·55], p=0·24). There was evidence of a survival benefit for adjuvant chemotherapy (median survival 19·7 months in 238 patients with chemotherapy vs 14·0 months in 235 patients without; hazard ratio 0·66 [0·52–0·83], p=0·0005).

Interpretation

This study showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant chemotherapy, justifying further randomised controlled trials of adjuvant chemotherapy in pancreatic cancer.

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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