Elsevier

The Lancet

Volume 359, Issue 9319, 18 May 2002, Pages 1727-1733
The Lancet

Articles
Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(02)08651-8Get rights and content

Summary

Background

The outlook for patients with oesophageal cancer undergoing surgical resection with curative intent is poor. We aimed to assess the effects of preoperative chemotherapy on survival, dysphagia, and performance status in this group of patients.

Methods

802 previously untreated patients with resectable oesophageal cancer of any cell type were randomly allocated either two 4-day cycles, 3 weeks apart, of cisplatin 80 mg/m2 by infusion over 4 h plus fluorouracil 1000 mg/m2 daily by continuous infusion for 4 days followed by surgical resection (CS group, n=400), or resection alone (S group, 402). Clinicians could choose to give preoperative radiotherapy to all their patients irrespective of randomisation. Primary outcome measure was survival time. Analysis was by intention to treat

Findings

No patients dropped out of the study. Resection was microscopically complete in 233 (60%) of 390 assessable CS patients and 215 (54%) of 397 S patients (p<0·0001). Postoperative complications were reported in 146 (41%) CS and 161 (42%) S patients. Overall survival was better in the CS group (hazard ratio 0·79; 95% Cl 0·67–0·93; p=0·004). Median survival was 512 days (16·8 months) in the CS group compared with 405 days (13·3 months) in the S group (difference 107 days; 95% Cl 30–196), and 2-year survival rates were 43% and 34% (difference 9%; 3–14)

Interpretation

Two cycles of preoperative cisplatin and fluorouracil improve survival without additional serious adverse events in the treatment of patients with resectable oesophageal cancer.

Introduction

The outlook for patients with oesophageal cancer who undergo surgical resection with curative intent is poor, with only about 20–30% survival at 2 years. Factors that contribute to this dismal outlook include presence of locally advanced disease and undetected metastatic cancer at diagnosis. Because of the high rates of locoregional and distant failure, there is much interest in the combination of systemic chemotherapy and local surgical treatment.

There is increasing evidence that oesophageal cancer responds to combination chemotherapy regimens based on cisplatin. Response rates before surgery of 40–60% for squamous carcinoma and 30–40% for adenocarcinoma, and 2-year survival rates of 30–40% with preoperative chemotherapy plus surgery, have been reported1, 2, 3, 4, 5, 6. However, what is not clear from the results of these studies is whether these survival rates are attributable to selection of patients or whether they are an effect of chemotherapy.

We therefore did a pragmatic randomised trial in patients thought to have resectable cancer of the oesophagus, comparing surgical resection as locally practised with or without preoperative chemotherapy, to investigate whether chemotherapy first lengthens survival and second affects dysphagia and performance status. We chose the combination of cisplatin and fluorouracil since they were two of the most active single agents in both squamous carcinoma and adenocarcinoma7, and because of reported efficacy in combination1, 3, 7, 8, 9 We decided to give only two cycles at modest doses in view of the reported rapidity with which responses to chemotherapy arose, to keep delay of definitive surgical treatment to a minimum, to avoid excessive toxicity and morbidity before major surgery in patients who are often old and undernourished, and to encourage acceptability of the trial design by patients.

Section snippets

Patients

Patients were eligible for the study if they had previously untreated cancer of the oesophagus that was judged resectable and had been microscopically confirmed as squamous carcinoma, adenocarcinoma, or undifferentiated carcinoma. Patients were invited to take part in the study by the clinician responsible for their care. We included tumours of the upper, middle, or lower third of the oesophagus and of the cardia, but not post-cricoid tumours. Patients were not eligible if they had other

Results

Between March, 1992, and June, 1998, 802 patients from 42 European centres were randomly assigned either chemotherapy followed by surgery (CS group, n=400) or surgery alone (S group, 402; figure 1). 69 patients from China were also randomly allocated (34 to CS, 35 to S) but, because of changes in funding of their health-care system, recruitment ceased, and we could not obtain follow-up data. These patients were therefore excluded from the analysis.

Patients' characteristics were well balanced

Discussion

We have shown that two cycles of preoperative cisplatin and fluorouracil improve overall and disease-free survival compared with surgical resection alone in patients with resectable oesophageal cancer. Adherence to chemotherapy was good, and survival benefit seemed to be consistent for squamous cancers and adenocarcinomas. In patients who received chemotherapy, surgical resection was more often complete, and resection specimens showed less extension into surrounding tissue and less lymph node

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