Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial

Abstract

Background: Neoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen.

Methods: OE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 10⁹ cells per L, platelet count at least 100 × 10⁹ platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m² intravenously on day 1] and fluorouracil [1 g/m² per day intravenously on days 1-4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m²] and cisplatin [60 mg/m²] intravenously on day 1, and capecitabine [1250 mg/m²] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4-6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed.

Findings: Between Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6-26·3) with CF and 26·1 months (22·5-29·7) with ECX (hazard ratio 0·90 (95% CI 0·77-1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis.

Interpretation: Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma.

Funding: Cancer Research UK and Medical Research Council Clinical Trials Unit at University College London.

Figure 1

Consort diagram CF=cisplatin and fluorouracil. ECX=epirubicin, cisplatin, and capecitabine. *Cause of death reported as cardiac failure. †Causes of death reported as cerebral vascular accident, multiple organ failure, pulmonary embolism, bronchopneumonia, and oesophageal cancer. ‡For patients not listed in † above, cause of death was reported as sepsis-related multiple organ failure in one patient and oesophageal cancer in the remaining two patients. Screening logs were not collected during the trial, so the number of potentially eligible patients is unknown.

Figure 2

Overall survival CF=cisplatin and fluorouracil. ECX=epirubicin, cisplatin, and capecitabine.

Figure 3

Subgroup analysis Data are number of patients who had a survival event (n) out of the total number of patients (N), or HR (95% CI). The subgroup of patients with T1 disease at randomisation is not shown because there were only three patients who had CF and five who had ECX treatment. p values for heterogeneity of treatment effect are 0·69 for sex, 0·05 for age, 0·46 for WHO performance status, 0·11 for T-stage, and 0·028 for N-stage. T-stage and N-stage refer to clinical staging collected at time of randomisation. CF=cisplatin and fluorouracil. ECX=epirubicin, cisplatin, and capecitabine.