Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2–3 trial

Abstract

SummaryBackgroundPeri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma.MethodsIn this multicentre, randomised, open-label phase 2–3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1–21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203.FindingsBetween Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5–54·9) in the chemotherapy alone group and 48·1% (43·2–52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91–1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with ...

Optimal management of gastroesophageal junction cancer

“…A benefit of preoperative chemoradiation over chemotherapy is the signal of an improvement in R0 rates for GEJ tumors. In contemporary preoperative chemotherapy studies, R0 rates were <70%, whereas patients who received chemoradiation in the CROSS trial had R0 resection rates >90% . In the FLOT4‐AIO study, the R0 rate was 84% in patients who received FLOT versus 77% in those who received ECF/ECX .…”

Management of metastatic esophagogastric junction adenocarcinoma

“…Bevacizumab, which is a monoclonal antibody that targets vascular endothelial growth factor A (VEGF-A), inhibiting tumor growth in preclinical studies [15,16] . In AVAGAST trial [phase III, including advanced EGJ (n = 103) and gastric adenocarcinoma (n = 671)], bevacizumab did not confer any survival benefit (median OS 12.1 months in bevacizumab plus XP; vs. median OS 10.1 months in XP alone).…”

Customization of therapy for gastroesophageal adenocarcinoma patients

“…In another study, 49 the addition of bevacizumab, that binds to vascular endothelial growth factor (VEGF), to peri-operative ECX for localized GEAC patients was studied but no benefit was noted (3-year OS rate, 50.3% in ECX alone group and 48.1% for ECX plus bevacizumab group; HR , 1.09; 95% CI : 0.91–1.29; P  = 0.36). More than 70% of all patients could receive post-operative therapies but wound healing complications were more prevalent in bevacizumab group (12% vs .…”