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.
Peri-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.



In 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/m2epirubicin and 60 mg/m2cisplatin on day 1 and 1250 mg/m2oral 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.



Between 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 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53).



The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing.



Cancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited.
Department of Oncology, Royal Marsden NHS Foundation Trust, London, UK. Electronic address: david.cunningham@rmh.nhs.uk.
David
D
Cunningham
Medical Research Council Clinical Trials Unit, University College London, London, UK.
Sally P
SP
Stenning
Department of Oncology, Royal Marsden NHS Foundation Trust, London, UK.
Elizabeth C
EC
Smyth
Department of Oncology, Royal Marsden NHS Foundation Trust, London, UK.
Alicia F
AF
Okines
Department of Oncology, Royal Marsden NHS Foundation Trust, London, UK; Department of Surgery, Royal Marsden NHS Foundation Trust, London, UK.
William H
WH
Allum
Medical Research Council Clinical Trials Unit, University College London, London, UK.
Sam
S
Rowley
Medical Research Council Clinical Trials Unit, University College London, London, UK.
Laura
L
Stevenson
Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands.
Heike I
HI
Grabsch
Department of Surgery, Queen Elizabeth Hospital, Birmingham, UK.
Derek
D
Alderson
Department of Clinical Oncology, Velindre Hospital, Cardiff, UK.
Thomas
T
Crosby
Northern Oesophagogastric Cancer Unit, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK.
S Michael
SM
Griffin
Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
Wasat
W
Mansoor
Department of Oncology, Newcastle Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK.
Fareeda Y
FY
Coxon
Department of Oncology, Bristol Haematology and Oncology Centre, Bristol, UK.
Stephen J
SJ
Falk
Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK.
Suzanne
S
Darby
Department of Oncology, Freeman Hospital, Newcastle-upon-Tyne, UK.
Kate A
KA
Sumpter
Centre for Surgical Research, School of Social and Community Medicine, University of Bristol, Bristol, UK.
Jane M
JM
Blazeby
Medical Research Council Clinical Trials Unit, University College London, London, UK.
Ruth E
RE
Langley
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D000069287:Capecitabine / Q000008:administration & dosage; D016022:Case-Control Studies; D002945:Cisplatin / Q000008:administration & dosage; D015251:Epirubicin / Q000008:administration & dosage; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D004943:Esophagogastric Junction / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D019990:Perioperative Care; D011379:Prognosis; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D015996:Survival Rate
D000068258:Bevacizumab; D015251:Epirubicin; D000069287:Capecitabine; D002945:Cisplatin