title: Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial.
abstract: BACKGROUND
  The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to standard chemotherapy, with the greatest effect in patients at high risk of disease progression. We report the final overall survival results of the trial.
  
  
  METHODS
  ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I-IIa, grade 3 or clear cell histology) or more advanced disease (FIGO stage IIb-IV), with an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of intravenous carboplatin [AUC 5 or 6] and paclitaxel 175 mg/m(2) of body surface area) or the same chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks, given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary endpoint was progression-free survival; the study was also powered to detect a difference in overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375.
  
  
  RESULTS
  Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the end of the trial on March 31, 2013, was 48·9 months (IQR 26·6-56·2), at which point 714 patients had died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed evidence of non-proportional hazards, so we used the difference in restricted mean survival time as the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted mean survival time 44·6 months [95% CI 43·2-45·9] in the standard chemotherapy group vs 45·5 months [44·2-46·7] in the bevacizumab group; log-rank p=0·85). In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone (restricted mean survival time 34·5 months [95% CI 32·0-37·0] with standard chemotherapy vs 39·3 months [37·0-41·7] with bevacizumab; log-rank p=0·03). However, in non-high-risk patients, the restricted mean survival time did not differ significantly between the two treatment groups (49·7 months [95% CI 48·3-51·1]) in the standard chemotherapy group vs 48·4 months [47·0-49·9] in the bevacizumab group; p=0·20). An updated analysis of progression-free survival showed no difference between treatment groups. During extended follow-up, one further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with standard chemotherapy) were reported.
  
  
  CONCLUSIONS
  Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer.
  
  
  BACKGROUND
  The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK. Electronic address: adrian.cook@ucl.ac.uk.
authors.forename: Adrian D
authors.initials: AD
authors.lastname: Cook
authors.affiliation: Gynecologic Oncology Center, AGO Study Group, Kiel, Germany.
authors.forename: Jacobus
authors.initials: J
authors.lastname: Pfisterer
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Embleton
authors.affiliation: Cancer Clinical Trials Unit, University College London Hospital, London, UK.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ledermann
authors.affiliation: AP-HP, Site Hôtel-Dieu, Université Paris Descartes, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Pujade-Lauraine
authors.affiliation: Department of Gynaecologic Oncology and Institute for Cancer Genetics and Informatics, Oslo University Hospital, Institute for Clinical Medicine, Oslo University, Norway.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kristensen
authors.affiliation: University of British Columbia, Vancouver, Canada.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Carey
authors.affiliation: Concord Hospital, Sydney, NSW, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Beale
authors.affiliation: Department of Haematology and Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Cervantes
authors.affiliation: Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany.
authors.forename: Tjoung-Won
authors.initials: TW
authors.lastname: Park-Simon
authors.affiliation: Mount Vernon Hospital, London, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Rustin
authors.affiliation: Centre François Baclesse, Caen, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Joly
authors.affiliation: Department of Oncology, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Mansoor R
authors.initials: MR
authors.lastname: Mirza
authors.affiliation: Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Plante
authors.affiliation: Royal Women's Hospital, Melbourne, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Quinn
authors.affiliation: Fundación Instituto Valenciano de Oncología, Valencia, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Poveda
authors.affiliation: Institute of Cancer Sciences and Christie Hospital, University of Manchester, Manchester, UK.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Jayson
authors.affiliation: St James Institute of Oncology, St James University Hospital, Leeds, UK.
authors.forename: Dan
authors.initials: D
authors.lastname: Stark
authors.affiliation: Norwich Clinical Trials Unit, University of East Anglia, Norwich, UK.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Swart
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Farrelly
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Kaplan
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Mahesh K B
authors.initials: MK
authors.lastname: Parmar
authors.affiliation: St James Institute of Oncology, St James University Hospital, Leeds, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Perren
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001315:Australia; D000068258:Bevacizumab; D002170:Canada; D016190:Carboplatin / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D057194:Intention to Treat Analysis; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009520:New Zealand; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D016190:Carboplatin; D017239:Paclitaxel