title: Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial.
abstract: BACKGROUND
  The international standard of care for women with suspected advanced ovarian cancer is surgical debulking followed by platinum-based chemotherapy. We aimed to establish whether use of platinum-based primary chemotherapy followed by delayed surgery was an effective and safe alternative treatment regimen.
  
  
  METHODS
  In this phase 3, non-inferiority, randomised, controlled trial (CHORUS) undertaken in 87 hospitals in the UK and New Zealand, we enrolled women with suspected stage III or IV ovarian cancer. We randomly assigned women (1:1) either to undergo primary surgery followed by six cycles of chemotherapy, or to three cycles of primary chemotherapy, then surgery, followed by three more cycles of completion chemotherapy. Each 3-week cycle consisted of carboplatin AUC5 or AUC6 plus paclitaxel 175 mg/m(2), or an alternative carboplatin combination regimen, or carboplatin monotherapy. We did the random assignment by use of a minimisation method with a random element, and stratified participants according to the randomising centre, largest radiological tumour size, clinical stage, and prespecified chemotherapy regimen. Patients and investigators were not masked to group assignment. The primary outcome measure was overall survival. Primary analyses were done in the intention-to-treat population. To establish non-inferiority, the upper bound of a one-sided 90% CI for the hazard ratio (HR) had to be less than 1.18. This trial is registered, number ISRCTN74802813, and is closed to new participants.
  
  
  RESULTS
  Between March 1, 2004, and Aug 30, 2010, we randomly assigned 552 women to treatment. Of the 550 women who were eligible, 276 were assigned to primary surgery and 274 to primary chemotherapy. All were included in the intention-to-treat analysis; 251 assigned to primary surgery and 253 to primary chemotherapy were included in the per-protocol analysis. As of May 31, 2014, 451 deaths had occurred: 231 in the primary-surgery group versus 220 in the primary-chemotherapy group. Median overall survival was 22.6 months in the primary-surgery group versus 24.1 months in primary chemotherapy. The HR for death was 0.87 in favour of primary chemotherapy, with the upper bound of the one-sided 90% CI 0.98 (95% CI 0.72-1.05). Grade 3 or 4 postoperative adverse events and deaths within 28 days after surgery were more common in the primary-surgery group than in the primary-chemotherapy group (60 [24%] of 252 women vs 30 [14%] of 209, p=0.0007, and 14 women [6%] vs 1 woman [<1%], p=0.001). The most common grade 3 or 4 postoperative adverse event was haemorrhage in both groups (8 women [3%] in the primary-surgery group vs 14 [6%] in the primary-chemotherapy group). 110 (49%) of 225 women receiving primary surgery and 102 (40%) of 253 receiving primary chemotherapy had a grade 3 or 4 chemotherapy related toxic effect (p=0.0654), mostly uncomplicated neutropenia (20% and 16%, respectively). One fatal toxic effect, neutropenic sepsis, occurred in the primary-chemotherapy group.
  
  
  CONCLUSIONS
  In women with stage III or IV ovarian cancer, survival with primary chemotherapy is non-inferior to primary surgery. In this study population, giving primary chemotherapy before surgery is an acceptable standard of care for women with advanced ovarian cancer.
  
  
  BACKGROUND
  Cancer Research UK and the Royal College of Obstetricians and Gynaecologists.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Sean
authors.initials: S
authors.lastname: Kehoe
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, London, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Hook
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, London, UK. Electronic address: m.nankivell@ucl.ac.uk.
authors.forename: Matthew
authors.initials: M
authors.lastname: Nankivell
authors.affiliation: Department of Medical Oncology, Christie Hospital and University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Jayson
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Kitchener
authors.affiliation: Royal Cornwall NHS Trust, Truro, UK.
authors.forename: Tito
authors.initials: T
authors.lastname: Lopes
authors.affiliation: Pan-Birmingham Gynaecological Cancer Centre, City Hospital, Birmingham, UK.
authors.forename: David
authors.initials: D
authors.lastname: Luesley
authors.affiliation: St James's Institute of Oncology, St James's University Hospital, Leeds, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Perren
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, London, UK.
authors.forename: Selina
authors.initials: S
authors.lastname: Bannoo
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, London, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Mascarenhas
authors.affiliation: Department of Gynaecological Oncology, Belfast City Hospital, Belfast, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Dobbs
authors.affiliation: St Lukes Cancer Centre, Royal Surrey County Hospital, Guildford, UK.
authors.forename: Sharadah
authors.initials: S
authors.lastname: Essapen
authors.affiliation: James Cook University Hospital, Middlesbrough, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Twigg
authors.affiliation: Department of Gynaecology, Liverpool Women's Hospital, Liverpool, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Herod
authors.affiliation: Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK.
authors.forename: Glenn
authors.initials: G
authors.lastname: McCluggage
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, London, UK.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Parmar
authors.affiliation: Medical Research Council Clinical Trials Unit, University College London, London, UK; Department of Medicine, University of East Anglia, Norwich, UK.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Swart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D061646:Operative Time; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery*; D017239:Paclitaxel / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D016190:Carboplatin; D017239:Paclitaxel