Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial

Background Carboplatin plus paclitaxel administered every 3 weeks is standard first-line chemotherapy for patients with advanced ovarian cancer. A weekly paclitaxel schedule combined with carboplatin every 3 weeks prolonged progression- free survival and overall survival in a Japanese phase 3 trial. The aim of our study was to assess whether a weekly schedule of carboplatin plus paclitaxel is more eff ective than the same drugs given every 3 weeks. Methods We did a multicentre, randomised, phase 3 study at 67 institutions in Italy and France. Women with FIGO stage IC- IV ovarian cancer, an ECOG performance status of 2 or lower, and who had never received chemotherapy were randomly allocated in a 1: 1 ratio to receive either carboplatin (AUC 6 mg/ mL per min) plus paclitaxel (175 mg/m(2)) every 3 weeks for six cycles or carboplatin (AUC 2 mg/ mL per min) plus paclitaxel (60 mg/m(2)) every week for 18 weeks. Randomisation was done by computer-based minimisation, stratified by centre, residual disease after surgery, and ECOG performance status. The study was not blinded. Coprimary endpoints were progression-free survival and quality of life (assessed by the Functional Assessment of Cancer Therapy Ovarian Trial Outcome Index [FACT- O/TOI] score), and analysis was by modified intention to treat. This report presents the final analysis. The study is registered with ClinicalTrials.gov, number NCT00660842. Findings 822 patients were enrolled into the study between Nov 20, 2008, and March 1, 2012; 12 withdrew their consent immediately after randomisation and were excluded, and 810 were eligible for analysis. 404 women were allocated treatment every 3 weeks and 406 were assigned to the weekly schedule. After median follow-up of 22 . 3 months (IQR 16 . 2-30 . 9), 449 progression-free survival events were recorded. Median progression-free survival was 17 . 3 months (95% CI 15 . 2-20 . 2) in patients assigned to treatment every 3 weeks, versus 18 . 3 months (16 . 8-20 . 9) in women allocated to the weekly schedule (hazard ratio 0 . 96, 95% CI 0 . 80-1 . 16; p= 0 . 66). FACT-O/ TOI scores differed significantly between the two schedules (treatment-by-time interaction p< 0.0001); with treatment every 3 weeks, FACT-O/ TOI scores worsened at every cycle (weeks 1, 4, and 7), whereas for the weekly schedule, after transient worsening at week 1, FACT-O/ TOI scores remained stable. Fewer patients assigned to the weekly group than those allocated treatment every 3 weeks had grade 3-4 neutropenia (167 [42%] of 399 patients vs 200 [50%] of 400 patients), febrile neutropenia (two [0 . 5%] vs 11 [3%]), grade 3-4 thrombocytopenia (four [1%] vs 27 [7%]), and grade 2 or worse neuropathy (24 [6%] vs 68 [17%]). Three deaths during the study were attributed to chemotherapy; two women died who were allocated treatment every 3 weeks and one death was recorded in the group assigned the weekly regimen. Interpretation A weekly regimen of carboplatin and paclitaxel might be a reasonable option for first-line treatment of women with advanced ovarian cancer.