Summary Background Risk of relapse or progression remains high in the treatment of most patients with epithelial ovarian cancer, and development of a molecular predictor could be a valuable tool for ...stratification of patients by risk. We aimed to develop a microRNA (miRNA)-based molecular classifier that can predict risk of progression or relapse in patients with epithelial ovarian cancer. Methods We analysed miRNA expression profiles in three cohorts of samples collected at diagnosis. We used 179 samples from a Multicenter Italian Trial in Ovarian cancer trial (cohort OC179) to develop the model and 263 samples from two cancer centres (cohort OC263) and 452 samples from The Cancer Genome Atlas epithelial ovarian cancer series (cohort OC452) to validate the model. The primary clinical endpoint was progression-free survival, and we adapted a semi-supervised prediction method to the miRNA expression profile of OC179 to identify miRNAs that predict risk of progression. We assessed the independent prognostic role of the model using multivariable analysis with a Cox regression model. Findings We identified 35 miRNAs that predicted risk of progression or relapse and used them to create a prognostic model, the 35-miRNA-based predictor of Risk of Ovarian Cancer Relapse or progression (MiROvaR). MiROvaR was able to classify patients in OC179 into a high-risk group (89 patients; median progression-free survival 18 months 95% CI 15–22) and a low-risk group (90 patients; median progression-free survival 38 months 24–not estimable; hazard ratio HR 1·85 1·29–2·64, p=0·00082). MiROvaR was a significant predictor of progression in the two validation sets (OC263 HR 3·16, 95% CI 2·33–4·29, p<0·0001; OC452 HR 1·39, 95% CI 1·11–1·74, p=0·0047) and maintained its independent prognostic effect when adjusted for relevant clinical covariates using multivariable analyses (OC179: adjusted HR 1·48, 95% CI 1·03–2·13, p=0·036; OC263: adjusted HR 3·09 2·24–4·28, p<0·0001; and OC452: HR 1·41 1·11–1·79, p=0·0047). Interpretation MiROvaR is a potential predictor of epithelial ovarian cancer progression and has prognostic value independent of relevant clinical covariates. MiROvaR warrants further investigation for the development of a clinical-grade prognostic assay. Funding AIRC and CARIPLO Foundation.
Summary Background Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and ...fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. Methods In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB–IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m2 ) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2–21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT01015118. Findings Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months 95% CI 16·6–19·9 vs 16·6 months 13·9–19·1; hazard ratio 0·84 95% CI 0·72–0·98; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 21% of 902 grade 3 and three <1% grade 4 vs placebo group nine 2% of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 20% grade 3 and 200 (22%) grade 4 vs placebo group 90 20% grade 3 and 72 16% grade 4; thrombocytopenia: 105 12% and 55 6% vs 21 5% and eight 2%; anaemia: 108 12% and 13 1% vs 26 6% and five 1%). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). Interpretation Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. Funding Boehringer Ingelheim.
Summary Background Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib is an anti-angiogenic drug active in ovarian cancer. We assessed the effect of adding ...pazopanib to paclitaxel for patients with platinum-resistant or platinum-refractory advanced ovarian cancer. Methods We did this open-label, randomised phase 2 trial at 11 hospitals in Italy. We included patients with platinum-resistant or platinum-refractory ovarian cancer previously treated with a maximum of two lines of chemotherapy, Eastern Cooperative Oncology Group performance status 0–1, and no residual peripheral neurotoxicity. Patients were randomly assigned (1:1) to receive weekly paclitaxel 80 mg/m2 with or without pazopanib 800 mg daily, and stratified by centre, number of previous lines of chemotherapy, and platinum-free interval status. The primary endpoint was progression-free survival, assessed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT01644825 . This report is the final analysis; the trial is completed. Findings Between Dec 15, 2010, and Feb 8, 2013, we enrolled 74 patients: 37 were randomly assigned to receive paclitaxel and pazopanib and 37 were randomly assigned to receive paclitaxel only. One patient, in the paclitaxel only group, withdrew from the study and was excluded from analyses. Median follow-up was 16·1 months (IQR 12·5–20·8). Progression-free survival was significantly longer in the pazopanib plus paclitaxel group than in the paclitaxel only group (median 6·35 months 95% CI 5·36–11·02 vs 3·49 months 2·01–5·66; hazard ratio 0·42 95% CI 0·25–0·69; p=0·0002). We recorded no unexpected toxic effects or deaths from toxic effects. Adverse events were more common in the pazopanib and paclitaxel group than in the paclitaxel only group. The most common grade 3–4 adverse events were neutropenia (11 30% in the pazopanib group vs one 3% in the paclitaxel group), fatigue (four 11% vs two 6%), leucopenia (four 11% vs one 3%), hypertension (three 8% vs none 0%), raised aspartate aminotransferase or alanine aminotransferase (three 8% vs none), and anaemia (two 5% vs five 14%). One patient in the pazopanib group had ileal perforation. Interpretation Our findings suggest that a phase 3 study of the combination of weekly paclitaxel plus pazopanib for patients with platinum-resistant or platinum-refractory advanced ovarian cancer is warranted. Funding National Cancer Institute of Napoli and GlaxoSmithKline.
Summary 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 effective 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/m2 ) every 3 weeks for six cycles or carboplatin (AUC 2 mg/mL per min) plus paclitaxel (60 mg/m2 ) 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. Funding None.
