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Background: Although most patients with epithelial ovarian cancer respond to frontline platinum-based chemotherapy, around 70% will relapse within 3 years. The phase 3 JAVELIN Ovarian 100 trial compared avelumab (anti-PD-L1 monoclonal antibody) in combination with chemotherapy followed by avelumab maintenance, or chemotherapy followed by avelumab maintenance, versus chemotherapy alone in patients with treatment-naive epithelial ovarian cancer., Methods: JAVELIN Ovarian 100 was a global, open-label, three-arm, parallel, randomised, phase 3 trial run at 159 hospitals and cancer treatment centres in 25 countries. Eligible women were aged 18 years and older with stage III-IV epithelial ovarian, fallopian tube, or peritoneal cancer (following debulking surgery, or candidates for neoadjuvant chemotherapy), and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to receive chemotherapy (six cycles; carboplatin dosed at an area under the serum-concentration-time curve of 5 or 6 intravenously every 3 weeks plus paclitaxel 175 mg/m 2 every 3 weeks or 80 mg/m 2 once a week [investigators' choice]) followed by avelumab maintenance (10 mg/kg intravenously every 2 weeks; avelumab maintenance group); chemotherapy plus avelumab (10 mg/kg intravenously every 3 weeks) followed by avelumab maintenance (avelumab combination group); or chemotherapy followed by observation (control group). Randomisation was in permuted blocks of size six and stratified by paclitaxel regimen and resection status. Patients and investigators were masked to assignment to the two chemotherapy groups without avelumab at the time of randomisation until completion of the chemotherapy phase. The primary endpoint was progression-free survival assessed by blinded independent central review in all randomly assigned patients (analysed by intention to treat). Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02718417. The trial was fully enrolled and terminated at interim analysis due to futility, and efficacy is no longer being assessed., Findings: Between May 19, 2016 and Jan 23, 2018, 998 patients were randomly assigned (avelumab maintenance n=332, avelumab combination n=331, and control n=335). At the planned interim analysis (data cutoff Sept 7, 2018), prespecified futility boundaries were crossed for the progression-free survival analysis, and the trial was stopped as recommended by the independent data monitoring committee and endorsed by the protocol steering committee. Median follow-up for progression-free survival for all patients was 10·8 months (IQR 7·1-14·9); 11·1 months (7·0-15·3) for the avelumab maintenance group, 11·0 months (7·4-14·5) for the avelumab combination group, and 10·2 months (6·7-14·0) for the control group. Median progression-free survival was 16·8 months (95% CI 13·5-not estimable [NE]) with avelumab maintenance, 18·1 months (14·8-NE) with avelumab combination treatment, and NE (18·2 months-NE) with control treatment. The stratified hazard ratio for progression-free survival was 1·43 (95% CI 1·05-1·95; one-sided p=0·99) with the avelumab maintenance regimen and 1·14 (0·83-1·56; one-sided p=0·79) with the avelumab combination regimen, versus control treatment. The most common grade 3-4 adverse events were anaemia (69 [21%] patients in the avelumab maintenance group, 63 [19%] in the avelumab combination group, and 53 [16%] in the control group), neutropenia (91 [28%], 99 [30%], and 88 [26%]), and neutrophil count decrease (49 [15%], 45 [14%], and 59 [18%]). Serious adverse events of any grade occurred in 92 (28%) patients in the avelumab maintenance group, 118 (36%) in the avelumab combination group, and 64 (19%) in the control group. Treatment-related deaths occurred in one (<1%) patient in the avelumab maintenance group (due to atrial fibrillation) and one (<1%) patient in the avelumab combination group (due to disease progression)., Interpretation: Although no new safety signals were observed, results do not support the use of avelumab in the frontline treatment setting. Alternative treatment regimens are needed to improve outcomes in patients with advanced epithelial ovarian cancer., Funding: Pfizer and Merck KGaA, Darmstadt, Germany., Competing Interests: Declaration of interests BJM reports receiving honoraria from and serving as a consultant or advisor for Agenus, Akeso, Aravive, AstraZeneca, Clovis Oncology, Eisai, Elevar Therapeutics, Genmab and Seattle Genetics, GOG Foundation, Gradalis, ImmunoGen, Karyopharm Therapeutics, Iovance Biotherapeutics, Merck & Co, US Oncology Network (owned by McKesson), Mersana Therapeutics, Novocure, Myriad Genetics, Pfizer, Puma Biotechnology, Genentech (subsidiary of Roche), Sorrento Therapeutics, Tesaro (owned by GlaxoSmithKline), and VBL Therapeutics. NC reports receiving honoraria from and serving as a consultant or advisor for Amgen, AstraZeneca, Clovis Oncology, GlaxoSmithKline, Pfizer, Roche, and Tesaro; receiving honoraria from Novartis; serving as a consultant or advisor for Advaxis, BioCad, ImmunoGen, OncXerna, Merck Sharp & Dohme, and Takeda; and participating on a data safety monitoring board or advisory board for Advaxis, Amgen, AstraZeneca, BioCad, Clovis Oncology, GlaxoSmithKline, ImmunoGen, Merck Sharp & Dohme, OncXerna, Pfizer, Roche, Takeda, and Tesaro. KF reports receiving research funding and reimbursement for travel, accommodation, and expenses from Pfizer. MJB reports participating on a data safety monitoring board or advisory board for AstraZeneca, Clovis Oncology, GlaxoSmithKline, OncoQuest, and VBL Therapeutics. LR reports receiving honoraria from AstraZeneca, GlaxoSmithKline, and Merck & Co; serving as a consultant or advisor for Agenus, Akeso Bio, AstraZeneca, Clovis Oncology, EMD Serono, GlaxoSmithKline, Genentech, Intuitive Surgical, Myriad, Novartis, and Rubius; and having received institutional research grants from Akeso Biopharma, AstraZeneca, Genentech, GOG Foundation, GlaxoSmithKline, Incyte, Karyopharm, Merck & Co, Mersana Therapeutics, On Target Laboratories, and Seagen. GS reports receiving honoraria from Clovis Oncology; serving as a consultant or advisor for Johnson & Johnson and Tesaro; and having received research funding from Merck Sharp & Dohme. JS has received institutional research funding from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Sanofi. KY reports receiving honoraria from AstraZeneca, Chugai Pharma, Eisai, Novartis, Pfizer, and Takeda; and serving as a consultant or advisor for AstraZeneca, Chugai Pharma, Eisai, Novartis, Ono Pharmaceutical, and Takeda. RAS reports employment at Pfizer at the time the study was done and owns stock in Pfizer. XZ reports employment at and owns stock in Pfizer. JPS reports employment at and owns stock in Pfizer. CL reports employment at Pfizer and owns stock in Eli Lilly and Pfizer. JAL reports receiving honoraria from AstraZeneca, GlaxoSmithKline, and Pfizer; and is the vice president of the European Society of Gynaecological Oncology and an editor of the gynaecological clinical practice guidelines for the European Society for Medical Oncology. AMO, EVP, YVS, MCL, and SMB declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer., Methods: JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m 2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints., Findings: Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6-21·9) for the combination group, 17·4 months (15·2-21·3) for the PLD group, and 18·2 months (15·8-21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3-5·1) in the combination group, 3·5 months (2·1-4·0) in the PLD group, and 1·9 months (1·8-1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 [repeated 93·1% CI 0·59-1·24], one-sided p=0·030; avelumab vs PLD: 1·68 [1·32-2·60], one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7-18·7) in the combination group, 13·1 months (11·8-15·5) in the PLD group, and 11·8 months (8·9-14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 [repeated 88·85% CI 0·74-1·24], one-sided p=0·21; avelumab vs PLD: 1·14 [0·95-1·58], one-sided p=0·83]). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combination group vs nine [5%] in the PLD group vs none in the avelumab group), rash (11 [6%] vs three [2%] vs none), fatigue (ten [5%] vs three [2%] vs none), stomatitis (ten [5%] vs five [3%] vs none), anaemia (six [3%] vs nine [5%] vs three [2%]), neutropenia (nine [5%] vs nine [5%] vs none), and neutrophil count decreased (eight [5%] vs seven [4%] vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction)., Interpretation: Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer., Funding: Pfizer and Merck KGaA, Darmstadt, Germany., Competing Interests: Declaration of interests EP-L reports personal fees from AstraZeneca, Clovis Oncology, Incyte, Pfizer, Roche, and Tesaro; non-financial support from AstraZeneca, Roche, and Tesaro; and is the chair of ARCAGY-Research. KF reports grants and personal fees from Pfizer during the conduct of the study; and grants and personal fees from AstraZeneca, Chugai Pharma, Eisai, Genmab, Merck & Co, Taiho Pharmaceutical, and Zeria Pharmaceutical; grants from GSK, Immunogen, Lilly, OncoTherapy, and Regeneron; and personal fees from Daiichi Sankyo, Janssen, Kyowa Hakko Kirin, Mochida, Nippon Kayaku, and Novartis outside the submitted work. JAL reports serving as a consultant or advisor for Artios Pharma, AstraZeneca, Clovis Oncology, Eisai, GSK, Merck & Co, and Pfizer; has received research funding from AstraZeneca and Merck & Co; has received honoraria from AstraZeneca, Clovis Oncology, Eisai, and GSK; and has participated in an independent monitoring committee for Regeneron. RK reports personal fees from Clovis Oncology, Eisai, GSK, Incyte, and Roche; has received non-financial support from GSK; and grants from Merck & Co. I-LR-C reports personal fees from AstraZeneca, Clovis Oncology, GSK, Merck KGaA, Mersana Therapeutics, and Roche; received grants from Bristol Myers Squibb and GSK; and has received reimbursement for travel and accommodation expenses from AstraZeneca and GSK. KY reports serving as a consultant or advisor for AstraZeneca, Chugai Pharma, Eisai, Novartis, and Takeda; and received honoraria from AstraZeneca, Eisai, Pfizer, Takeda, and Taiho Pharmaceutical. SB reports personal fees from AstraZeneca, Clovis Oncology, Genmab, Immunogen, Merck KGaA, Mersana Therapeutics, Pfizer, Roche, and Tesaro; and has received grants from AstraZeneca, GSK, Merck & Co, and Tesaro. AL reports grants from Pfizer during the conduct of the study; serving as a consultant or advisor for AstraZeneca, BIOCAD, Clovis Oncology, GSK/Tesaro, Merck KGaA, Merck & Co, and Zentalis Pharmaceuticals; and has received reimbursement for travel and accommodation expenses from AstraZeneca, Clovis Oncology, and GSK/Tesaro. AVT has received honoraria and grants from AstraZeneca. KHJ reports personal fees from AstraZeneca, Celgene, Novartis, Roche, and Takeda Pharmaceuticals. FZ reports employment at and holds stock in Pfizer. RAS reports employment at Pfizer at the time when the study was conducted. CW reports employment at and holds stock in Pfizer. SSD reports employment at Pfizer. BJM reports serving as a consultant or advisor for and has received honoraria from Agenus, Akeso Bio, Aravive, AstraZeneca, Clovis Oncology, Eisai, Elevar Therapeutics, Genmab/Seattle Genetics, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Merck & Co, Mersana Therapeutics, Myriad Pharma, Novocure, Pfizer, Puma Biotechnology, Roche/Genentech, Tesaro/GSK, and VBL Therapeutics; is a member of a speakers' bureau for AstraZeneca, Clovis Oncology, Eisai, Merck & Co, Roche/Genentech, and Tesaro/GSK; and reports employment at McKesson/US Oncology. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The ICON8 study reported no significant improvement in progression-free survival (a primary endpoint) with weekly chemotherapy compared with standard 3-weekly treatment among patients with epithelial ovarian cancer. All ICON8 patients were eligible to take part in the accompanying health-related quality-of-life study, which measured the effect of treatment on self-reported wellbeing, reported here., Methods: In this open-label, randomised, controlled, phase 3, three-arm, Gynecologic Cancer Intergroup (GCIG) trial done at 117 hospital sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland, women (aged at least 18 years) with newly diagnosed, histologically confirmed International Federation of Gynecology and Obstetrics stage IC-IV ovarian cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1:1) centrally using minimisation to group 1 (intravenous carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m 2 intravenous paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m 2 paclitaxel weekly), or group 3 (carboplatin AUC2 weekly and 80 mg/m 2 paclitaxel weekly). Randomisation was stratified by GCIG group, disease stage, and outcome and timing of surgery. Patients and clinicians were not masked to treatment assignment. Patients underwent immediate or delayed primary surgery according to clinicians' choice. Patients were asked to complete European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 questionnaires at enrolment, before each chemotherapy cycle, then 6-weekly up to 9 months, 3-monthly up to 2 years, and 6-monthly up to 5 years. Quality of life was a prespecified secondary outcome of the ICON8 study. Within the quality-of-life study, the co-primary endpoints were QLQ-C30 global health score at 9 months (cross-sectional analysis) and mean QLQ-C30 global health score from randomisation to 9 months (longitudinal analysis). Data analyses were done on an intention-to-treat basis. The trial is registered on ClinicalTrials.gov, NCT01654146 and ISRCTN Registry, ISRCTN10356387, and is currently in long-term follow up., Findings: Between June 6, 2011, and Nov 28, 2014, 1566 patients were recruited into ICON8 (522 were included in group 1, 523 in group 2, and 521 in group 3). Baseline quality-of-life questionnaires were completed by 1438 (92%) of 1566 patients and 9-month questionnaires by 882 (69%) of 1280 patients. We observed no significant difference in global health score at 9 months (cross-sectional analysis) between study groups (group 2 vs group 1, difference in mean score 2·3, 95% CI -0·4 to 4·9, p=0·095; group 3 vs group 1, -0·8, -3·8 to 2·2, p=0·61). Using longitudinal analysis, we found lower global health scores for those receiving weekly paclitaxel than for those receiving 3-weekly chemotherapy (group 2 vs group 1, mean difference -1·8, 95% CI -3·6 to -0·1, p=0·043; group 3 vs group 1, -2·9, -4·7 to -1·1, p=0·0018)., Interpretation: We found no evidence of a difference in global quality of life between treatment groups at 9 months; however, patients receiving weekly treatment reported lower mean quality of life across the 9-month period after randomisation. Taken together with the lack of progression-free survival benefit, these findings do not support routine use of weekly paclitaxel-containing regimens in the management of newly diagnosed ovarian cancer., Funding: Cancer Research UK, Medical Research Council, Health Research Board Ireland, Irish Cancer Society, and Cancer Australia., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer., Methods: In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m 2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m 2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m 2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3)., Findings: Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m 2 in group 1; 1233 mg/m 2 in group 2; 1274 mg/m 2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0-26·0] in group 1, 24·9 months [24·0-25·9] in group 2, 25·3 months [23·9-26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6-not reached] in group 1, 20·8 months [11·9-59·0] in group 2, 21·0 months [12·0-54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups., Interpretation: Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations., Funding: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: In the randomized phase 3 ICON7 trial (ISRCTN91273375), adding bevacizumab to chemotherapy for newly diagnosed ovarian cancer significantly improved progression-free survival (PFS; primary endpoint) but not overall survival (OS; secondary endpoint) in the intent-to-treat (ITT) population. We explored treatment effect according to stage and extent of residual disease., Methods: Patients with stage IIB-IV or high-risk (grade 3/clear-cell) stage I-IIA ovarian cancer were randomized to receive six cycles of carboplatin and paclitaxel either alone or with bevacizumab 7.5 mg/kg every 3 weeks followed by single-agent bevacizumab for 12 further cycles (total duration 12 months). Post hoc exploratory analyses of subgroups defined by stage and extent of residual disease at diagnosis within the stage IIIB-IV population (European indication) was performed., Results: The PFS benefit from bevacizumab was seen consistently in all subgroups explored. The PFS hazard ratio was 0.77 (95% confidence interval [CI], 0.59-0.99) in 411 patients with stage IIIB-IV ovarian cancer with no visible residuum and 0.81 (95% CI, 0.69-0.95) in 749 patients with stage IIIB-IV disease and visible residuum. As in the ITT population, no OS difference was detected in any subgroup except the previously described 'high-risk' subgroup. Safety results in analyzed subgroups were consistent with the overall population., Conclusions: Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease. In patients with stage III with >1 cm residuum, stage IV or inoperable disease, this translates into an OS benefit. No OS benefit or detriment was seen in other subgroups explored., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although women with endometrial cancer generally have a favourable prognosis, those with high-risk disease features are at increased risk of recurrence. The PORTEC-3 trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer., Methods: PORTEC-3 was an open-label, international, randomised, phase 3 trial involving 103 centres in six clinical trials collaborating in the Gynaecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both), endometrioid-type stage II or III, or stage I to III with serous or clear cell histology. Women were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m 2 given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m 2 ) using a biased-coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The co-primary endpoints were overall survival and failure-free survival. We used the Kaplan-Meier method, log-rank test, and Cox regression analysis for final analysis by intention to treat and adjusted for stratification factors. The study was closed on Dec 20, 2013, after achieving complete accrual; follow-up is ongoing. PORTEC-3 is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138., Results: 686 women were enrolled between Nov 23, 2006, and Dec 20, 2013. 660 eligible patients were included in the final analysis, of whom 330 were assigned to chemoradiotherapy and 330 were assigned to radiotherapy. Median follow-up was 60·2 months (IQR 48·1-73·1). 5-year overall survival was 81·8% (95% CI 77·5-86·2) with chemoradiotherapy versus 76·7% (72·1-81·6) with radiotherapy (adjusted hazard ratio [HR] 0·76, 95% CI 0·54-1·06; p=0·11); 5-year failure-free survival was 75·5% (95% CI 70·3-79·9) versus 68·6% (63·1-73·4; HR 0·71, 95% CI 0·53-0·95; p=0·022). Grade 3 or worse adverse events during treatment occurred in 198 (60%) of 330 who received chemoradiotherapy versus 41 (12%) of 330 patients who received radiotherapy (p<0·0001). Neuropathy (grade 2 or worse) persisted significantly more often after chemoradiotherapy than after radiotherapy (20 [8%] women vs one [1%] at 3 years; p<0·0001). Most deaths were due to endometrial cancer; in four patients (two in each group), the cause of death was uncertain. One death in the radiotherapy group was due to either disease progression or late treatment complications; three deaths (two in the chemoradiotherapy group and one in the radiotherapy group) were due to either intercurrent disease or late treatment-related toxicity., Interpretation: Adjuvant chemotherapy given during and after radiotherapy for high-risk endometrial cancer did not improve 5-year overall survival, although it did increase failure-free survival. Women with high-risk endometrial cancer should be individually counselled about this combined treatment. Continued follow-up is needed to evaluate long-term survival., Funding: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Project Grant and Cancer Australia, L'Agenzia Italiana del Farmaco, and Canadian Cancer Society Research Institute., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC-BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The ICON6 trial showed that cediranib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, improved clinical outcomes for patients with platinum-sensitive relapsed ovarian cancer when it was used with chemotherapy and was continued as maintenance therapy. This study describes health-related quality of life (QOL) during the first year of treatment., Methods: Four hundred fifty-six women were randomly allocated to receive standard chemotherapy only, chemotherapy with concurrent cediranib, or chemotherapy with cediranib administered concurrently and continued as maintenance. Patients completed QOL questionnaires until disease progression every 3 weeks during chemotherapy and then every 6 weeks to 1 year. Patients alive with disease progression completed a QOL form 1 year after randomization. The primary QOL endpoint was the global score from the Quality of Life Questionnaire Core 30 (of the European Organization for Research and Treatment of Cancer) at 1 year, with the standard chemotherapy group compared with the concurrent-maintenance cediranib group., Results: The rate of questionnaire compliance was 90% at the baseline and 76% at 1 year and was similar across the 3 groups. The mean global QOL score at 1 year was 62.6 points for the standard chemotherapy group and 68.7 points for the concurrent-maintenance group (+4.5; 95% confidence interval, -2.0 to 11.0; P = .18). Sensitivity analyses suggested that this finding was robust to the effect of missing data, and the improvement became statistically significant after adjustments for self-reported diarrhea., Conclusions: The 6th study by the International Collaboration in Ovarian Neoplasm (ICON6) showed a significant improvement in progression-free survival with cediranib as concurrent and maintenance therapy. No QOL detriment with cediranib was found 1 year after treatment was commenced. The maintenance of QOL along with prolonged cancer control suggests that cediranib has a valuable role in the treatment of relapsed ovarian cancer. Cancer 2017;123:2752-61. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., (© 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Objective: To assess the outcome of patients with advanced ovarian cancer (OC) who were treated without surgery, having received upfront chemotherapy and no interval debulking surgery (IDS)., Methods: Retrospective analysis of medical and chemotherapy records of consecutive patients with OC between 2005 and 2013 at UCL Hospitals London, UK who received neoadjuvant chemotherapy (NACT) was then found to be unsuitable for IDS following review by the multidisciplinary team., Results: Eighty-three patients (18%) out of 467 receiving NACT did not undergo IDS. Median age was 70years (range 33-88); out of these 83 patients, 43 (51.8%) presented with stage IV disease. Forty-three of these 83 patients received carboplatin and paclitaxel (CP) (51.8%) and 37 received carboplatin alone (C) (44.6%); 3 patients (3.6%) received other platinum-based combinations. Reasons for not proceeding to surgery were: poor response to chemotherapy after 3-4 cycles of NACT (61/83, 73.5%); comorbidities (12/83, 14.5%); patient decision (4/83, 4.8%). Six patients (7.2%) received <3 cycles of NACT due to a worsening clinical condition. The median overall survival (OS) for patients not undergoing IDS was 18months (95% CI 10-20months). Forty-four of 83 patients (53%) received >2 lines of chemotherapy. In a univariate analysis CP, age <70years, and absence of comorbidities were factors influencing OS. In a multivariate analysis only having received CP remained independently associated with OS (HR 0.49, 95% CI 0.29-0.84)., Conclusions: Chemotherapy alone can provide reasonable disease control in patients unsuitable for IDS and CP should be used if possible., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: About 15% of patients with endometrial cancer have high-risk features and are at increased risk of distant metastases and endometrial cancer-related death. We designed the PORTEC-3 trial to investigate the benefit of adjuvant chemoradiotherapy compared with radiotherapy alone for women with high-risk endometrial cancer., Methods: PORTEC-3 was a multicentre, open-label, randomised, international trial. Women with high-risk endometrial cancer were randomly allocated (1:1) to radiotherapy alone (48·6 Gy) in 1·8 Gy fractions five times a week or chemoradiotherapy (two cycles concurrent cisplatin 50 mg/m(2) and four adjuvant cycles of carboplatin area under the curve [AUC] 5 and paclitaxel 175 mg/m(2)) using a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The primary endpoints of the PORTEC-3 trial were overall survival and failure-free survival analysed in the intention-to-treat population. This analysis focuses on 2-year toxicity and health-related quality of life as secondary endpoints; analysis was done according to treatment received. Health-related quality of life was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) the cervix cancer module and chemotherapy and neuropathy subscales of the ovarian cancer module at baseline, after radiotherapy and at 6, 12, 24, 36, and 60 months after randomisation. Adverse events were graded with Common Terminology Criteria for Adverse Events version 3.0. The study was closed on Dec 20, 2013, after achieving complete accrual, and follow-up remains ongoing for the primary outcomes analysis. This trial is registered with ISRCTN.com, number ISRCTN14387080, and with ClinicalTrials.gov, number NCT00411138., Findings: Between Sept 15, 2006, and Dec 20, 2013, 686 women were randomly allocated in the PORTEC-3 trial. Of these, 660 met eligibility criteria, and 570 (86%) were evaluable for health-related quality of life. Median follow-up was 42·3 months (IQR 25·8-55·1). At completion of radiotherapy and at 6 months, EORTC QLQ-C30 functioning scales were significantly lower (worse functioning) and health-related quality of life symptom scores higher (worse symptoms) for the chemoradiotherapy group compared with radiotherapy alone, improving with time. At 12 and 24 months, global health or quality of life was similar between groups, whereas physical functioning scores remained slightly lower in patients who received chemoradiotherapy compared with patients who received radiotherapy alone. At 24 months, 48 (25%) of 194 patients in the chemoradiotherapy group reported severe tingling or numbness compared with 11 (6%) of 170 patients in the radiotherapy alone group (p<0·0001). Grade 2 or worse adverse events were found during treatment in 309 (94%) of 327 patients in the chemoradiotherapy group versus 145 (44%) of 326 patients in the radiotherapy alone group, and grade 3 or worse events were found in 198 (61%) of 327 patients in the chemoradiotherapy group versus 42 (13%) of 326 patients in the radiotherapy alone group (p<0·0001), with most of the grade 3 adverse events being haematological (45%). At 12 and 24 months, no significant differences in grade 3 or worse adverse events were found between groups; only grade 2 or higher sensory neuropathy adverse events persisted at 24 months (25 [10%] of 240 patients in the chemoradiotherapy group vs one [<1%] of 247 patients in the radiotherapy alone group; p<0·0001)., Interpretation: Despite the increased physician and patient-reported toxicities, this schedule of adjuvant chemotherapy given during and after radiotherapy in patients with high-risk endometrial cancer is feasible, with rapid recovery after treatment, but with persistence of patient-reported sensory neurological symptoms in 25% of patients. We await the analysis of primary endpoints before final conclusions are made., Funding: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and Canadian Cancer Society Research Institute., (Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.)

Background: Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1-3 inhibitor that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer., Methods: In this randomised, three-arm, double-blind, placebo-controlled phase 3 trial, we randomly assigned patients aged 18 years or older with relapsed platinum-sensitive ovarian cancer at 63 centres in Australia, Canada, New Zealand, Spain, and the UK. Participants received up to six cycles of platinum-based chemotherapy (once every 3 weeks) then entered a maintenance phase. Participants were randomly allocated (2:3:3), with five stratification factors and in alternating blocks, to receive placebo alongside chemotherapy and then placebo only maintenance (arm A; reference), cediranib 20 mg once-daily alongside chemotherapy then placebo only maintenance (arm B; concurrent), or cediranib 20 mg once-daily alongside chemotherapy then cediranib 20 mg once-daily maintenance (arm C; maintenance). Patients continued treatment to progression or excessive toxic effects. The primary efficacy endpoint was progression-free survival between arms A and C. Efficacy analysis was by intention to treat. Safety was assessed in all patients who received the allocated study drug. This trial is registered with ClinicalTrials.gov, number NCT00532194; the ISRCTN registry, number ISRCTN68510403; and ANZ Clinical Trials Registry, number ACTRN1261000016003., Findings: We randomly assigned 486 [corrected] women between Nov 13, 2007, and Dec 23, 2011; results presented are for 456 patients randomly assigned subsequent to the 30mg safety phase. During a median of 19·5 months (IQR 14-26) follow-up, 113 (96%) of 118 women assigned to arm A and 141 (86%) of 164 assigned to arm C had disease progression. Median progression-free survival was 11·0 months (95% CI 10·4-11·7) in arm C and 8·7 months (7·7-9·4) in arm A (hazard ratio 0·56, 0·44-0·72, p<0·0001). 156 (90%) of 174 patients in arm B had disease progression, and median progression-free survival was 9·9 months (95% CI 9·4-10·5). Diarrhoea, neutropenia, hypertension, and voice changes were significantly more common, during chemotherapy with cediranib, and diarrhoea, hypothyroidism and voice changes were more common during maintenance. Poor compliance with cediranib was noted during maintenance treatment with toxic effects being the most common cause for discontinuation., Interpretation: Cediranib, when given orally with chemotherapy and continued as maintenance, yielded a meaningful improvement [corrected] in progression-free survival in women with recurrent platinum-sensitive ovarian cancer, albeit with added toxic effects. The positive results in ICON6 could provide women with a new therapeutic option for recurrent ovarian cancer. Assessment of the secondary endpoint of overall survival will need longer follow-up., Funding: Medical Research Council, Cancer Research UK, Canadian Cancer Society Research Institute, Cancer Australia, National Gynecological Cancer Centre, and AstraZeneca., (Copyright © 2016 Ledermann et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

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., Findings: 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., Interpretation: 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., Funding: The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche., (Copyright © 2015 Oza et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Objective: To describe the outcome of primary chemotherapy for women with advanced-stage epithelial ovarian or primary peritoneal cancer and delayed surgery when optimal debulking surgery cannot be achieved at diagnosis., Methods: Between 1998 and 2006, we retrospectively reviewed the overall survival and examined prognostic markers in consecutive patients who were not suitable for initial radical surgery because of the extent of disease and/or poor performance status. They were treated with a policy of primary platinum-based chemotherapy, followed whenever possible in responding patients by debulking surgery., Results: A total of 171 patients received least one cycle of chemotherapy. Eighty-six patients proceeded to surgery and 53 (31% of 171 and 62% of 86) had optimal (<1 cm) residual disease. Eighty-five patients did not undergo surgery because they remained unfit or had not responded sufficiently to chemotherapy. The median overall survival was 18.7 months (95% confidence interval [CI], 16.5-24.2). The median OS in the surgical group for optimal and suboptimal surgery was 40.8 (95% CI, 32.5-50.0) and 22.5 (95% CI, 17.7-37.1) months (P = 0.005). On multivariate analysis, interval surgery and optimal surgery were the only independent prognostic factors (hazard ratios, 0.45 and 0.43, respectively; P = 0.009). In the nonsurgical group, CA125 response was an independent prognostic factor (hazard ratio, 0.34; P = 0.001) with an OS of 21.7 months (95% CI, 14.0-35.4) in women with a normal CA125 after treatment compared with 6.7 (95% CI, 4.5-7.8) months., Conclusions: In one third of the women, the tumor was optimally debulked after primary chemotherapy and their median survival was 40.8 months. Suboptimal debulking surgery after primary chemotherapy did not result in a better survival than that achieved after a chemotherapy response alone, suggesting that surgery may be avoided when imaging after chemotherapy demonstrates residual disease that cannot be optimally debulked.

Background: Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease., Methods: We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival., Results: A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months., Conclusions: Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.).

Purpose: Inhibiting angiogenesis is one of the most promising avenues for new therapies for ovarian cancer. We investigated the efficacy and safety of a novel agent, BIBF 1120, a triple angiokinase inhibitor, after chemotherapy for relapsed disease., Patients and Methods: We conducted a randomized, double-blind, controlled phase II trial in 83 patients who had just completed chemotherapy for relapsed ovarian cancer, with evidence of response, but at high risk of further early recurrence. The patients were randomly assigned to receive maintenance therapy using BIBF 1120 250 mg or placebo, twice per day, continuously for 36 weeks. End points were progression-free survival (PFS), toxicity, and overall survival., Results: Thirty-six-week PFS rates were 16.3% and 5.0% in the BIBF 1120 and placebo groups, respectively (hazard ratio, 0.65; 95% CI, 0.42 to 1.02; P = .06). Four patients continued on BIBF 1120, including two patients for another year or more. The proportion of patients with any grade 3 or 4 adverse events was similar between the groups (34.9% for BIBF 1120 v 27.5% for placebo; P = .49; mostly grade 3). However, more patients on BIBF 1120 experienced diarrhea, nausea, or vomiting (mainly grade 1 or 2 and no grade 4). There was a higher rate of grade 3 or 4 hepatotoxicity in patients on BIBF 1120 (51.2%) compared with patients on placebo (7.5%; P < .001), but this was rarely of clinical significance, and patients continued with the trial treatment. A single-level dose reduction to 150 mg was made in 15 patients, all on active drug., Conclusion: BIBF 1120 is well tolerated and associated with a potential improvement in PFS. The observed treatment effect is sufficient to justify further study within a large phase III trial.

Background: In the non-curative setting, the sequence in which anticancer agents are used, singly or in combination, may be important if patients are to receive the maximum period of disease control with the minimum of adverse effects. We compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic colorectal cancer, who were regarded as not potentially curable irrespective of response., Methods: We studied patients with advanced colorectal cancer, starting treatment with non-curative intent. 2135 unpretreated patients were randomly assigned to three treatment strategies in the ratio 1:1:1. Strategy A (control group) was single-agent fluorouracil (given with levofolinate over 48 h every 2 weeks) until failure, then single-agent irinotecan. Strategy B was fluorouracil until failure, then combination chemotherapy. Strategy C was combination chemotherapy from the outset. Within strategies B and C, patients were randomly assigned to receive, as the combination regimen, fluorouracil plus irinotecan (groups B-ir and C-ir) or fluorouracil plus oxaliplatin (groups B-ox and C-ox). The primary endpoint was overall survival, analysed by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 79877428., Results: Median survival of patients allocated to control strategy A was 13.9 months. Median survival of each of the other groups was longer (B-ir 15.0, B-ox 15.2, C-ir 16.7, and C-ox 15.4 months). However, log-rank comparison of each group against control showed that only C-ir--the first-line combination strategy including irinotecan--satisfied the statistical test for superiority (p=0.01). Overall comparison of strategy B with strategy C was within the predetermined non-inferiority boundary of HR=1.18 or less (HR=1.06, 90% CI 0.97-1.17)., Interpretation: Our data challenge the assumption that, in this non-curative setting, maximum tolerable treatment must necessarily be used first-line. The staged approach of initial single-agent treatment upgraded to combination when required is not worse than first-line combination, and is an alternative option for discussion with patients.

The majority of patients with ovarian cancer will relapse despite state-of-the-art first-line surgery and chemotherapy. There are two subgroups of patients with recurrent ovarian cancer: those with platinum-resistant disease and those with platinum-sensitive disease. Re-treatment with single-agent platinum has long been considered standard therapy for patients with platinum-sensitive disease, and, based on its favorable therapeutic profile, carboplatin has become the treatment agent of choice. High response rates are seen with platinum agents used in combination with paclitaxel or gemcitabine. The International Collaborative Group for Ovarian Neoplasia (ICON) and the Arbeitsgemeinschaft für Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) recently conducted a trial (ICON4/AGO-OVAR-2.2) comparing platinum monotherapy with platinum plus paclitaxel combined. Results showed that overall survival and progression-free survival are improved by combination therapy. Similarly, a significant benefit in progression-free survival for carboplatin plus gemcitabine versus carboplatin monotherapy was seen in the Gynecologic Cancer InterGroup trial. The toxicity profiles and schedules of carboplatin plus paclitaxel and carboplatin plus gemcitabine are different, with the taxane combination having greater neurotoxicity and alopecia, less hematologic toxicity, and requiring longer drug infusions (although fewer days of treatment per cycle) than the gemcitabine combination. Based on the results of these two trials, combination chemotherapy should be considered the standard treatment of recurrent platinum-sensitive ovarian cancer. The choice of treatment needs to take into account the increase in side effects when using combination chemotherapy compared with carboplatin monotherapy, and the different toxicities of the two combination regimens.

Purpose: The purpose of our study was to determine the maximum-tolerated dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the polyamine synthesis inhibitor SAM486A given in combination with 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients., Experimental Design: Patients with advanced colorectal cancer were treated with 5-FU [bolus (400 mg/m(2)) followed by a 22-h infusion (600 mg/m(2))] and LV (200 mg/m(2)) and escalating doses of SAM486A, 1-3-h infusion daily for 3 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of the combination, Results: Twenty-seven patients with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were treated. Twenty-six patients received SAM486A in the combination at doses ranging from 25 to 150 mg/m(2)/day. Dose-limiting toxicity consisting of fatigue grade 3 was seen at 150 mg/m(2)/day. Other adverse events included neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and constipation. Fifteen of 26 patients evaluable for best response according to the Southwest Oncology Group criteria achieved a partial response [8 (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that when used as a single agent., Conclusions: The novel molecular agent SAM486A is tolerable and safe in combination with a standard 5-FU regimen in patients with advanced colorectal cancer. The dose of SAM486A recommended for additional studies with this combination is 125 mg/m(2)/day. A disease-directed evaluation of SAM486A using this regimen is warranted.

Decisions about the treatment of recurrent ovarian cancer are usually based on the treatment-free interval. Patients relapsing with an interval of more than six months are usually retreated with platinum-based chemotherapy. Non platinum drugs (such as paclitaxel, gemcitabine, liposomal doxorubicin or topotecan) are also active in relapsed disease. A high response rate is consistently seen with combinations of platinum and these drugs in phase II trials. ICON 4, the first large-scale randomised trial in 'platinum-sensitive' relapsed ovarian cancer demonstrated a survival benefit for using platinum-based therapy in combination with paclitaxel. More studies are needed to explore other combinations of treatment in this group of women as the choice and timing of second-line therapy needs to take account of the benefits and toxicity of treatment.

UNLABELLED: In the phase III JAVELIN Ovarian 200 trial, 566 patients with platinum-resistant/refractory ovarian cancer were randomized 1:1:1 to receive avelumab alone, avelumab plus pegylated liposomal doxorubicin (PLD), or PLD alone. Cardiac monitoring was included for all patients. We report left ventricular ejection fraction (LVEF) data from the trial. Grade ≥3 cardiac adverse events (AEs) occurred in 4 (2.1%), 1 (0.5%), and 0 patients in the avelumab, combination, and PLD arms, respectively. LVEF decreases of ≥10% to below institutional lower limit of normal at any time during treatment were observed in 1 (0.8%), 3 (1.9%), and 2 (1.5%) patients, respectively; 4 had subsequent assessments, and these showed transient decreases. No patient had a cardiovascular AE related to LVEF decrease. This analysis is, to our knowledge, the first analysis of LVEF in patients receiving immune checkpoint inhibitors. CLINICALTRIALS.GOV IDENTIFIER: NCT02580058.