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Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/2) mutation using a tablet formulation of olaparib. This international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed ovarian cancer patients with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status at baseline of 0–1 and histologically confirmed, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer. Patients were randomly assigned 2:1 to olaparib (300 mg in two 150 mg tablets, twice daily) or matching placebo tablets using an interactive voice and web response system. Randomisation was stratified by response to previous platinum chemotherapy (complete vs partial) and length of platinum-free interval (6–12 months vs ≥12 months) and treatment assignment was masked for patients, those giving the interventions, data collectors, and data analysers. The primary endpoint was investigator-assessed progression-free survival and we report the primary analysis from this ongoing study. The efficacy analyses were done on the intention-to-treat population; safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01874353, and is ongoing and no longer recruiting patients. Between Sept 3, 2013, and Nov 21, 2014, we enrolled 295 eligible patients who were randomly assigned to receive olaparib (n=196) or placebo (n=99). One patient in the olaparib group was randomised in error and did not receive study treatment. Investigator-assessed median progression-free survival was significantly longer with olaparib (19·1 months [95% CI 16·3–25·7]) than with placebo (5·5 months [5·2–5·8]; hazard ratio [HR] 0·30 [95% CI 0·22–0·41], p<0·0001). The most common adverse events of grade 3 or worse severity were anaemia (38 [19%] of 195 patients in the olaparib group vs two [2%] of 99 patients in the placebo group), fatigue or asthenia (eight [4%] vs two [2%]), and neutropenia (ten [5%] vs four [4%]). Serious adverse events were experienced by 35 (18%) patients in the olaparib group and eight (8%) patients in the placebo group. The most common in the olaparib group were anaemia (seven [4%] patients), abdominal pain (three [2%] patients), and intestinal obstruction (three [2%] patients). The most common in the placebo group were constipation (two [2%] patients) and intestinal obstruction (two [2%] patients). One (1%) patient in the olaparib group had a treatment-related adverse event (acute myeloid leukaemia) with an outcome of death. Olaparib tablet maintenance treatment provided a significant progression-free survival improvement with no detrimental effect on quality of life in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Apart from anaemia, toxicities with olaparib were low grade and manageable. AstraZeneca.

Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p<0·0001). Most common grade 3–4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. Hoffmann–La Roche and Associazione Italiana per la Ricerca sul Cancro.

Metastatic leiomyosarcomas have a poor prognosis, and currently doxorubicin alone is used as the standard first-line treatment. Doxorubicin combined with trabectedin has shown promising results in phase 1 and 2 studies. We aimed to identify and compare the progression-free survival of patients with metastatic or unresectable uterine or soft tissue leiomyosarcoma treated with doxorubicin and trabectedin combined as first-line therapy versus doxorubicin alone in a phase 3 trial. LMS-04 was a randomised, multicentre, open-label, superiority phase 3 trial, which included patients from 20 centres of the French Sarcoma Group (anticancer centers or hospitals with an oncological unit) in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–1, and had metastatic or relapsed unresectable leiomyosarcomas that had not previously been treated with chemotherapy. Patients were randomly assigned (1:1), by means of an interactive web response system (permuted blocks of different sizes from two to six), to receive either intravenous doxorubicin alone (75 mg/m2) once every 3 weeks for up to six cycles or of intravenous doxorubicin (60 mg/m2) plus intravenous trabectedin (1·1 mg/m2) once every 3 weeks up to six cycles followed by maintenance with trabectedin alone. Surgery for residual disease was allowed in both groups after six cycles of treatment. Randomisation was stratified by tumour location (uterine vs soft tissue) and disease (locally advanced vs metastatic). The primary endpoint was progression-free survival assessed by blinded independent central review and according to Response Evaluation Criteria in Solid Tumours 1.1 criteria. Efficacy analyses were performed on all randomly assigned patients, based on the intention-to-treat principle. The safety population included all randomly assigned patients who received at least one cycle of treatment. This trial is registered with ClinicalTrials.gov, NCT02997358, and is closed to enrolment. Between Jan 18, 2017, and March 21, 2019, 150 patients were enrolled (67 with uterine leiomyosarcomas and 83 with soft tissue leiomyosarcomas) and included in the intention-to-treat population: 76 in the doxorubicin alone group and 74 in the doxorubicin plus trabectedin group. The median duration of follow-up was 36·9 months (IQR 30·0–43·2) in the doxorubicine group and 38·8 months (32·7–44·2) in the doxorubicin plus trabectedin group. Median progression-free survival was significantly longer with doxorubicin plus trabectedin versus doxorubicin alone (12·2 months [95% CI 10·1–15·6] vs 6·2 months [4·1–7·1]; adjusted hazard ratio 0·41 [95% CI 0·29–0·58]; p<0·0001). The most common grade 3–4 adverse events were neutropenia (ten [13%] of 75 patients in the doxorubicin alone group vs 59 [80%] in the doxorubicin plus trabectedin group), anaemia (four [5%] vs 23 [31%]), thrombocytopenia (0 vs 35 [47%]), and febrile neutropenia (seven [9%] vs 21 [28%]). Nine (12%) patients in the doxorubicin alone group and 15 (201%) patients in the doxorubicin plus trabectedin group has serious adverse events. There was only one treatment-related death, reported in the doxorubicin alone group (cardiac failure). Doxorubicin plus trabectedin in first-line therapy was found to significantly increase progression-free survival in patients with metastatic or unresectable leiomyosarcomas compared with doxorubicin alone, despite a higher but manageable toxicity, and could be considered an option for the first-line treatment of metastatic leiomyosarcomas. PharmaMar.

The European Society of Gynaecological Oncology and the European Society for Paediatric Oncology jointly developed clinically relevant and evidence-based guidelines for the management of adolescents and young adults aged 15 to 25 years with non-epithelial ovarian cancers, including malignant ovarian germ cell tumours, sex cord-stromal tumours, and small cell carcinoma of the ovary of hypercalcaemic type. The developmental process of these guidelines is based on a systematic literature review and critical appraisal process involving an international multidisciplinary developmental group consisting of experts from relevant disciplines (paediatric oncology, paediatric surgery, medical oncology, pathology, psycho-oncology, gynaecological oncology, and reproductive endocrinology). Given the specific and often complex issues involved in treating this group of patients, fertility sparing surgery and decrease of acute and long-term toxicities from treatment were important criteria for guidelines definition. Prior to publication, the guidelines were reviewed by 54 independent international practitioners in cancer care delivery.

ObjectiveThe aim of this study was to assess the outcomes of a large series of patients treated conservatively for stage II or III serous borderline tumors of the ovary (SBOTs) with a long-term follow-up.MethodsPatients with SBOTs and peritoneal implants, treated in or referred to our institution, were retrospectively reviewed. Outcomes of patients treated conservatively (preservation of the uterus and at least a part of one ovary) to promote subsequent fertility were specifically analyzed.ResultsBetween 1971 and 2017, 212 patients were identified and followed-up. Among these patients, 65 underwent conservative treatment; eight patients had invasive implants. Among patients treated conservatively, 38 (58%) patients recurred. Twenty-eight recurrences were observed under the form of borderline tumor on the spared ovary and/or noninvasive implants, but eight patients had a recurrence under the form of invasive disease. Compared with radical surgery, the use of conservative treatment (p < 0.0001) was a prognostic factor on disease-free survival (DFS), but without an impact on overall survival (OS). Nevertheless, three deaths occurred. Twenty-four pregnancies (13 spontaneous) were observed in 20 patients (29 patients wanted to become pregnant).ConclusionIn this series collecting the largest number of patients undergoing conservative surgery for stage II/III SBOTs, spontaneous pregnancies can be achieved after conservative treatment of advanced-stage disease, but the recurrence rate is high and three deaths were observed. These patients were spared their fertility but with a high rate of recurrence. Uncertainties regarding the safety of conservative treatment should be exposed to these patients.

BackgroundMost frequent borderline ovarian tumors are serous and mucinous subtypes. Less frequent borderline diseases are endometrioid, clear-cell, and Brenner tumors (BBOT). Very little is known about the latter subtype, and most studies include very short series or case reports. The aim of this study is to determine the prognosis of a continuous series of BBOT and analyze data published in the literature on this rare entity.Patients and MethodsA retrospective review of patients with BBOT treated or referred to our institutions was conducted. A centralized histological review by a reference pathologist and data on the clinical characteristics, management, and outcomes of patients were required for inclusion.ResultsOverall, 17 patients were identified. Median age was 62 (range 42–85) years. Six patients underwent unilateral salpingo-oophorectomy, and 11 bilateral salpingo-oophorectomy +/− hysterectomy and/or staging surgery. In total, 16 patients had unilateral tumor, and all patients had stage I disease. Stromal microinvasion was observed in three cases. Median follow-up was 60 months (range 7–118 months). One patient developed a recurrence in contralateral ovary after unilateral salpingo-oophorectomy. One patient had previous history of urothelial tumor.ConclusionsPeritoneal staging surgery is not required because all patients reported had stage I disease. One recurrence occurred. When reviewing all the 82 cases reported in the literature (including ours), 9% had previous history or synchronous urothelial tumor, suggesting the need to carefully check for urological disease in patients with BBOT.

Mirvetuximab soravtansine, an antibody-drug conjugate that binds with high affinity to folate receptor-α to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-α-positive, platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer. Patients will be randomized in a 2:1 ratio. The primary end point is progression-free survival, and key secondary objectives include comparison of overall response rates, overall survival and duration of response.

BackgroundClear cell borderline ovarian tumor (CCBOT) is one of the rarest subtypes of borderline ovarian malignancies. The aim of this study was to determine the prognosis of a series of CCBOT.Patients and MethodsA retrospective review of patients with CCBOT treated or referred to our institutions. A centralized histological review by a reference pathologist and data on the clinical characteristics, management, and outcomes of patients were required for inclusion.ResultsNineteen patients were identified. Median age was 62 (range 36–83) years. Four patients underwent a conservative surgery and 14 a bilateral salpingo-oophorectomy +/– hysterectomy (unknown in 1 case). One patient had bilateral tumor, and all cases were stage-I disease. All CCBOTs showed an adenofibromatous pattern. Stromal microinvasion was observed in seven cases and intraepithelial carcinoma in two cases. Endometriosis was histologically associated in one case. The median follow-up was 76 (range 6–231) months. No recurrence occurred. Two patients died of intercurrent disease.ConclusionsPeritoneal staging procedures should always be associated, but restaging surgery could be omitted if there was no suspicious lesion in the peritoneum during initial surgery, since all patients reported had stage-I disease. Fertility-sparing surgery appears to be a safe alternative in young patients. Synchronous endometrial disorders with atypia are infrequent. Prognosis is generally excellent, and long-term risk of recurrence is low. The two recurrences described in literature occurred in stage-IC diseases, highlighting the importance of avoiding perioperative rupture.