PURPOSE:Malignant ovarian germ cell tumors (MOGCTs) are rare, aggressive malignancies predominantly affecting young women. Unlike testicular germ cell tumors, prognostic factors are poorly understood, with small studies suggesting advanced stage as an adverse factor. Here, we examine a large international series to identify relevant prognostic factors. METHODS:We analyzed data from 254 patients with International Federation of Gynecology and Obstetrics stage IC-IV MOGCT, requiring surgery and chemotherapy between 1971 and 2018 at two UK and the Multicenter Italian Trials in Ovarian Cancer centers. RESULTS:The median age was 27 years (IQR, 21-31). Initial treatment was surgery in 87.8% of patients (50.4% fertility sparing, 37.4% nonsparing) or neoadjuvant chemotherapy. Most underwent BEP or POMB/ACE chemotherapy, with 32.5% receiving high-dose chemotherapy (HDCT) at relapse. First-line treatment resulted in a complete response in 84.6% (n = 215) and partial response or stable disease in 7.9% (n = 20), while 4.7% (n = 12) progressed. Overall, 37 patients (14.6%) died of disease. Ten-year progression-free survival and cancer-specific survival (CSS) was 82.8% (95% CI, 77.2 to 87.2) and 83.2% (95% CI, 77.3 to 87.7), respectively. CSS for stage IV disease was 79.4% (95% CI, 69.5 to 86.4). Age ≥35 years (hazard ratio [HR], 2.8 [95% CI, 1.5 to 5.4]; P = .003), stage III/IV disease (HR, 1.4 [95% CI, 1,0.2 to 1.9]; P = .035), and nondysgerminoma histology (HR, 7.3 [95% CI, 1.9 to 64.8]; P = .01) had worse CSS on multivariable analysis. By contrast, CSS of immature grade 2/3 MOGCT mirrored dysgerminomas. HDCT appeared to improve survival in first but not later relapses. CONCLUSION:Advanced stage (III/IV), age >35 years, and nondysgerminoma (excluding grade 2/3 immature teratomas) are adverse prognostic factors. Stage IV disease can achieve 80% long-term survival rates, and HDCT improves survival in first but not second relapse.

BACKGROUND:Most chemotherapy regimens for poor-risk non-seminomatous germ cell tumours (PRGCT) deliver a fixed number of cycles; the role of variable treatment duration aiming for maximal response is unknown. Since the 1970s, we have utilised POMB/ACE chemotherapy for PRGCT, treating until marker normalisation. From mid-1990s, treatment was limited to 7 cycles. We describe outcomes with POMB/ACE for PRCGT, evaluating the association between treatment duration and survival. METHODS:We conducted a retrospective cohort study across two UK tertiary cancer centres, identifying patients treated between 1978-2013. Complete response was defined based on normalisation of elevated tumour markers, absence of viable cancer in resection material and resolution of radiological abnormalities. Regression techniques were used to investigate the relationship between therapy duration and outcomes. RESULTS:132 PRGCT patients completed POMB/ACE with 69.7% (n = 92) alive at 5 years. Number of cycles delivered significantly correlated with recurrence free survival (HR 0.52; 95% CI 0.38-0.71; p < 0.001) and complete biochemical response (OR 1.27; 95% CI 1.10-1.49; p = 0.0018). POMB/ACE discontinuation amongst patients with responding but not normalised tumour markers was associated with worse survival. Study limitations include the retrospective design. CONCLUSION:POMB/ACE is highly active for PRGCT. Treatment until maximal biochemical response is associated with superior survival outcomes and warrants further exploration.

501 Background: Prognosis in stage I seminoma is excellent. Most patients are cured by orchiectomy and, for the 15%-20% that relapse, salvage treatment is generally successful (survival approaching 100%). Relapse risk is reduced with adjuvant carboplatin but may unnecessarily expose young patients to long-term health risks. Effective and reliable risk stratification could guide use of adjuvant treatment and potentially reduce intensity of surveillance for the lowest risk patients. We used data from a UK multicentre, phase III trial to evaluate prognostic factors for relapse in stage I seminoma, including validation of a recently proposed model from the European Association of Urology (EAU)(1). Methods: TRISST used a randomised, factorial design to evaluate imaging schedules (3 vs 7 scans) and modality (MRI vs CT) in surveillance for men who had undergone orchidectomy for stage I seminoma (n=669). In this secondary analysis, model selection was used to fit a multivariable Cox regression to TRISST data to investigate factors predicting time to relapse, including: age, tumour mass size, rete testis invasion (RTI), T stage, lymphovascular invasion (LVI), side of tumour, and tumour markers (LDH, β-HCG). The final model was used to divide the cohort into risk groups. Relapse risk was also estimated according to EAU prognostic groups. Harrell’s C-index was used to measure model fit. Results: Based on TRISST data, tumour size ≥4cm and pT3 disease were associated with the highest risk (multivariable hazard ratio for ≥4cm vs <2cm: HR=4.00, 95% confidence interval 2.00-8.01; pT3 vs pT1: HR=3.89, 1.77-8.57). Patients with one or both of these features (24% of the cohort) had 5-year relapse rate of 22.0%. Medium risk (age<30 years and/or 2-4cm and/or pT2) and low risk (age≥30 years, <2cm and pT1) groups had 5-year relapse rates 12.0% and 2.3% respectively. The EAU model was a good fit to the TRISST data (C-index=0.62); 66%, 33% and 2% fell into the very low, low and high-risk EAU groups respectively with 5-year relapse rates of 10.1%, 16.1% and 45.5%. Conclusions: In stage I seminoma, relapse risk in patients managed with surveillance following orchiectomy is low for the majority of patients. Tumour size is consistently shown to be the best predictor of relapse. The EAU prognostic model, validated here, identifies a small group (>5cm, with RTI and LVI) with particularly high risk who may benefit from adjuvant therapy. Reference: 1. Boormans J, et al. Journal of Clinical Oncology 2023; 41 (6_suppl): 410. Clinical trial information: ISRCTN65987321 .

Introduction/Background Malignant ovarian germ cell tumours (MOGCTs) are rare and aggressive malignancies mainly affecting young women. Unlike testicular GCTs, prognostic factors are poorly understood, but small series have most consistently suggested that advanced stage best predicts worse outcomes. Here, we examine a large, international patient series to identify new adverse prognostic factors. Methodology We evaluated 254 patients treated in Charing Cross Hospital and Mount Vernon Cancer Centre, UK and in Multi-centre Italian Trials in Ovarian Cancer (MITO) group between 1971 and 2018. Descriptive statistical, survival and Cox regression techniques were performed using STATA (StataCorp, v.16, Texas, USA). Results Median age was 26 years (IQR, 20–32). There were 22.4% dysgerminomas, 18.5% immature teratomas, 33.5% yolk sac, 17.7% mixed, 1.2% embryonal, 2.4% choriocarcinoma and 4.3% unclassified. FIGO stage distribution was 31.5% (IC/M), 12.6% (II), 40.5% (III) and 15.4% (IV). First line chemotherapy consisted of BEP, POMB/ACE or other regimens for 48.0%, 42.5% and 9.5% of patients, respectively. Recurrences received high dose chemotherapy (HDCT), conventional chemotherapy ± surgery, and surgery alone in 24.4%, 65.9% and 7.3% of cases. At multivariable analysis, age ≥35 at presentation [HR 2.3, 95%CI (1.0–5.0), p=0.04], stage [HR 1.5, 95%CI (1.0–2.1), p=0.032], and non-dysgerminoma versus dysgerminoma [HR 12.7, 95%CI (1.7–94.0), p=0.013] were significantly associated with worse cancer-specific survival (CSS). Twenty-year CSS for stage IC/M, II, III, and IV were 94.8%, 82.3%, 83.2% and 84.3%, respectively. In patients relapsing or failing to achieve a complete response, HDCT showed a trend for improved 5-year CSS compared to conventional treatments [HR 0.5, 95%CI (0.2–1.5), p=0.241]. Conclusion This study demonstrated that in addition to advanced stage, age ≥35 years, and non-dysgerminoma, but not immature teratomas, are independent adverse prognostic factors for CSS. Strikingly, stage IV disease can still achieve >80% long-term survival rates. HDCT may improve outcomes for relapsing/incomplete responding patients.

Rising CA-125 levels can detect relapsed ovarian cancer about six months before symptoms develop. Therefore, many asymptomatic patients have routine CA-125 measurements during follow-up. The only trial of CA-125 surveillance after first-line therapy randomized patients to early or delayed treatment after a doubling of CA-125 level. It showed those in the early arm had no survival benefit and worse quality of life. The trial was criticized as few patients had secondary surgery, yet randomized trials show conflicting results on the value surgery. Patients should be aware that recurrent ovarian cancer is not curable and require information on surveillance options.

ObjectiveTo assess fertility outcomes in long-term survivors of malignant ovarian germ cell tumors treated with fertility-sparing surgery with or without additional chemotherapy.MethodsWomen diagnosed and treated for malignant ovarian germ cell tumors at Charing Cross Hospital or Mount Vernon Cancer Centre between 1977 and 2015 were included. Questionnaires assessing fertility issues were sent to patients treated with fertility-sparing surgery. Fertility outcomes were evaluated according to the treatment received. The effect of the mean total dose of cyclophosphamide and cisplatin was assessed.ResultsA total of 146 patients were sent the questionnaire; 77 (56.5%) patients were included in the analysis. A total of 49 (64%) patients received platinum-based chemotherapy after surgery, 39 (79.6%) of these with cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, and etoposide, while 10 (20.4%) with bleomycin, etoposide, and cisplatin. After any treatment, 39/46 patients (85%) became pregnant: the conception rate was not different between those receiving surgery only and those receiving also chemotherapy (85.7% vs 84.4%, p=1.0). Live birth rate was 80.4% (37/46), with no statistically significant difference between the treatment groups (p=0.42). Median age of women achieving conception was 29 years (IQR 26-33). The probability of live birth at 5 years was 48% and 40% for patients in the surgery only and chemotherapy group, respectively (p=0.55). Infertility and miscarriage rates did not differ significantly between the two treatment groups (p=0.30 and p=0.32). The mean doses of cisplatin and cyclophosphamide received by patients failing and achieving conception were not different (p=0.10, p=0.47).ConclusionsOur results suggest that fertility may not be hampered in patients with malignant ovarian germ cell tumor treated with fertility-sparing surgery or receiving additional chemotherapy.

Supplementary Figures 1-2 from Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents

408 Background: Risk of radiation exposure from standard computed tomography (CT) surveillance is a major concern in the management of stage I seminoma testis patients. The TRISST randomized trial (NCT00589537) demonstrated that effective monitoring could be achieved with a reduced scan schedule or using Magnetic Resonance Imaging (MRI) instead of CT. Here, TRISST data is used to evaluate the economic consequences and health outcomes of different surveillance schedules in seminoma patients in the UK. Methods: 669 men were randomized to 4 surveillance groups undergoing 7 CTs over 5 years, 3 CTs over 3 years, 7 MRIs, or 3 MRIs of the retroperitoneum. Resource use (including investigations, scans, hospitalisations and treatment for relapse) and health outcomes data (EQ-5D 3L) on each patient were collected at baseline and over a period of 6 years after randomization. Health resources were costed using publicly available national unit costs. Within-trial mean total costs and quality-adjusted life years (QALYs) were estimated for each alternative schedule. Under the perspective of the UK health system, cost-effectiveness was evaluated using a cost per QALY gained framework. Probabilistic sensitivity analysis was used to reflect parameter uncertainty and evaluate results robustness. Results: Since only 82 men (12%) relapsed, most health resource consumption (76%) happened during the disease-free period. Patients undergoing 7 MRIs yielded, on average, slightly higher health benefits (5.20 QALYs) but at higher costs (GBP £6,632, see table). Compared to 7 CTs, 7 MRIs was estimated to have 63% probability of being cost-effective at a system willingness to pay threshold of £20k/QALY. 3 MRIs had similar costs and benefit to 7 CTs, whereas 3CTs was more expensive than 7 CTs and 3 MRIs, providing marginal additional benefits. Conclusions: Overall, small differences exist in total costs and total QALYs between different strategies. A 7 scan MRI schedule yielded more health benefits than other strategies, but at higher costs. Considering possible capacity constraints with MRI, the reduced radiation exposure relative to CT, and non-inferiority for clinical outcomes in the primary analysis, a 3 scan MRI schedule may be the best option to replace current CT-based longer surveillance practice. Clinical trial information: NCT00589537 . [Table: see text]

Background/Aim: The occurrence of germ cell tumour (GCT) in the elderly is rare, with scarce data available. The aim of this study was to understand the clinical outcomes of patients with GCT in patients aged > 45 years. Materials and Methods: A retrospective study was conducted in a large tertiary cancer centre in north-west London. Between 1 January 2003 and 31 March 2022, 108 cases of GCT in men aged > 45 years were identified and treated at the Mount Vernon Cancer Centre. The median age at diagnosis was 54 years (range = 45–70 years). Results: The 5-year survival rate of all patients was 96%, and the toxicity profile was similar to the younger age group. Conclusion: Older patients with GCT are able to tolerate chemotherapy; however, care must be taken to prevent life-threatening complications using appropriate dose modification.

PURPOSE Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses. METHODS A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI ( v CT) or three scans ( v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed. RESULTS Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (–3.5 to –0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths. CONCLUSION Surveillance is a safe management approach—advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule.

Monitoring with regular computed tomography (CT) is an effective means of identifying relapse in patients treated for stage I seminoma testis; however, risks of radiation exposure are a major concern in these young patients, many of whom won't relapse. The TRISST randomized trial assessed whether a reduced CT or Magnetic Resonance Imaging (MRI) schedule could be effective alternatives to standard CT-based surveillance. It found that fewer CTs or MRIs were non-inferior in terms of clinical outcomes. This study used the TRISST trial data to evaluate the health care resource consequences and health-related quality-of-life of different surveillance strategies in patients with seminoma testicular cancer in the UK.

Background: Radiotherapy and cisplatin-based combination chemotherapy are accepted standard-of-care treatments for metastatic seminoma with excellent survival outcomes but with established short-and long-term morbidity. Carboplatin monotherapy may be a less toxic alternative; however early historic studies at AUC7 showed inferior outcomes.Objectives: To evaluate multi-institutional data on and toxicity and longer-term survival for metastatic seminoma patients treated with the single-agent carboplatin AUC10.Methods: We undertook a multi-institutional analysis incorporating all men with the International Germ Cell Cancer Collaborative Group good-prognosis metastatic seminoma treated until 2018. Carboplatin AUC10 was given every 21 days. Toxicity, progression-free survival (PFS), disease-specific survival (DSS) and overall survival were noted. Variables predictive of progression were identified.Results and limitations: 216 patients were treated. The three-year PFS rate was 96.5%, and five-year DSS was 98.3%. There were seven relapses, of which 5 were successfully salvaged with further chemotherapy +/- surgery, and three non-seminoma-related deaths. There were no treatment-related deaths. Of 148/216 evaluable patients for toxicity, 37% and 27% suffered >/ Z grade III neutropenia and thrombocytopenia, respectively. Twelve percent of patients needed a platelet or blood transfusion (or both). The incidence of febrile neutropenia was 5%.Conclusion: For metastatic seminoma, carboplatin AUC10 harbours a similar oncological efficacy to established therapies, with a low failure risk. The major acute toxicity was myelosuppression. Our study establishes carboplatin AUC10 as another standard-of-care treatment option for good-prognosis metastatic seminoma, with a potentially lower toxicity profile than other therapies.(C) 2020 Elsevier Ltd. All rights reserved.

Outcomes in stage I seminoma are excellent. 15% relapse when managed with surveillance and survival approaches 100%. Risk stratification would allow management to be tailored, avoiding unnecessary treatment and/or irradiation. However, validated factors based on contemporary data are lacking. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST, ISRCTN65987321) - the largest in this setting - investigated optimal frequency and modality of imaging. Here, trial data are used to determine prognostic factors for relapse.

Background: Cediranib, an oral anti-angiogenic VEGFR 1-3 inhibitor, was studied at a daily dose of 20 mg in combination with platinum-based chemotherapy and as maintenance in a randomised trial in patients with first relapse of 'platinum-sensitive' ovarian cancer and has been shown to improve progression-free survival (PFS). Patients and methods: ICON6 (NCT00532194) was an international three-arm, double-blind, placebo-controlled randomised trial. Between December 2007 and December 2011, 456 women were randomised, using stratification, to receive either chemotherapy with placebo throughout (arm A, reference); chemotherapy with concurrent cediranib, followed by maintenance placebo (arm B, concurrent); or chemotherapy with concurrent cediranib, followed by maintenance cediranib (arm C, maintenance). Due to an enforced redesign of the trial in September 2011, the primary endpoint became PFS between arms A and C which we have previously published, and the overall survival (OS) was defined as a secondary endpoint, which is reported here. Results: After a median follow-up of 25.6 months, strong evidence of an effect of concurrent plus maintenance cediranib on PFS was observed [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.44-0.72, P < 0.0001]. In this final update of the survival analysis, 90% of patients have died. There was a 7.4-month difference in median survival and an HR of 0.86 (95% CI: 0.67-1.11, P = 0.24) in favour of arm C. There was strong evidence of a departure from the assumption of non-proportionality using the Grambsch-Therneau test (P = 0.0031), making the HR difficult to interpret. Consequently, the restricted mean survival time (RMST) was used and the estimated difference over 6 years by the RMST was 4.8 months (95% CI: -0.09 to 9.74 months). Conclusions: Although a statistically significant difference in time to progression was seen, the enforced curtailment in recruitment meant that the secondary analysis of OS was underpowered. The relative reduction in the risk of death of 14% risk of death was not conventionally statistically significant, but this improvement and the increase in the mean survival time in this analysis suggest that cediranib may have worthwhile activity in the treatment of recurrent ovarian cancer and that further research should be undertaken.

Background. We investigated the safety and efficacy of a combination of the oral tyrosine kinase inhibitor, nintedanib (BIBF 1120) with oral cyclophosphamide in patients with relapsed ovarian cancer. Patients and methods. Patients with relapsed ovarian, fallopian tube or primary peritoneal cancer received oral cyclophosphamide (100 mg o.d.) and were randomised (1,1) to also have either oral nintedanib or placebo. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), response rate, toxicity, and quality of life. Results. 117 patients were randomised, 3 did not start trial treatment, median age 64 years. Forty-five (39%) had received >= 5 lines chemotherapy. 30% had received prior bevacizumab. The median OS was 6.8 (nintedanib) versus 6.4 (placebo) months (hazard ratio 1.08; 95% confidence interval 0.72-1.62; P=0.72). The 6-month PFS rate was 29.6% versus 22.8% (P=0.57). Grade 3/4 adverse events occurred in 64% (nintedanib) versus 54% (placebo) of patients (P = 0.28); the most frequent G3/4 toxicities were lymphopenia (18.6% nintedanib versus 16.4% placebo), diarrhoea (13.6% versus 0%), neutropenia (11.9% versus 0%), fatigue (10.2% versus 9.1%), and vomiting (10.2% versus 7.3%). Patients who had received prior bevacizumab treatment had 52 days less time on treatment (P<0.01). 26 patients (23%) took oral cyclophosphamide for >= 6 months. There were no differences in quality of life between treatment arms. Conclusions. This is the largest reported cohort of patients with relapsed ovarian cancer treated with oral cyclophosphamide. Nintedanib did not improve outcomes when added to oral cyclophosphamide. Although not significant, more patients than expected remained on treatment for >= 6 months. This may reflect a higher proportion of patients with more indolent disease or the higher dose of cyclophosphamide used. (C) 2020 Published by Elsevier Inc.

It has been another busy year for Canadian Cancer Trials Group at the American Society of Clinical Oncology Annual Meeting. This conference brings together oncology professionals from around the world to discuss state-of-the-art treatments, new therapies with the best minds in the field of cancer research. CCTG is well represented on this world stage with three recognition awards, fifteen poster presentations, and four oral abstracts. See below for more details. For more information on the event see the ASCO 2017 website or you can follow the conversation on our twitter account @CDNCancerTrial #ASCO17

Outcomes for men with stage I seminoma are excellent and avoiding intensive chemotherapy in these young patients is important. CT surveillance is a standard of care following orchiectomy. 10-20% relapse, but treatment is curative in almost 100%. In an ongoing trial of surveillance in seminoma [TRISST, NCT00589537], RMH stage IIC or worse relapse is defined as the primary outcome, reflecting the watershed for treatment with combination chemotherapy (BEP/EP) when TRISST was initiated. To re-assess the relevance of this endpoint we planned to assess current UK practices in treating relapse. In 2020, a survey of UK clinicians was conducted to determine factors affecting management decisions at relapse, and the treatments recommended according to tumour stage or size. 28 clinicians (24 centres) responded representing the majority of UK centres treating testicular cancer. 23 (82%) consider both stage and IGCCCG factors in determining relapse treatment, either with (57%) or without (25%) tumour size. In stage IIC disease, of 27 respondents, all indicated use of BEP/EP (3/4 cycle) or 3-4 cycles of carboplatin AUC10 (HDC); with only 3 (11%) also considering radiotherapy (RT, with carboplatin AUC7x1) as an option. Treatment of IIB disease was more varied: whilst 9 (of 27 respondents, 33%) only use BEP/EP and 5 (19%) only use HDC, 13 (48%) use RT +/- carboplatin AUC7 as either the only treatment (9, 33%) or as an option (4, 15%). However, when size is considered: for >3cm relapses, patterns were similar to IIC disease, but below 3cm management of stage IIB disease was less consistent. A subgroup of respondents use BEP/EP or HDC for all stage of seminoma relapse. 3 cycles of BEP is the most common combination regimen (20, 71%). In the UK, stage IIC remains a criterion for using intensive chemotherapy in relapsed seminoma. However, most clinicians also consider tumour size, with >3cm as a watershed between the use of intensive chemotherapy and locally-based treatments. As a result, detection of relapse >3cm has been added as key secondary endpoint in TRISST, with results due later in 2020. The trial will provide insights into current treatments at relapse and outcomes, as well as informing surveillance practices.

Objectives. We evaluated four different treatment regimens for advanced-stage mucinous epithelial ovarian cancer. Methods. We conducted a multicenter randomized factorial trial (UK and US). Patients were diagnosed with primary mEOC: FIGO stage II-IV or recurrence after stage 1 disease. Treatment arms were paclitaxel-carboplatin, oxaliplatin-capecitabine, paclitaxel-carboplatin-bevacizumab, or oxaliplatin-capecitabine-bevacizumab. Chemotherapy was given 3-weekly for 6 cycles, and bevacizumab (3-weekly) was continued as maintenance (for 12 cycles). Endpoints included overall-survival (OS), progression-free survival (PFS), toxicity and quality of life (QoL). Results. The trial stopped after 50 patients were recruited due to slow accrual. Median follow-up was 59 months. OS hazard ratios (HR) for the two main comparisons were: 0.78 (p = 0.48) for Oxal-Cape vs. Pac-Carbo (each with/without bevacizumab), and 1.04 (p = 0.92) for bevacizumab vs. no bevacizumab. Corresponding PFS HRs were: 0.84 and 0.80. Retrospective central pathology review revealed only 45% (18/40) cases with available material had confirmed primary mEOC. Among these, OS HR for Oxal-Cape vs. Pac-Carbo was 036 (p = 0.14); PFS HR = 0.62 (p = 0.40). Grade 3-4 toxicity was seen in 61% Pac-Carbo, 61% Oxal-Cape, 54% Pac-Carbo-Bev, and 85% Oxal-Cape-Bev. QoL was similar between the four arms. Conclusion. mEOC/GOG0241 represents an example of a randomized rare tumor trial, Logistical challenges led to early termination, including difficulties in local histopathological diagnosis and accessing drugs outside their labelled indication. There was misalignment between central funders who support clinical trials in rare cancers and the deprioritisation of such work by those managing and funding research at a local level. Rare cancer trials should include centralised pathology review before treatment. (C) 2019 The Authors. Published by Elsevier Inc.