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Background: Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly (ie, once every 3 weeks) carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8. Here, we present the final coprimary outcomes of overall survival and updated progression-free survival analyses of ICON8., Methods: In this open-label, randomised, controlled, phase 3 trial (ICON8), women aged 18 years or older with newly diagnosed stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (here collectively termed ovarian cancer, as defined by International Federation of Gynecology and Obstetrics [FIGO] 1988 criteria) and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 117 hospitals with oncology departments in the UK, Australia and New Zealand, Mexico, South Korea, and Ireland. Patients could enter the trial after immediate primary surgery (IPS) or with planned delayed primary surgery (DPS) during chemotherapy, or could have no planned surgery. Participants were randomly assigned (1:1:1), using the Medical Research Council Clinical Trials Unit at University College London randomisation line with stratification by Gynecologic Cancer Intergroup group, FIGO disease stage, and outcome and timing of surgery, to either 3-weekly carboplatin area under the curve (AUC)5 or AUC6 and 3-weekly paclitaxel 175 mg/m 2 (control; group 1), 3-weekly carboplatin AUC5 or AUC6 and weekly paclitaxel 80 mg/m 2 (group 2), or weekly carboplatin AUC2 and weekly paclitaxel 80 mg/m 2 (group 3), all administered via intravenous infusion for a total of six 21-day cycles. Coprimary outcomes were progression-free survival and overall survival, with comparisons done between group 2 and group 1, and group 3 and group 1, in the intention-to-treat population. Safety was assessed in all patients who started at least one chemotherapy cycle. The trial is registered on ClinicalTrials.gov, NCT01654146, and ISRCTN registry, ISRCTN10356387, and is closed to accrual., Findings: Between June 6, 2011, and Nov 28, 2014, 1566 patients were randomly assigned to group 1 (n=522), group 2 (n=523), or group 3 (n=521). The median age was 62 years (IQR 54-68), 1073 (69%) of 1566 patients had high-grade serous carcinoma, 1119 (71%) had stage IIIC-IV disease, and 745 (48%) had IPS. As of data cutoff (March 31, 2020), with a median follow-up of 69 months (IQR 61-75), no significant difference in overall survival was observed in either comparison: median overall survival of 47·4 months (95% CI 43·1-54·8) in group 1, 54·8 months (46·6-61·6) in group 2, and 53·4 months (49·2-59·6) in group 3 (group 2 vs group 1: hazard ratio 0·87 [97·5% CI 0·73-1·05]; group 3 vs group 1: 0·91 [0·76-1·09]). No significant difference was observed for progression-free survival in either comparison and evidence of non-proportional hazards was seen (p=0·037), with restricted mean survival time of 23·9 months (97·5% CI 22·1-25·6) in group 1, 25·3 months (23·6-27·1) in group 2, and 24·8 months (23·0-26·5) in group 3. The most common grade 3-4 adverse events were reduced neutrophil count (78 [15%] of 511 patients in group 1, 183 [36%] of 514 in group 2, and 154 [30%] of 513 in group 3), reduced white blood cell count (22 [4%] in group 1, 80 [16%] in group 2, and 71 [14%] in group 3), and anaemia (26 [5%] in group 1, 66 [13%] in group 2, and 24 [5%] in group 3). No new serious adverse events were reported. Seven treatment-related deaths were reported (two in group 1, four in group 2, and one in group 3)., Interpretation: In our cohort of predominantly European women with epithelial ovarian cancer, we found that first-line weekly dose-dense chemotherapy did not improve overall or progression-free survival compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality front-line therapy in this patient group., Funding: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia., Competing Interests: Declarations of interests ARC reports institutional funding from Cancer Research UK for the present Article, consulting fees from AstraZeneca, payment or honoraria for lectures and presentations from Clovis Oncology and AstraZeneca, and support for attending meetings from GSK/Tesaro. IAM reports consulting fees from Clovis Oncology, AstraZeneca, GSK/Tesaro, and Roche; honoraria for lectures of presentations from AstraZeneca and GSK; travel support for attending meetings from AstraZeneca and GSK; and participation on an Independent Data Monitoring Committee for Transgene. SBl reports consulting fees from Ellipses Pharma, Theolytics, Amphista, and RApport Global Strategic Services; honoraria for lectures or presentations from Nucana and the Norwegian Cancer Society; has a planned patent (WO1999062548A90); being a member of advisory boards for the UCB6114, TORCH, AVAT-M, MROC, and OCTOVA studies; being founder and treasurer of La-Related Protein Society; and has received institutional support to conduct clinical trials from Nucana, UCB, Nurix, Astex, BergenBio, MSD, Redx, and MiNA Therapeutics. JBr reports royalties from Inivata; consulting fees from AstraZeneca; payment or honoraria for lectures or presentations from GSK and AstraZeneca; holding two patents that have been issued (1818159.5 and 1818159.4); being a cofounder and shareholder of Tailor Bio; and being a previous cofounder and shareholder of Inivata. TJP reports consulting fees from AstraZeneca, Exact Health, and MSD, and support for attending meetings from Gilead. SS reports honoraria for lectures or presentations from AstraZeneca and MSD, participation in advisory board meetings for AstraZeneca, and is current President of the British Gynaecological Cancer Society. RL reports advisory works for and honoraria for educational events and support for travel and enrolment at conferences from AstraZeneca and GSK. MH reports consulting fees and payment or honoraria for lectures or presentations from GSK and Clovis Oncology. SBa reports grants from AstraZeneca, Tesaro, and GSK; consulting fees from Amgen, AstraZeneca, Genmabs, GSK, Immunogen, MSD, Merck Sereno, Mersana, Oncxerna, Seagen, and Shattuck Labs; payment or honoraria for lectures from Amgen, AstraZeneca, Clovis Oncology, GSK, Immunogen, MSD, Mersana, Pfizer, Roche, and Takeda; and is European Society for Medical Oncology (ESMO) Director of Membership. RMG reports grants from Clovis Oncology, Boehringer Ingelheim, and Lily/Ignyta; consulting fees from Clovis Oncology, AstraZeneca, MSD, GSK, Sotio, Immunogen, and Novartis; payment or honoraria for lectures or presentations from Clovis Oncology, AstraZeneca, and GSK; support for attending conferences from GSK; being a member of the Independent Data Monitoring Committee for the Glasgow Cancer Research Trials Unit and Swiss GO Trials Group; and receipt of equipment (drugs) to institution from GSK. CLH reports royalties from Cambridge University Press, support for attending conferences from Tesaro, being chair of the Wales Cancer Network Gynaecological Cancer Site Group, and a member of British Gynaecological Society Guidelines Group. JAL reports institutional research grants from AstraZeneca and MSD/Merck; payment or honoraria for lectures or presentations from Pfizer, AstraZeneca, GSK, MSD, Clovis Oncology, Eisai, Bristol Myers Squibb, Artios Pharma, VBL Therapeutics, and Neopharm; being chair of an Independent Data Monitoring Committee for Regeneron; being editor of the Gynaecological Clinical Practice Guidelines (for ESMO); and former Vice President of European Society of Gynaecological Oncology. All other authors declare no competing interests., (Copyright © 2022 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: Fluoropyrimidine chemotherapy is used across many tumor types and settings. The incidence of severe adverse events (SAEs) is around 20%. Mortality is 0.5%-1%. Dihydropyrimidine dehydrogenase (DPD) plays a key role in fluoropyrimidine inactivation. Key DPYD mutations are linked to a high risk of SAEs. Pretreatment DPD screening was mandated by EMA guidelines in April 2020 and widely adopted thereafter. Uncertainty remains regarding optimal dosing practice., Methods: We retrospectively examined records of all 23 patients with DPYD mutation who started chemotherapy between April and November 2020. Our center tests for the mutations considered clinically actionable by Clinical Pharmacogenetics Implementation Consortium and uses the Gene Activity Score (GAS) to guide dose reduction., Results: Most patients started on a 50% dose. One started on 100% and experienced mild diarrhea after cycle 2; DPD was tested belatedly, subsequent cycles were reduced to 50% and he remained well. Three patients receiving chemo-radiotherapy started on 76% dose; 50% was felt to be subtherapeutic. One of them had no toxicities; another had grade 2 nausea and a hospital attendance with non-neutropenic fever; the third was admitted for 6 weeks with pancolitis. Seven patients did not have toxicities above grade 1 and no hospital attendances. Five patients had further dose reductions. None had dose escalation., Conclusion: As our experience shows, patients with DPD deficiency are heterogeneous. Worryingly, SAEs occur despite dose reduction according to GAS. Others had minimal toxicity and may be under-dosed by GAS. There are clearly many factors at play other than the 4 DPYD variants. The DPD result must be available and inform first cycle dosing. Dose should be cautiously titrated up if tolerated; this was not done at our center due to clinician caution. Further research is needed to guide this. Patients should be reviewed frequently, counselled regarding their DPD status, and empowered to seek advice promptly when they feel unwell., (Copyright © 2021 Elsevier Inc. All rights reserved.)