Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial

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/m2 (control; group 1), 3-weekly carboplatin AUC5 or AUC6 and weekly paclitaxel 80 mg/m2 (group 2), or weekly carboplatin AUC2 and weekly paclitaxel 80 mg/m2 (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

Partially overlapping spatial environments trigger reinstatement in hippocampus and schema representations in prefrontal cortex

When we remember a city that we have visited, we retrieve places related to finding our goal but also non-target locations within this environment. Yet, understanding how the human brain implements the neural computations underlying holistic retrieval remains unsolved, particularly for shared aspects of environments. Here, human participants learned and retrieved details from three partially overlapping environments while undergoing high-resolution functional magnetic resonance imaging (fMRI). Our findings show reinstatement of stores even when they are not related to a specific trial probe, providing evidence for holistic environmental retrieval. For stores shared between cities, we find evidence for pattern separation (representational orthogonalization) in hippocampal subfield CA2/3/DG and repulsion in CA1 (differentiation beyond orthogonalization). Additionally, our findings demonstrate that medial prefrontal cortex (mPFC) stores representations of the common spatial structure, termed schema, across environments. Together, our findings suggest how unique and common elements of multiple spatial environments are accessed computationally and neurally. © 2021, The Author(s).Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Overall survival results from ICON8, a GCIG phase 3 randomised controlled trial assessing weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment

Background: Standard of care first line chemotherapy for epithelial ovarian cancer (EOC) is carboplatin and paclitaxel administered once every three weeks. The JGOG3016 trial reported significant improvement in progression-free (PFS) and overall survival (OS) with dose-dense weekly paclitaxel and three-weekly carboplatin. However, this benefit was not observed in the progression free survival results of ICON8, previously reported. Here, we present the final co-primary OS and updated PFS outcomes. Methods: Women aged 18 or above with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IC-IV EOC were recruited. Patients were randomly assigned to one of three groups; group 1: 3-weekly carboplatin area under the curve (AUC) 5/6 and 3-weekly paclitaxel 175mg/m2, group 2: 3-weekly carboplatin AUC5/6 and weekly paclitaxel 80mg/m2, group 3: weekly carboplatin AUC2 and weekly paclitaxel 80mg/m2, all administered by intravenous infusion. Patients entered the trial after immediate primary surgery (IPS) or received delayed primary surgery (DPS) during chemotherapy. Randomisation was performed using minimisation with stratification factors of GCIG group, disease stage and outcome and timing of surgery. Co-primary outcomes were PFS and OS, with comparisons performed between group 2 and group 1, and group 3 and group 1. Intention-to-treat analyses were powered to detect a hazard ratio of 0.75 in favour of the experimental groups. The trial is registered on clinicaltrials.gov as NCT01654146 and controlled-trials.com asISRCTN10356387. Findings: Between 6 Jun 2011 and 28 Nov 2014, 1566 women were recruited; group 1 (N=522), group 2 (N=523) and group 3 (N=521). Baseline characteristics include median age 62, 69% high grade serous carcinoma, 72% stage IIIC-IV disease, 48% IPS. By March 2020, with a median follow up of 69 months (IQR 61-75 months), 324, 309 and 313 deaths had occurred in groups 1, 2 and 3 respectively. No significant difference in OS was observed in either comparison: HR 0.87 (97.5% CI 0.73, 1.05) group 2 vs group 1, HR 0.91 (97.5% CI 0.76, 1.09) group 3 vs group 1. Most common G3/4 adverse events were reduced neutrophils (78, 183, 154 in groups 1, 2, 3) reduced white blood cell count (22, 80, 71 In groups 1, 2, 3) and anaemia (26, 66, 25 in groups 1, 2, 3). No new serious adverse events were reported. Interpretation: First-line weekly dose-dense chemotherapy does not improve OS for patients with EOC compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality ovarian cancer treatment for Caucasian women in the front-line setting. Funding: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia

The Relationship between Country of Residence, Gender and the Quality of Life in Australian and Taiwanese Midlife Residents

midlife men and women, multi-cultural quality of life research, probability proportional sampling,