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

Physicochemical and textural quality attributes of gluten-free bread formulated with guar gum

The objective of this study was to assess the combined effect of guar gum (GG) and water content (WC) on the rheological properties of batter, and the physicochemical and textural properties of bread. Batches of gluten-free bread used a base formulation of rice (50%), maize (30%) and quinoa flour (20%), with different levels of GG (2.5, 3.0 or 3.5%) and water (90, 100 or 110%) in a full factorial design. Higher GG doses (p<0.001) tended to produce batters of lower stickiness, work of adhesion and cohesive strength; yet, of higher firmness, consistency, cohesiveness and viscosity index. These batters yielded loaves of lower (p<0.001) specific volume and baking loss; and crumbs of lower (p<0.001) aw, pH, mean cell area, void fraction, mean cell aspect ratio; and higher (p<0.001) hardness, adhesiveness, springiness, cohesiveness, chewiness, resilience, mean cell density, cell size uniformity and mean cell compactness. The sticker and less consistent batters produced with higher WC rendered larger bread loaves of softer and more cohesive and springy/resilient crumbs with greater mean cell size and void fraction. Gluten-free loaves of good appearance in terms of higher specific volume, lower crumb hardness, higher crumb springiness, and open grain visual texture were obtained in formulations with 110% WC and GG doses between 2.5 and 3.0%.Eng. Encina-Zelada acknowledges the financial aid provided by the Peruvian National Programme of Scholarships and Student Loans (PRONABEC) in the mode of PhD grants (Presidente de la República-183308). The authors are grateful to Eng. Andrea Oliveira from Prodipani, Portugal, for her kind advice and providing breadmaking ingredients.info:eu-repo/semantics/publishedVersio

Targeted anti-vascular therapies for ovarian cancer: current evidence

Ovarian cancer presents at advanced stage in around 75% of women, and despite improvements in treatments such as chemotherapy, the 5-year survival from the disease in women diagnosed between 1996 and 1999 in England and Wales was only 36%. Over 80% of patients with advanced ovarian cancer will relapse and despite a good chance of remission from further chemotherapy, they will usually die from their disease. Sequential treatment strategies are employed to maximise quality and length of life but patients eventually become resistant to cytotoxic agents. The expansion in understanding of the molecular biology that characterises cancer cells has led to the rapid development of new agents to target important pathways but the heterogeneity of ovarian cancer biology means that there is no predominant defect. This review attempts to discuss progress to date in tackling a more general target applicable to ovary cancer-angiogenesis

Drawings of very preterm-born children at 5 years of age: a first impression of cognitive and motor development?

INTRODUCTION: The aim of this study was to examine differences in drawing skills between very preterm and term children, and to determine whether very preterm children's cognitive and motor development is reflected in the draw-a-person test (DAP) at age 5. Seventy-two very preterm children (birth weight <1,500 g and/or gestational age <32 weeks) and 60 term children at 5 years of age were compared on the DAP. Cognitive and motor skills of the very preterm children had been assessed four times, at 1/2, 1, 2, and 5 years of age. Very preterm children showed a developmental delay in drawing ability. Structural equation modeling revealed a positive relation between both cognitive as well as motor development and the DAP. CONCLUSION: The DAP could be a crude parameter for evaluating cognitive and motor deficits of very preterm children. A worrisome result should be followed by more standardized tests measuring cognitive and motor skill

Ovarian cancer

Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly(ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer (such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies

Psychological interventions prior to cancer surgery: A review of reviews

The majority of women requiring chemotherapy for gestational trophoblastic disease (GTN) are cured with their initial chemotherapy treatment. However, a small percentage either become refractory to treatment, or relapse after the completion of treatment. This study investigates the characteristics and outcome of these patients. Patients were identified from the Charing Cross Hospital GTD database. The outcome of these patients with relapsed disease was compared to those with refractory disease. Between 1980 and 2004, 1708 patients were treated with chemotherapy for GTN. Sixty (3.5%) patents relapsed following completion of initial therapy. The overall 5-year survival for patients with relapsed GTN was 93% (95% CI 86–100%). The overall survival for patients with low-risk and high-risk disease at presentation, who subsequently relapsed was 100% (n=35), and 84% (n=25) (95% CI: 66–96%: P<0.05), respectively. Eleven patients were identified who failed to enter remission and had refractory disease. These patients had a worse outcome compared to patients with relapsed disease (5-year survival 43% (95% CI:12–73% P<0.01)). The outcome of patients with relapsed GTN is good. However, patients with primary chemo-refractory disease do poorly and novel therapies are required for this group of patients

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