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Background: Ovarian cancer is the most lethal gynecological cancer, causing over 200,000 deaths worldwide in 2020. Initial standard treatment for primary ovarian cancer is optimal cytoreductive surgery (CRS) preceded and/or followed by intravenous platinum-based chemotherapy. However, most women develop recurrence within the peritoneal cavity and die of disease. Results of the OVIHIPEC 1 trial (2018) showed improved survival of 34% when hyperthermic intraperitoneal chemotherapy (HIPEC) was given immediately following interval-CRS in women with stage III disease. However, it is unknown if the effect of HIPEC is due to hyperthermia, one extra cycle of intraperitoneal (IP) chemotherapy, or other factors. There is also concern that hyperthermia might be associated with an increase in adverse events (AEs) due to a heightened systemic inflammatory response. HyNOVA is a seamless, multi-stage randomized study that attempts to answer these questions by comparing HIPEC to normothermic intraperitoneal chemotherapy (NIPEC), focusing on safety (stage 1), then assessing activity (stage 2) and effectiveness (stage 3). In this initial study, we hypothesize that NIPEC will result in a lower rate of severe AEs compared to HIPEC., Methods: This initial stage of HyNOVA is a phase II study of 80 women with International Federation of Gynaecology and Obstetrics stage III epithelial ovarian cancer, with at least stable disease following 3-4 cycles of neoadjuvant chemotherapy, achieving interval-CRS to <2.5 mm residual disease. Participants are randomized 1:1 to receive IP cisplatin 100 mg/m² for 90 minutes either as HIPEC, heated to 42°C (41.5°C-42.5°C), or NIPEC, at 37°C (36.5°C-37.5°C). The primary outcome is the proportion of AEs ≥ grade 3 occurring within 90 days. Secondary outcomes are AE of interest, surgical morbidity, patient reported outcomes, resource allocation, feasibility, progression-free survival and overall survival. AEs are measured using both CTCAE v5.0 and Clavien-Dindo classification, particularly infection, pain, bowel dysfunction, and anemia. Tertiary outcomes are potential predictive biomarkers measured before and after HIPEC/NIPEC including circulating cell-free tumor DNA, tissue factors, and systemic inflammatory markers. There are 4 participating Australian sites with experience in CRS and HIPEC for peritoneal malignancy. HyNOVA is funded by an MRFF grant (APP1199155)., Trial Registration: ANZCTR Identifier: ACTRN12621000269831., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2022. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Health related quality of life (HRQOL) is a key priority for patients with ovarian cancer as there is significant morbidity associated with the disease and the treatment. It is therefore essential to include measures of HRQOL and patient reported outcomes (PROs) in all clinical trials and ideally report them in the initial manuscript. The results of these analyses help interpret the primary trial endpoints which are typically progression free survival and overall survival from the perspective of the patients, but can also assist with regulatory approval of new drugs and inform future patients regarding the potential benefits and downsides of the treatment as well as help support clinical recommendations. Including PROs in clinical trials allows patient-defined clinical benefits to be assessed in parallel to traditional survival outcomes to provide a more holistic overview and aid in the interpretation of the trial results. Given the importance of these instruments in clinical trials, greater effort is required to improve the appropriate inclusion, quality of analyses and reporting of PROs. It is also essential that all clinicians understand the intricacies of the selection, implementation and interpretation of these measures of HRQOL and PRO's and how important their contribution is to clinical trials as well as clinical practice. This review is a practical guide for clinicians to gain a better understanding of PROs and how they can be incorporated into ovarian cancer trials., Competing Interests: M K Wilson has received travel support from MSD and Roche. M Friedlander has received honoraria for being part of the advisory board for Astra Zeneca and MSD. R Mercieca-Bebber has no conflicts., (Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Purpose: Patient-reported outcomes (PROs) provide the patient's perspective of the impact of treatment. Evidence suggests that PRO content of randomised controlled trials (RCTs) protocols is generally sub-optimal. This study aimed to describe and evaluate the PRO-specific content of ovarian cancer RCT protocols., Methods: Published, phase III, ovarian cancer RCTs with PRO endpoints were identified following a systematic search of Medline and Cochrane databases (Jan 2000 to Feb 2016). Corresponding RCT protocols were downloaded (if published) or obtained by contacting authors. Two investigators independently assessed adherence of PRO-specific content of included protocols to a checklist of 58 recommended PRO protocol items currently being developed by the International Society for Quality of Life Research. Discrepancies were resolved with a third investigator., Results: Of 41 eligible trials identified, 26 protocols were assessed (developed 1995-2010). We were unable to obtain the remaining 15 protocols. Protocols addressed a mean of 28 % PRO checklist items (range 8-66 %). Fifteen (58 % of assessed protocols) provided a rationale for PRO assessment, 8 (31 %) described a PRO objective, 24 (92 %) included a PRO assessment schedule, but only 6 (23 %) justified timing of PRO assessments. Twelve protocols (46 %) provided staff data collection instructions, 4 (15 %) included plans for monitoring PRO compliance, and 16 (62 %) included a PRO analysis plan., Conclusions: On average, protocols addressed less than one-third of PRO protocol checklist items. In some cases, key guidance regarding PRO administration was lacking, which may lead to inconsistent and sub-optimal PRO methodology. Efforts are needed to improve PRO protocol content in cancer trials.

Despite increased recognition of the value of including patient-reported outcomes (PROs) as important end points in phase III clinical trials, there has been a lack of pre-specified PRO hypotheses and shortcomings with the analyses and interpretation of PROs in many ovarian cancer trials. This paper discusses and provides examples of the so-called lost opportunities in ovarian cancer trials. These include: (i) no clear pre-specified PRO hypotheses; (ii) PRO end points not included; (iii) insensitive PRO end point selection; (iv) collection of poor-quality PRO data not suitable for analysis; (v) differences in PROs between treatment arms ignored; and (vi) poor reporting quality. We can learn from the past and with relatively little additional effort, improve the collection and interpretation of PRO data in future ovarian cancer trials. The importance of doing so is underpinned by recent initiatives to improve the standard and usefulness of PRO data in clinical trials. These include the Food and Drug Administration (FDA) Guidance for PROs to support labelling claims, the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO MCBS), the International Society for Quality-of-Life Research PRO reporting guidance and the Consolidated Standards of Reporting Clinical Trials (CONSORT)-PRO-extension statement which includes a checklist of recommended items to include in PRO sections of trial protocols. Promoting the importance of hypothesis-driven PROs in ovarian cancer clinical trials will lead to improvements in the design of these trials and the interpretation of their results., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The aim of this study was to determine the optimal patient-reported outcome measure (PROM) for assessing symptom benefit in trials of palliative chemotherapy for women with symptomatic ovarian cancer., Methods: Candidate PROMs were EORTC QLQ-C30 plus ovarian-specific QLQ-OV28, Functional Assessment of Cancer Therapy-Ovarian (FACT-O), FACT Ovarian Symptom Index (FOSI), and gynecologic cancer-specific Symptom Representation Questionnaire. Predefined optimality criteria were inclusion of all symptoms necessary for the specified purpose, recall period covering typical length of palliative chemotherapy, numerical item rating scales, and all necessary symptoms included in a single symptom index. Qualitative and quantitative methods were applied to data from stage 1 of the Gynecologic Cancer Intergroup Symptom Benefit Study to determine the set of necessary symptoms and to objectively assess candidate PROMs against the optimality criteria., Results: Ten necessary symptoms were identified: pain, fatigue, abdominal bloating/discomfort, sleep disturbance, bowel disturbance, nausea and vomiting, shortness of breath, poor appetite, urinary symptoms, and weight changes. Although QLQ-C30 and QLQ-OV28 together cover all these symptoms, they split them into numerous scales, dissipating potential symptom-benefit signal. Conversely, FACT-O does not cover all necessary symptoms and contains many other HRQoL-related items and treatment side effects, diluting potential symptom-benefit signal when summed into scales. Item response scales and composite scoring of all candidate PROMs were suboptimal to our specific purpose. We therefore developed a new PROM, the Measure of Ovarian Symptoms and Treatment (MOST) concerns, to provide optimal measurement for the specified purpose., Conclusions: This article documents the development of the MOST, a new PROM designed to assess patient-reported benefits and burden as end points in clinical trials of palliative chemotherapy for women with symptomatic ovarian cancer. The validity, reliability, and statistical efficiency of the MOST, relative to the best candidate scales of existing PROMs, will be assessed in the stage 2 of Gynecologic Cancer Intergroup Symptom Benefit Study.