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Objective: Stage IVA patients comprise a small proportion of participants in cervical cancer trials, yet survival outcomes are disproportionately poor. We aim to perform a systematic review evaluating stage IVA cervical cancer., Methods: This systematic review was completed via PRISMA 2020 guidelines using two databases. Inclusion criteria comprised Phase III trials (2004-2024) assessing stage IVA cervical cancer including patients by stage. Searches had MeSH terms: ((cervical cancer) AND (stage IVA) AND (locally advanced)). 761 were articles identified, including books, trials, reviews, and meta-analyses. Of the articles identified, 12 met inclusion criteria., Results: A total of 133 (3.8% of study populations) stage IVA and 818 (40% of study populations) stage III-IVA cervical cancer patients were analyzed. Two studies (stage IVA n = 15; 3.1%) established cisplatin as chemoradiotherapy agent of choice, while one study (stage IVA n = 2; 1%) showed no benefit with cisplatin versus radiotherapy alone. Four studies (stage IVA n = 32; 3.6%; stages IIIB-IVA n = 220; 24%) found no benefit with adjuvant chemotherapy, with one analyzing stage IIIB-IVA patients (progression-free survival (PFS) hazard ratio (HR) = 0.84; 95% confidence interval (CI): 0.57-1.23). Three studies (stage IVA n = 71; 5%) found no benefit adding immunomodulator (stage IVA overall survival HR = 3.48; 95% CI: 0.52-23.29), hypoxic cell sensitizer, or immunotherapy (stage III-IVA PFS HR = 0.71; 95% CI: 0.49-1.03) to chemoradiotherapy. One study (stages III-IVA n = 598; 56%) found benefit adding immunotherapy to chemoradiotherapy (stage III-IVA PFS HR = 0.58; 95% CI: 0.42-0.8). One study (stage IVA n = 13; 3.5%) showed benefit with induction chemotherapy., Conclusion: Trials have not included substantial IVA patients to draw reasonable conclusions. Despite mixed results for immunotherapy, adjuvant chemotherapy, and induction chemotherapy, the exact benefit for stage IVA patients remains unknown. Future clinical trials should include a greater number of stage IVA cervical cancer patients and analyze them individually., Competing Interests: Declaration of competing interest There are no conflicts of interest for this systematic review., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Due to limited data on homologous recombination deficiency (HRD) in older patients (≥ 70 years) with advanced stage high grade serous ovarian cancer (HGSC), we aimed to determine the rates of HRD at diagnosis in this age group., Methods: From the Phase 3 trial VELIA the frequency of HRD and BRCA1/2 pathogenic variants (PVs) was compared between younger (< 70 years) and older participants. HRD and somatic(s) BRCA1/2 pathogenic variants (PVs) were determined at diagnosis using Myriad myChoice® CDx and germline(g) BRCA1/2 PVs using Myriad BRACAnalysis CDx®. HRD was defined if a BRCA PV was present, or the genomic instability score (GIS) met threshold (GIS ≥ 33 & ≥ 42 analyzed)., Results: Of 1140 participants, 21% were ≥ 70 years. In total, 26% (n = 298) had a BRCA1/2 PV and HRD, 29% (n = 329) were HRD/BRCA wild-type, 33% (n = 372) non-HRD, and 12% HR-status unknown (n = 141). HRD rates were higher in younger participants, 59% (n = 476/802), compared to 40% (n = 78/197) of older participants (GIS ≥ 42) [p < 0.001]; similar rates demonstrated with GIS ≥ 33, 66% vs 48% [p < 0.001]. gBRCA PVs observed in 24% younger vs 8% of older participants (p < 0.001); sBRCA in 8% vs 10% (p = 0.2559), and HRD (GIS ≥ 42) not due to gBRCA was 35% vs 31% (p = 0.36)., Conclusions: HRD frequency was similar in participants aged < 70 and ≥ 70 years (35% vs 31%) when the contribution of gBRCA was excluded; rates of sBRCA PVs were also similar (8% v 10%), thus underscoring the importance of HRD and BRCA testing at diagnosis in older patients with advanced HGSC given the therapeutic implications., Competing Interests: Declaration of competing interest The following authors have no disclosures relating to this manuscript: Omali Pitiyarachchi, Laura Holman, Paul DiSilvestro, Mark Morgan, William Tew, Christine Lee, Meredith Newton, Babak Edraki, Thomas Reid and Jay Carlson. Peter J. Ansell and Minh H Dinh are AbbVie employees receiving stock or stock options. Robert L. Coleman: has received grants or contracts from AstraZeneca, Clovis, Genelux, Genmab, Merck, Immunogen, Roche/Genentech, Karyopharm; consulting fees from Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, OncoQuest, Onxerna, Regeneron, Karyopharm, Roche/Genentech, Novocure, Merck, Abbvie, Novocure; royalties or licenses with Up-To-Date; payment or honoraria for speakers bureaus from AstraZeneca, Clovis, Roche/Genentech, Merck; participation in data safety monitoring or advisory boards from NRG Oncology, Elsai/BMS; leadership or fiduciary role in Onxeo/Valerio, Vaniam Group, GOG Foundation, International Gynecologic Cancer Society, OCNA, Ovarcome. Charles A. Leath III: Grant to institution provided by National Institutes of Health (NCI UG1 CA233330). Theresa Werner has received consulting fees from Mersana; and research funding to the institution - AbbVie, Acrivon, Astra Zeneca, BluePrint, Clovis Oncology, Genmab, GSK-Tesaro, Mersana, Repare Therapeutics, Roche-Genentech. Mary Cunningham: funds to institution provided by Abbvie, AstraZeneca, Clovis Oncology, Tesaro, Vascular Biogenics; and spouse is a stockholder of Intuitive Surgical. Peter Lim: has received payment or honoraria for Speakers Bureau from Astra Zeneca and Merck and is on Advisory Boards for Astra Zeneca, Clovis, Mersana, OncoC4, Immunogen. Joyce Barlin: has received payment/honoraria for Speakers Bureaus from Astra Zeneca and Merck and is on Advisory Boards for Astra Zeneca, Clovis, Mersana, OncoC4, Immunogen. Nicola M. Spirtos: has received institutional grants from NRG and the GOG Foundation. Krishnansu S. Tewari: reports grants to institution (UC Irvine) provided by AbbVie; consulting fees from Merck, Astra Zeneca, Eisai, Seagen, GSK; and payment/honoraria for Speakers Bureaus from Merck, Astra Zeneca, Eisai, Seagen, GSK. Mitchell Edelson: has received funding to attend meetings from Intuitive Surgical; received stock options from Merck when employed. Spouse was a salaried employee at Merck until 8/2022 and spouse is a salaried employee at Pfizer since 3/2023. Michael Friedlander: has received consulting fees from Astra Zeneca, Novartis and GSK; has consulted without payment for Incyclix; has received payment or honoraria for Speakers Bureaus from Astra Zeneca, GSK and MSD; has participated on Data Safety Monitoring or Advisory Boards for AGITG IDSMB and ENDO-3; received institutional support in the form of research grants from Astra Zeneca, Beigene and Novartis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl)., Methods: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event., Results: AUC statistics (range, 0.52-0.64) showed log(CrCl Jelliffe ) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%-15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively., Conclusion: The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials., Competing Interests: Declaration of Competing Interest Dr. O'Cearbhaill reports support for this study from NCI/NIH P30 CA008748 and grants to Institution from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, AbbVie/Stemkens, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, Marker Therapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Genentech, Kite Pharma, Acrivon and Gynecologic Oncology Foundation. Outside of the submitted work, Dr. O'Cearbhaill reports honoraria from GSK, Bayer, Regeneron, SeaGen, Fresenius Kabi, Immunogen, MJH Life Sciences and Curio. Dr. O'Cearbhaill reports receiving support to attend meetings and/or travel from Hitech Health, Gathering Around Cancer, Ireland, GOG Foundation and SGO. Dr. O'Cearbhaill participated on Data Safety Monitoring Board or Advisory Board for each of the following: AstraZeneca (DUO-0), GSK (moonstone, Prima), Acrivon, Carina Biotech, Link therapeutics, Tesaro/GSK, Regeneron, Seattle Genetics/Seagen, Immunogen, Bayer, R-Pharm, 2seventybio, Miltenyi and Fresenius Kabi. Dr. O'Cearbhaill also served as Vice-chair for the CPC, SGO as well a Chair, Developmental Therapeutics Committee for NRG Oncology. Dr. Aghajanian received research grants from AbbVie, Clovis, Genentech and Astra Zeneca and served on advisory boards for AbbVie, AstraZeneca/Merck, Eisai/Merck, Mersana Therapeutics, Repare Therapeutics and Roche/Genentech and received consulting fees for serving. Dr. Aghajanian served on the Blueprint Medicine Advisory Board (uncompensated). Dr. Aghajanian also serves on the GOG Foundation, Board of Directors (travel cost reimbursement for attending meetings) as well as the NRG Oncology Board of Directors (unpaid). Dr. Floor Backes wishes to report research grants from Immunogen, Clovis, Merck, Eisai, Natera and Beigene. Dr. Backes reports receiving consulting fees received from Eisai, Merck, Agenus, AstraZeneca, GlaxoSmithKline; Myriad, Clovis Oncology and Immunogen. Dr. Backes received honoraria for serving on advisory boards from Medlearning Group, CEC Oncology, OncLive, i3Health, and Medscape. Dr. Backes serves as Co-Chair of the NRG Oncology Developmental Therapeutics. Dr. Backes is a member of the Uterine Corpus Committee as well as a NCCN Ovary member and serves as an SGO Board Member. Dr. Michael Bookman reports payment to his Institution from Immunogen Data Monitoring Committee (unrelated to this project). Dr. David Cohn reports receiving honoraria from UpToDate as an Author as well as receiving payment for his role with Elsevier, Gynecologic Oncology as an Editor-in-Chief. Dr. Michael Friedlander reports that personally receiving consulting fees from AstraZeneca, Novartis, GSK and Incyclix (Nil). Dr. Friedlander also reports receiving honoraria from AstraZeneca and GSK and also received travel funding from AstraZeneca. Dr. Friedlander reports participating on Data Safety Monitoring Board/Advisory Board for AGITG IDSMB and ENDO-3. Dr. Friedlander reports that his Institution received grants from AstraZeneca, Beigene and Novartis. Dr. David Gershenson reports support from NRG Oncology with regard to this Study. Dr. Gershenson also acknowledges grants to his Institution from Novartis, GOG Foundation, and the NCI. Dr. Gershenson personally received royalties from Elsevier and UpToDate and consulting fees from Genentech (uncompensated) and Verastem. Dr. Gershenson received honoraria from University of Washington OB/GYN Grand Rounds and Yale University OB/GYN Grand Rounds and participating in a data safety monitoring/advisory board for Onconova, Aadi and Springworks. Dr. Gershenson also served on the International Consortium for Low-Grade Serous Ovarian Cancer and NCCN Ovarian Cancer Panel (uncompensated). Dr. Gershenson also wishes to disclose having stock in managed accounts for Bristol Myers Squibb, Johnson & Johnson and Procter & Gamble. Dr. Michael Goodheart reports receiving consulting fees from GlasoSmithKlein GSK/Tesaro, Merck, AstraZeneca, Clovis Oncology, SeaGen and Eisai. Dr. Angeles Alvarez Secord reports clinical trial grants received from the following: AbbVie, Aravive, AstraZeneca, BoehringerIngelheim, Clovis, Eisai, Ellipses, I-MAB Biopharma, Immunogen, Merck, Oncoquest/Canaria Bio, Seagen Inc., TapImmune, Tesaro/GSK, VBL Therapeutics. Dr. Secord also wishes to report receiving clinical trial grant/translational research grant from Roche/Genentech as well as Consulting fee from Myriad. Dr. Secord also received support for attending meetings/travel from GSK, GOG Foundation and NRG. Dr. Secord also served on the Clinical Trial Steering Committees for Aravive, Genentech/Roche, VBL Therapeutics and Oncoquest/Canaria Bio without compensation. Dr. Secord personally received compensation from GOG Foundation and NRG Oncology paid compensation to Institution. Dr. Secord also served in Leadership roles for Society of Gynecologic Oncology and American Association of Obstetrics and Gynecology Foundation (uncompensated). Dr. Judith Smith received honoraria for Speaking at the HOPA Annual Meeting 2016 – Harmonization of Carboplatin Dosing, Dr. Smith serves as Chair on the NRG Oncology Pharmacy Subcommittee. Dr. Tewari also reports receiving honoraria from Eisai, AstraZeneca, Clovis, GSK/Tesaro, Merck and Seagen/Genmab. Dr. Krishnansu Tewari reports receiving consulting fees from Regeneron, Eisai, AstraZeneca, Clovis, GSK/Tesaro, Merck, Seagen/Genmab. Dr. Andrea Wahner Hendrickson reports receiving Clinical Trial support from Prolynx and Site PI Clinical Trial Support from both Amgen and TORL Biotherapeutics. Dr. Wahner Hendrickson reports serving on Oxcia Advisory Board (uncompensated). Dr. Wahner Hendrickson reports serving on an Advisory Board for the Mayo Clinic Data Safety Monitoring Board (uncompensated). Dr. Wahner Hendrickson also served on the NCCN Ovarian Cancer Committee (uncompensated). Dr. Robert Wenham reports personal and institutional grants received from Merck and Ovation Diagnostics. Dr. Wenham reports receiving consulting fees from Merck, Legend Biotech, Genentech, Ovation Diagnostics, GSK/Tesaro, Clovis, AstraZeneca, AbbVie, Legend Biotech, Regeneron, Seagen, Sonic Biotherapeutics, Shattuck Labs, Novacure, Eisai and Immunogen. Dr. Wenham also reports receiving Institutional Clinical Trial Fees from AbbVie, AstraZeneca, Regeneron and Eisai. Dr. Wenham reports serving on Advisory Board for Seagen and GSK/Tesaro. Dr. Wenham would like to disclose personally owning stock in Ovation Diagnostics. Dr. Peter Argenta, Dr. Heidi Gray, Dr. Roger Lee, Dr. Stuart Lichtman, Dr. Austin Miller, Dr. David Mutch, Dr. Aaron Praiss, Dr. Paul Sabbatini and Dr. Linda Van Le have no potential conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To assess the effect of age on overall survival (OS) in women with ovarian cancer receiving chemotherapy. Secondary objectives were to describe the effect of age on treatment compliance, toxicities, progression free survival (PFS), time from surgery to chemotherapy, and rates of optimal cytoreduction., Methods: Women enrolled in GOG 0182-ICON5 with stage III or IV epithelial ovarian cancer (EOC) who underwent surgery and chemotherapy between 2001 and 2004 were included. Patients were divided into ages <70 and ≥ 70 years. Baseline characteristics, treatment compliance, toxicities, and clinical outcomes were compared., Results: We included a total of 3686 patients, with 620 patients (16.8%) ≥ 70 years. OS was 37.2 months in older compared to 45.0 months in younger patients (HR 1.21, 95% CI, 1.09-1.34, p < 0.001). Older patients had an increased risk of cancer-specific-death (HR 1.16, 95% CI, 1.04-1.29) as well as non-cancer related deaths (HR 2.78, 95% CI, 2.00-3.87). Median PFS was 15.1 months in older compared to 16.0 months in younger patients (HR 1.10, 95% CI, 1.00-1.20, p = 0.056). In the carboplatin/paclitaxel arm, older patients were just as likely to complete therapy and more likely to develop grade ≥ 2 peripheral neuropathy (35.7 vs 19.7%, p < 0.001). Risk of other toxicities remained equal between groups., Conclusions: In women with advanced EOC receiving chemotherapy, age ≥ 70 was associated with shorter OS and cancer specific survival. Older patients receiving carboplatin and paclitaxel reported higher rates of grade ≥ 2 neuropathy but were not more likely to suffer from other chemotherapy related toxicities. Clintrials.gov: NCT00011986., Competing Interests: Declaration of Competing Interest Each coauthor must complete an icmje form so that this page can be completed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To determine whether a non‑platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma., Methods: Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m 2 plus topotecan 0.75 mg/m 2 days 1-3 (n = 223) vs cisplatin 50 mg/m 2 plus paclitaxel 135 or 175 mg/m 2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS., Results: At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91-1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82-1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86-1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86-1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75-1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones., Conclusions: Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. NCT00803062., Competing Interests: Declaration of Competing Interest Dr. Tewari reports receiving honoraria for lectures, presentations, speakers' bureaus for Merck, Astra Zeneca, Eisai, Seagen, Tesaro and Clovis. He also reports serving on Data Safety Monitoring Board/Advisory Board for Iovance. Dr. Penson reports grants received from Array BioPharma Inc., AstraZeneca, Eisai Inc., Genentech, Inc., Regeneron, Sanofi-Aventis US LLC, Tesaro Inc. and Vascular Biogenics Ltd. Dr. Penson also reports receiving consulting fees from AstraZeneca, Eisai, GSK Inc., ImmunoGen Inc., Merck & Co, Mersana, Novacure, Roche Pharma, Sutro Biopharma, and Vascular Biogenics Ltd. and reports participating on Advisory Boards for AstraZeneca and Roche Pharma. Dr. Oaknin reports grants to her institution from the following: Abbvie Deutschland Gmbh & Co Hg, Ability Pharmaceuticals, Advaxis, Agenus, Aprea Therapeutics AB, AstraZeneca AB, BeiGene USA, Inc., Belgian Gynecological Oncology Group (BGOG), Bristol-Myers Squibb International Corporation (BMSM Clovis Oncology, Corcept Therapeutics, Eisai, F. Hoffmann-La Roche, Grupo Española de Investigación en Cáncer de Ovario (GEICO)), Immunogen, Iovance Biotherapeutics, Lilly, Medimmune, Merck Healthcare, Merck Sharp & Dohme, Millennium Pharmaceuticals, Unipharm Research, Novartis Farmacéutica, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem. Dr. Oaknin also reports receiving consulting fees from: Agenus, AstraZeneca Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, ROCHE FARMA, Sattucklabs, and Sutro Biopharma, Inc., and GEICO. Dr. Oaknin reports personally receiving honoraria for lectures, presentations and Speakers bureaus from ESMO, Edizioni Minerva Medica SpA, Doctaforum Servicios S.L and received support for travel from Roche, AstraZeneca, PharmaMar as well as Clovis. Dr. Oaknin participated on Data Safety Monitoring Board/Advisory Board for Agenus, AstraZeneca Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, GOG, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, ROCHE FARMA, Sattucklabs and Sutro Biopharma. Dr. Leitao reports receiving consulting fees from Medtronic, honoraria for lectures from Intuitive Surgical, Inc. as an Ad-hoc Speaker and participating on an Advisory Board for JnJ/Ethicon. Dr. Monk reports receiving consulting fees from the following: Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, UmmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pleris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, Verastem and Zentalis. He also reports receiving honoraria from: AstraZeneca, Merck, Myriad, Tesaro/GSK, Roche/Genentech, Clovis and Easai. All other authors had no conflicts of interest to disclose with regard to this Study., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The primary purpose of this study was to determine if farletuzumab, an antifolate receptor-α monoclonal antibody, improved progression-free survival (PFS) versus placebo when added to standard chemotherapy regimens in patients with platinum-sensitive recurrent ovarian cancer (OC) in first relapse (platinum-free interval: 6-36 months) with low cancer antigen 125 (CA-125) levels., Methods: Eligibility included CA-125 ≤ 3 x upper limit of normal (ULN, 105 U/mL), high-grade serous, platinum-sensitive recurrent OC, previous treatment with debulking surgery, and first-line platinum-based chemotherapy with 1st recurrence between 6 and 36 months since frontline platinum-based treatment. Patients received investigator's choice of either carboplatin (CARBO)/paclitaxel (PTX) every 3 weeks or CARBO/pegylated liposomal doxorubicin (PLD) every 4 weeks x6 cycles in combination with either farletuzumab [5 mg/kg weekly] or placebo randomized in a 2:1 ratio. Maintenance treatment with farletuzumab (5 mg/kg weekly) or placebo was given until disease progression or intolerance., Results: 214 patients were randomly assigned to farletuzumab+chemotherapy (142 patients) versus placebo+chemotherapy (72 patients). The primary efficacy endpoint, PFS, was not significantly different between treatment groups (1-sided α = 0.10; p-value = 0.25; hazard ratio [HR] = 0.89, 80% confidence interval [CI]: 0.71, 1.11), a median of 11.7 months (95% CI: 10.2, 13.6) versus 10.8 months (95% CI: 9.5, 13.2) for farletuzumab+chemotherapy and placebo+chemotherapy, respectively. No new safety concerns were identified with the combination of farletuzumab+chemotherapy., Conclusions: Adding farletuzumab to standard chemotherapy does not improve PFS in patients with OC who were platinum-sensitive in first relapse with low CA-125 levels. Folate receptor-α expression was not measured in this study. (Clinical Trial Registry NCT02289950)., Competing Interests: Declaration of Competing Interest TH reports medical writing support; consulting fees from Astra Zeneca (AZ), Caris, Clovis, Genentech, Gradalis, Epsilogen, Merck (MSD), Eisai, Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ, Clovis, GlaxoSmithKline (GSK); participation on a Data Safety Monitoring Board or Advisory Board from Incyte, Corcept; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid as Treasurer GOG Foundation and Associate Director GOG-P. SP reports no conflicts of interest. SG reports payments for clinical trial conduct from Eisai; grants or contracts for clinical trial conduct from GSK, Merck, Mersana, Jounce, AZ, Seagen, Clovis; consulting fees from Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eisai and GSK; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid as GOG foundation, GASCO, National Cancer Institute Cervix committee. MR reports no conflicts of interest. KF reports grants and contracts from Eisai; consulting fees from Eisai. CV reports medical writing support from Eisai; consulting fees from Janssen-Cilag, Roche, GSK, Atheneum Partners, Astellas Pharma, MSD, Bristol Myers Squibb (BMS), Leo-Pharma; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssens Cilag, Leo Pharma, Bayer; support for attending meetings and/or travel from Roche and Pfizer. DA reports clinical trial support from Eisai. JS reports consulting fees from Eisai, Roche, Novocure, AZ, GSK, Tesaro, Pfizer, MSD, Merck, Clovis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eisai, Roche, Novocure, AZ, GSK, Tesaro, Pfizer, MSD, Merck; payment for expert testimony from Eisai, Roche, Novocure, AZ, GSK, Tesaro, Pfizer, MSD, Merck; support for attending meetings and/or travel from GSK, Roche, AZ; participation on a Data Safety Monitoring Board or Advisory Board from Eisai, Roche, Novocure, AZ, GSK, Tesaro, Pfizer, MSD, Merck, Clovis; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid as ESGO council, NOGGO council, AGO Executive Board, GCIG member; RC reports grants or contracts from AZ, Clovis, Genelux, Genmab, Merck, Immunogen Janssen, Roche/Genentech; consulting fees from Agenus, Alkermes, AZ, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, Janssen, OncoQuest, Onxeo, Onxerna, Regeneron, Roche/Genentech, Novocure, Merck, Abbvie; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ, Clovis, Roche/Genentech, Merck; participation on a Data Safety Monitoring Board or Advisory Board from VBL Therapeutics. HG reports no conflicts of interest. GS reports grants or contracts from MSD Italia; consulting fees from Tesaro Bio Italy srl, Johnson and Johnson; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Clovis Oncology Italy srl. BM reports consulting fees from Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AZ, Bayer, Clovis, Eisai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyopharm, Lovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, Verastem, Zentalis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ, Clovis, Eisai, Merck, Myriad, Roche/Genentech, Tesaro/GSK. JA reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from BMS, Merck, Astellas, Eisai, Ipsen, Pfizer; support for attending meetngs and/or travel from Ipsen. KU reports grants or contracts from Eisai. RH reports grants or contracts from AZ, Clovis, GSK; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ, Clovis, GSK; multiple cases for medicolegal expert witness; participation on a Data Safety Monitoring Board or Advisory Board from AZ, Clovis, GSK. CZ reports grants or contracts from Novartis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Novartis, Pfizer, Lilly, AstraZeneca, MSD, Eisai, GSK; support for attending meetings or travel from Roche, Novartis, Pfizer, Lilly, AstraZeneca, MSD, Eisai, GSK, ExactSciences, Clovis; participation on a Data Safety Monitoring Board or Advisory Board from Roche, Novartis, Pfizer, Lilly, AstraZeneca, MSD, Eisai, GSK, DaichiSankyo. RW reports support for medical writing from Eisai; grants or contracts from OnTarget Labs, Merck, Anixa Bioscience; consulting fees from Novocure, Mersana, AZ, Ovation Diagnostics, Sonnet Biotherapeutics, Shattuck Labs, Clovis, Abbvie, Tesaro/GSK, Seagen, Genentech, Merck, Regeneron, Legend Biotech, Eisai; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AZ and GSK; support for attending meetngs and/or travel from Sonnet Biotherapeutics and Tapimmune; participation on a Data Safety Monitoring Board or Advisory Board from Tesaro, Seagen; stock or stock options from Ovation Diagnostics; AG reports grants or contracts from Roche and Tesaro/GSK; consulting fees from AZ, Genmab, MSD, Oncoinvent, PharmaMar, SOTIO, Clovis, Immunogen, Amgen Merck/Pfizer, Roche, GSK/Tesaro; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Tesaro/GSK, Clovis, Immunogen, Pfizer, Amgen, SOTIO, Marcrogenics, AZ, MSD, Genmab, Oncoinvent, EMD Serono, Mersana, SUTRO, PharmaMar; support for attending meetngs and/or travel from Roche, PharmaMar, AZ, Tesaro/GSK; BS reports consulting fees from AZ, Clovis, GSK, Merck, Eisai, Lilly, Novartis, Immunogen, Seagen, Genmab, Genentech; YJ reports employment from Eisai; LR reports employment from Eisai. KT reports support for the manuscript from Eisai; consulting fees from Merck, GSK, Clovis, AZ, Regeneron, Eisai, Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Merck, GSK, Clovis, AZ, Regeneron, Eisai, Seagen; participation on a Data Safety Monitoring Board or Advisory Board from Lovance. SW reports employment from Eisai. IV reports grants or contracts from Oncoinvent, AS, Amgen, Roche; consulting fees from Agenus, Akesobio, AZ BMS, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Exelixis, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Regeneron, Sanofi, Seagen, Sotio, Verastem Oncology, Zentalis; support for attending meetngs and/or travel from Karyopharm, Genmab, Novocure., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: To determine the clinical and prognostic significance of CA-125 trends prior to, during, and after chemotherapy in high-risk early-stage epithelial ovarian cancer patients., Methods: All patients were enrolled in a phase III randomized trial (GOG 157) following upfront surgery for grade 3 stage IA/IB, stage IC, or stage II disease, and had been treated with either three or six cycles of carboplatin/paclitaxel. Kaplan-Meier method and Cox proportional hazards model were used to evaluate recurrence-free survival (RFS) and overall survival (OS)., Results: Of 350 patients, the median pre-chemotherapy CA-125 was 65 (IQR: 31-129). 71% of Whites had an elevated CA-125 compared to 47% of non-Whites (p = 0.006). Following the first cycle of chemotherapy, 74% of those with elevated CA-125 had normalization. Those who had normalization of CA-125 after 1 cycle had significantly better 5-year RFS (81% vs. 65%, p = 0.003) and OS (87% vs. 75%, p = 0.009) compared to those who did not normalize (defined as ≤35 U/mL). The pattern of CA-125 change following chemotherapy cycle 1, from normal to normal vs. elevated to normal vs. elevated to elevated had corresponding RFS of 87% vs. 80% vs. 68% (p = 0.013), and OS of 92% vs. 88% vs. 77% (p = 0.009). However, the percent decline (p = 0.993) and absolute nadir normal value of CA-125 (0-10 vs. 11-35 U/mL) were not predictive of outcome (p = 0.4)., Conclusions: Normal baseline CA125 and normalization of this biomarker after the first cycle of chemotherapy were associated with better survival in high-risk early-stage epithelial ovarian cancer patients., Competing Interests: Declaration of Competing Interest The following authors reports no conflicts of interests: Drs. Chunqiao Tian, Michael Richardson, Ken Y Lin, Daniel S Kapp, Leah McNally, and Samuel Lentz. The following authors discloses various conflicts of interests: Dr. Robert M Wenham discloses receiving personal and institutional grants, consulting and clinical trial fees from Merck. The consulting fees are also received from Legend Biotech and Novacure as well as Merck. He also received personal and institutional grants and stock options from Ovation Diagnostics. His participation on a Data Safety Monitoring Board or Advisory Board and personal fees is supported by Seagen and GSK/Tesaro. More personal fees from Clovis, Seagen, Sonnet Biotherapeutics, Shattuck Labs, Novocurem Eisai and Immunogen. Institutional Clinical Trial fees are received from AstraZeneca, Abbvie, Regeneron, and Eisai. Sonnet Biotherapeutics also supported for Scientific Advisory Board. Dr. Nick M Spirtos discloses receiving support from NRG/GOG for manuscript funding and study materials and attending meetings or for institutional travel support as Co-chair of Surgical Oncology Committee. Dr. Thomas J. Herzog discloses receiving personal consulting fees from Aravive, AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genentech Roche, GSK, and Merck. His participation on a Data Safety and Monitoring Board or Advisory Board is supported by Corcept and Incyte. GOG Foundation also supported for his leadership or fiduciary role in other board. Dr. Bradley J. Monk discloses receiving honorarium as a consultant and investigator from Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Eisai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, Immunogen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, Verastern and Zentalis. Dr. Krishnansu S. Tewari discloses receiving sconsulting fees from Abbvie, Genentech, Merch, AstraZeneca, Tesaro/GSK, and Seagen. Dr. Tewari also received honoraria for lectures, presentations, and for manuscript writing from Merck, Astra Zeneca, and Clovis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Patients with advanced epithelial ovarian cancer (EOC) alive without progression at a landmark time-point of 10 years from diagnosis are likely cured. We report the proportion of patients with Stage III EOC who were long-term disease-free survivors (LTDFS≥10 years) following either intraperitoneal (IP) or intravenous (IV) chemotherapy as well as the predictors of LTDFS., Methods: Data from 3 mature NRG/GOG trials (104, 114, 172) were analyzed and included demographics, clinicopathologic details, route of administration, and survival outcomes of patients living ≥10 years assessed according to the Kaplan-Meier method. Cox regression survival analysis was performed to evaluate independent prognostic predictors of LTDFS., Results: Of 1174 patients randomized, 10-year overall survival (OS) was 26% (95% CI, 23-28%) and LTDFS ≥10 years was 18% (95% CI, 16-20%). Patients with LTDFS ≥10 years had a median age of 54.6 years (p < 0.001). Younger age (p < 0.001) was the only independent prognostic factor for LTDFS≥10 years on multivariate Cox analysis., Conclusions: Approximately 18% of patients were LTDFS ≥10 years. They form the tail end of the survival curve and are likely cured. Our results provide a comparative benchmark to evaluate the impact of PARP inhibitors in 1st line maintenance trials on survival outcomes., Competing Interests: Declaration of Competing Interest MF reports honoraria from Astra Zeneca;GSK;Novartis;MSD;Takeda;Lilly;Eisei for advisory boards/consulting.Speaker fees from Astra Zeneca;GSK and MSD. Institutional research funding from Astra Zeneca;Novartis and Beigene. Travel expenses for Astra Zeneca. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: In the Phase 3 VELIA trial (NCT02470585), veliparib added to carboplatin plus paclitaxel concomitantly and as maintenance for women with newly-diagnosed advanced ovarian cancer significantly improved progression-free survival (PFS) versus chemotherapy alone. Here we present exploratory analyses by paclitaxel dosing schedule and germline BRCA (gBRCA) status., Methods: Women with untreated ovarian carcinoma were randomized (1:1:1) to: veliparib during chemotherapy and maintenance (veliparib-throughout), veliparib during chemotherapy followed by placebo maintenance (veliparib-combination only), or placebo during chemotherapy and maintenance (control). Chemotherapy included carboplatin plus dose-dense (DD; weekly) or every-3-week (Q3W) paclitaxel (a stratification factor at randomization), selected at the investigator's discretion pre-randomization. PFS was assessed by paclitaxel dosing schedule using a Cox proportional hazard model adjusted by treatment arm and stratification factors; safety was analyzed based on paclitaxel dosing schedule and gBRCA status., Results: 1132 patients were analyzed by paclitaxel schedule. Pooled treatment arms demonstrated longer median PFS with DD (n = 586) versus Q3W (n = 546) paclitaxel (ITT: 20.5 vs 15.7 months, hazard ratio [HR] 0.77; homologous recombination proficient cancer: 15.1 vs 11.8 months, HR 0.64; BRCAwt: 18.0 vs 12.9 months, HR 0.70). Comparison between arms favored veliparib-throughout versus control in both DD (PFS, 24.2 vs 18.3 months, hazard ratio 0.67) and Q3W (19.3 vs 14.6, hazard ratio 0.69) subgroups. DD paclitaxel was associated with higher incidence of Grade 3/4 neutropenia, fatigue, and anemia versus Q3W. There were no differences in toxicity between gBRCAm (n = 211) and gBRCAwt (n = 902) subgroups., Conclusions: DD paclitaxel was tolerable and associated with longer PFS in the HR proficient and gBRCAwt groups, versus Q3W. gBRCA status did not impact safety., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Age and ethnicity are among several factors that influence overall survival (OS) in ovarian cancer. The study objective was to determine whether ethnicity and age were of prognostic significance in women enrolled in a clinical trial evaluating the addition of bevacizumab to front-line therapy., Methods: Women with advanced stage ovarian, primary peritoneal, or fallopian tube cancer were enrolled in a phase III clinical trial. All women had surgical staging and received adjuvant chemotherapy with one of three regimens. Cox proportional hazards models were used to evaluate the relationship between OS with age and race/ethnicity among the study participants., Results: One-thousand-eight-hundred-seventy-three women were enrolled in the study. There were 280 minority women and 328 women over the age of 70. Women age 70 and older had a 34% increase risk for death when compared to women under 60 (HR = 1.34; 95% CI 1.16-1.54). Non-Hispanic Black women had a 54% decreased risk of death with the addition of maintenance bevacizumab (HR = 0.46, 95% CI:0.26-0.83). Women of Asian descent had more hematologic grade 3 or greater adverse events and a 27% decrease risk of death when compared to non-Hispanic Whites (HR = 0.73; 95% CI: 0.59-0.90)., Conclusions: Non-Hispanic Black women showed a decreased risk of death with the addition of bevacizumab and patients of Asian ancestry had a lower death rate than all other minority groups, but despite these clinically meaningful improvements there was no statistically significant difference in OS among the groups., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Chemotherapy plus radiation (Cis-RT + CP) did not demonstrate superiority in prolonging relapse-free survival compared to chemotherapy alone in patients with stage III or IVA endometrial carcinoma. The impact of treatment on quality of life (QOL), neurotoxicity (NTX) and psychometric properties of the gastrointestinal (GI) symptoms subscale during treatment and up to 1 year are described herein., Methods: QOL assessments were scheduled at baseline, 6 weeks (post completion of RT (Cis-RT + CP) or prior to cycle 3 (CP)), then 18 weeks (end of treatment) and 70 weeks (1 year after the end of treatment) after starting treatment. QOL instruments included the FACT-En TOI, FACT/GOG-neurotoxicity (Ntx) subscale (short), and the gastrointestinal (GI) symptoms subscale., Results: At the end of treatment, patients receiving Cis-RT + CP reported a statistically significant decreased QOL when compared to CP. The decline in QOL was reflected in physical well-being, functional well-being, and endometrial cancer specific concerns, but the minimally important differences (MID) were not considered clinically meaningful. Patients in both groups reported increased chemotherapy-induced Ntx symptoms with the CP group having worse scores and reaching peak symptoms at the time of chemotherapy completion. Patients on Cis-RT + CP reported statistically significantly worse GI symptoms after radiation therapy compared to patients on CP, this occurred across assessment intervals, though the MID was not meaningful. Psychometric evaluations indicated that the GI symptom scale is reliable, valid, and responsive to change., Conclusions: PROs indicate that the chemoradiotherapy group experienced worse HRQoL and GI toxicity compared to patients randomized to chemotherapy alone for locally advanced endometrial cancer though based on the MID, these were not clinically meaningful differences. The GI symptom subscale was a reliable and valid scale that has value for future trials., Trial Registration: NCT00942357., Competing Interests: Declaration of Competing Interest Dr. Matulonis reports receiving consulting fees received from Merck, Novartis, Blueprint Medicine and Next Cure as well as participating on a Data Safety Monitoring Board or Advisory Board for Symphogen and Advaxis. Ms. Helen Huang, Dr. Marcus Randall, Dr. Paul DiSilvestro, Dr. Fowler, Dr. Powell, Dr. Dr. Spirtos, Dr. Tewari, Dr. Nakayama, Dr. Mutch have no conflicts of interest to disclose. Dr. Virginia L. Filiaci reports receiving support for the present manuscript from NCTN and NCORP SDMC grant funding from the NIH/NCI. She also reports grants from GOG Foundation, Inc. for contracts with institution for clinical trial work and NCI/NIH for IOTN, BIQSFP, MP2PRT and miscellaneous other subcontracts. Dr. Filiaci also reports receiving support for attending IDMC meeting from VBL Therapeutics as well as participating on Advisory Board for Tesaro. Monitoring Board. Dr. Katherine Moxley reports P20 grant to University of Oklahoma for Drug Resistance Core from the NIH as well as support for travel to attend NRG Oncology 2019 Winter and Summer meetings. Additionally, Dr. Moxley reports serving in a Leadership role for the SGO Program Committee. Dr. David Miller reports grants received from EMD Serono Research and Development Institute to him as well as grants to his Institution from the following entities: US Biotest, Advenchen Laboratories, Tesaro, Xenetic Biosciences, Advaxis, Janssen, Aeterna Zentaris, TRACON Pharma, Pfizer, Immunogen, Mateon Therapeutics, Merck Sharp & Dohme, AstraZeneca, Millenium Pharmaceuticals, Aprea AB, Regeneron, NVision, Leap Therapeutics, Novartis, Syros Pharmaceuticals, Karyopharm Therapeutics, Agenus and Akesobio. Dr. Miller also personally received consulting fees from the following: Genentech, Tesaro, Eisai, AstraZeneca, Guardant Health, Janssen Oncology, Alexion Pharmaceuticals, Karyopharm Therapeutics, Incyte, Guardant Health, Janssen, Alexion Pharmaceuticals, Clovis Oncology, Asymmetric Therapeutics, LLC, Boston Biomedical Research Institute, Tarveda Therapeutics, Myriad Genetic Laboratories Inc., GlaxoSmithKline LLC, AbbVie Inc., Incyte, EMD Serono Inc. and Seager Inc. as well as consulting fees paid to his Institution from Merck Sharp & Dohme. Dr. Miller also received honoraria from Clovis Oncology and Genentech. He also reports participating on an Advisory Board for Incyte. Dr. Lari Wenzel reports serving as Co-Chair of the NRG Oncology PCOR Committee. Dr. Daniela Matei reports NCI NRG Support grant received. Due to his unfortunate passing before publication, no statement is available for Dr. William Richards., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Platinum resistance, defined as the lack of response or relapse within six months of platinum-based chemotherapy, is an important determinant of survival in gynecologic cancer. We used quantitative Mass Spectrometry to identify metabolic signatures that predict platinum resistance in patients receiving chemotherapy for gynecologic cancers., Methods: In this study 47 patients with adenocarcinoma of the ovary or uterus who were candidates for carboplatin plus paclitaxel submitted blood for quantitation of metabolites and surgical specimens for the isolation 3-dimensional organoids used to measure individual patient platinum resistance, ex vivo. Results were correlated with response, time to progression and survival., Results: Of 47 patients, 27 (64.3%) achieved complete remission with a mean time to progression of 1.9 years (± 1.5), disease-free survival of 1.7 years (± 1.4) and overall survival of 2.6 years (± 1.6) and a mean cisplatin lethal concentration 50% (LC50) = 1.15 μg/ml (range 0.4-3.1). Cisplatin LC50's correlated with a non-significant decrease in complete remission (RR [95% CI] =0.76 [0.46-1.27]), diminished disease-free survival (median: 1.15 vs. 2.99 years, p = 0.038) and with biochemical signatures of 186 metabolites. Receiver operating curves (ROC) of lipid ratios, branched chain amino acids and the tryptophan to kynurenine ratio identified patients at the highest risk of relapse and death (AUC = 0.933) with a sensitivity of 92.0% and specificity of 86.0% (p < 0.001)., Conclusions: Metabolic signatures in gynecologic cancer identify patients at the highest risk of relapse and death offering new diagnostic and prognostic tools for management of the advanced gynecologic tumors., Competing Interests: Declaration of Competing Interest Krishnansu S. Tewari, Robert E. Bristow, Fabio Cappuccini, Marcia B. Salzgeber, Anton M. Palma, Dirce M. L. Marchioni, Antonio A.F. Carioca, Kristine R. Penner, Jill Alldredge and Teresa Longoria have no conflicts of interest to declare. Paulo D'Amora (research grants from funding agencies: São Paulo Research Foundation (FAPESP); financial support for attending symposia and for educational programs: Nagourney Cancer Institute, American Association for Cancer Research, Rivkin Center; consultation: Metabolomycs, Inc.; intellectual property rights: Metabolomycs, Inc.; stockholder: Metabolomycs, Inc.). Steven S. Evans (employment: Nagourney Cancer Institute; stockholder: Metabolomycs, Inc.). Paula J. Addis-Bernard (employment: Nagourney Cancer Institute). Ismael Dale C.G. Silva (board director: Metabolomycs, Inc.; stockholder: Metabolomycs, Inc.). Robert A. Nagourney (board director: Nagourney Cancer Institute and Metabolomycs, Inc.; stockholder: Metabolomycs, Inc.). We certify that the submission is original work and is not under review at any other publication., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The Sedlis criteria define risk factors for recurrence warranting post-hysterectomy radiation for early-stage cervical cancer; however, these factors were defined for squamous cell carcinoma (SCC) at an estimated recurrence risk of ≥30%. Our study evaluates and compares risk factors for recurrence for cervical SCC compared with adenocarcinoma (AC) and develops histology-specific nomograms to estimate risk of recurrence and guide adjuvant treatment., Methods: We performed an ancillary analysis of GOG 49, 92, and 141, and included stage I patients who were surgically managed and received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were used to evaluate independent risk factors for recurrence by histology and to generate prognostic histology-specific nomograms for 3-year recurrence risk., Results: We identified 715 patients with SCC and 105 with AC; 20% with SCC and 17% with AC recurred. For SCC, lymphvascular space invasion (LVSI: HR 1.58, CI 1.12-2.22), tumor size (TS ≥4 cm: HR 2.67, CI 1.67-4.29), and depth of invasion (DOI; middle 1/3, HR 4.31, CI 1.81-10.26; deep 1/3, HR 7.05, CI 2.99-16.64) were associated with recurrence. For AC, only TS ≥4 cm, was associated with recurrence (HR 4.69, CI 1.25-17.63). For both histologies, there was an interaction effect between TS and LVSI. For those with SCC, DOI was most associated with recurrence (16% risk); for AC, TS conferred a 15% risk with negative LVSI versus a 25% risk with positive LVSI., Conclusions: Current treatment standards are based on the Sedlis criteria, specifically derived from data on SCC. However, risk factors for recurrence differ for squamous cell and adenocarcinoma of the cervix. Histology-specific nomograms accurately and linearly represent risk of recurrence for both SCC and AC tumors and may provide a more contemporary and tailored tool for clinicians to base adjuvant treatment recommendations to their patients with cervical cancer., Competing Interests: Declaration of Competing Interest Dr. Van Le reports royalties from Wolters Kluwer (as an editor of TeLinde's textbook). Dr. Huh reports money paid to him from consultancy with DYSIS. Dr. Miller reports money paid to him from consultancy with Tesaro, Eisai, Incyte, Karyopharm, and Genentech as well as money paid to his institution from Merck. He also reports money paid to his institution from grants or grants pending with nVision Medical, Advenchen, Forty Seven, Merck, Syros, and US BIOTEST. Dr. Ragab reports money paid to him from Consultancy with Regeneron. Dr. Viswanathan reports employment with money paid to her from Elsevier as the Ediotr in Chief for Seminars in Radiation Oncology. She also has an R01 NIH grant with money to her institution, and she received textbook royalties from Springer. Dr. Tewari has received money paid to him from consultancy with Clovis, Merck, Abbvie, Amgen, GSK, and Astra-Zenega, as well as payment for lectures from Clovis, Merck, Abbvie, Amgen, GSK, Astra-Zenega. Drs. Levinson, Fader, Beavis, Wolfson, Waggoner, Guntupalli, Lee, Kelly, McNally, Casablanca, Rositch, Spirtos, Wilkinson, Holman and Chris Purdy have no financial disclosures., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Increasing measures of adiposity have been correlated with poor oncologic outcomes and a lack of response to anti-angiogenic therapies. Limited data exists on the impact of subcutaneous fat density (SFD) and visceral fat density (VFD) on oncologic outcomes. This ancillary analysis of GOG-218, evaluates whether imaging markers of adiposity were predictive biomarkers for bevacizumab (bev) use in epithelial ovarian cancer (EOC)., Patients and Methods: There were 1249 patients (67%) from GOG-218 with imaging measurements. SFD and VFD were calculated utilizing Hounsfield units (HU). Proportional hazards models were used to assess the association between SFD and VFD with overall survival (OS)., Results: Increased SFD and VFD showed an increased HR for death (HR per 1-SD increase 1.12, 95% CI:1.05-1.19 p = 0.0009 and 1.13, 95% CI: 1.05-1.20 p = 0.0006 respectively). In the predictive analysis for response to bev, high VFD showed an increased hazard for death in the placebo group (HR per 1-SD increase 1.22, 95% CI: 1.09-1.37; p = 0.025). However, in the bev group there was no effect seen (HR per 1-SD increase: 1.01, 95% CI: 0.90-1.14) Median OS was 45 vs 47 months in the VFD low groups and 36 vs 42 months in the VFD high groups on placebo versus bev, respectively., Conclusion: High VFD and SFD have a negative prognostic impact on patients with EOC. High VFD appears to be a predictive marker of bev response and patients with high VFD may be more likely to benefit from initial treatment with bev., Competing Interests: Declaration of Competing Interest Megan Buechel: No conflicts of interest. Danielle Enserro: No conflicts of interest. Robert A. Burger: Served as a consultant for Amgen, Astra Zeneca, Tesaro, Clovis Oncology, Genentech, Immunogen, Agenus, Gradalis, Janssen Research & Development, Merck, and VBL Therapeutics. Mark F. Brady: No conflicts of interest. Katrina Wade: No conflicts of interest. Angeles Alvarez Secord: Recieved clinical trial grant funding from AbbVie, Amgen, Astellas Pharma Inc., Astex Pharmaceuticals Inc., Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Eisai, Endocyte, Exelixis, Immutep Ltd., Incyte, Merck, PharmaMar, Roche/Genentech, Seattle Genetics, Inc., Tesaro/GSK, and VBL Therapeutics; honoraria for Advisory Boards from Aravive, AstraZeneca, Clovis, Cordgenics, Eisai, Janssen/Johnson & Johnson, Merck, Mersana, Oncoquest, Roche/Genentech, and Tesaro/GSK; participated on Steering Committees for OVAL and AtTend clinical trials (uncompensated); and is a member of GOG Foundation Board of Directors within the past 36 months. Andrew B. Nixon: Receives industry funding from Genentech, MedImmune/AstraZeneca, Medpacto, Seattle Genetics, HTG Molecular Diagnostics, Tracon Pharmaceuticals, Eureka Therapeutics, Leadiant Biosciences, Acceleron Pharma, OncoMed Pharmaceuticals.Does consulting for GSK, Promega, Kanghong Pharma, Eli Lilly. Travel with Powering Precision Health. Seyedehnafiseh Mirniaharikandehei: No conflicts of interest. H. Liu: No conflicts of interest. Bin Zheng: No conflicts of interest. Heidi Gray: No conflicts of interest. Krishnansu S. Tewari: Consultant and Speaker's Bureau with Genentech/Roche, Abbvie, Essai, GSK/Tesaro, Merck, Clovis, Astra Zeneca. David M. O'Malley: Reports personal fees and institutional support for clinical research from AstraZeneca, personal fees and institutional support for clinical research from Clovis, personal fees and institutional support for clinical research from Tesaro, personal fees and institutional support for clinical research from Immunogen, personal fees from Ambry, personal fees and institutional support for clinical research from Janssen/J&J, personal fees and institutional support for clinical research from Abbvie, personal fees and institutional support for clinical research from Regeneron, personal fees and institutional support for clinical research from Amgen, personal fees and institutional support for clinical research from Novocure, personal fees and institutional support for clinical research from Genentech/Roche, institutional support for clinical research from VentiRx, institutional support for clinical research from Array Biopharma, institutional support for clinical research from EMD Serono, institutional support for clinical research from Ergomed, institutional support for clinical research from Ajinomoto Inc., institutional support for clinical research from Ludwig Cancer Research, institutional support or clinical research from Stemcentrx, Inc., institutional support for clinical research from CERULEAN PHARMA, personal fees and institutional support for clinical research from GOG Foundation, institutional support for clinical research from Bristol-Myers Squibb Co, institutional support for clinical research from Serono Inc., institutional support for clinical research from TRACON Pharmaceuticals, institutional support for clinical research from Yale University, institutional support for clinical researchfrom New Mexico Cancer Care Alliance, institutional support for clinical researchfrom INC Research, Inc., institutional support for clinical researchfrom inVentiv Health Clinical, institutional support for clinical researchfrom Iovance Biotherapeutics, Inc., institutional support for clinical research from PRA Intl, personal fees from Myriad Genetics, personal fees and institutional support for clinical research from Eisai, personal fees and institiional support from Agenus, personal fees and institutional support for clinical research from GSK, personal fees from Tarveda, personal fees and institutional support for clinical research from Merck. Robert S. Mannel: Has received honorarium from Tesaro for an Advisory Board. Michael J. Birrer: No conflicts of interest. Kathleen N. Moore: Advisory board participation for Abbvie, Aravive, Astra Zeneca, Clovis, Eisai, Genentech/Roche, GSK/Tesaro, Immunogen, Merck, Mersana, Tarveda, VBL Therapeutics, Vavotar. Her institution receives research funding from PTC Therapeutics, Merck, Genentech/Roche., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Report the results from a preplanned interim analysis of a phase III, double blind, randomized controlled study of ofranergene obadenovec (VB-111), a targeted anti-cancer gene therapy, in combination with paclitaxel in patients with platinum resistant ovarian cancer (PROC)., Methods: The OVAL (NCT03398655) study is an on-going study where patients are randomly assigned in a 1:1 ratio to weekly paclitaxel 80 mg/m 2 with VB-111 or placebo. The protocol specifies a pre-planned unblinded futility interim analysis of CA-125 response per GCIG criteria in the first 60 evaluable patients. The futility rule determined for this analysis was that the response rate of VB-111 must be greater than the response rate of placebo by at least 10% in order to continue the study. Coincident with the interim analysis, the blinded CA-125 response rate was estimated as a proportion of the first 60 evaluable patients with CA-125 response per GCIG criteria. Post-treatment fever is provided as a possible surrogate marker of VB-111 therapy activity., Results: The median age of the evaluable patients was 62 years (range 41-82); 97% had high-grade serous cancer; 58% had been treated with 3 or more previous lines of therapy, 70% received prior anti-angiogenic treatment, 43% received prior PARP inhibitors. CA-125 response in the VB-111 and weekly paclitaxel treated arm met the pre-specified interim criterion of an absolute advantage of 10% or higher compared to the control. Blinded results show a 53% CA-125 response rate (32/60) with 15% complete response (n=9). Assuming balanced randomization and an absolute advantage of 10% or higher to the VB-111 arm, it may be deducted that the response in the VB-111 treatment arm is 58% or higher. Among patients with post-treatment fever, the CA-125 response rate was 69%., Conclusions: At the time of the interim analysis, response rate findings are comparable to the responses seen in a similar patient population in the phase I/II study. The independent data and safety monitoring committee (iDSMC) recommended continuing the OVAL trial as planned. No new safety signals were identified., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P., Methods: TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P., Results: Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53., Conclusions: This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574., Competing Interests: Declaration of competing interest Kimberly K. Leslie: Dr. Leslie attests that she has no conflicts of interest. Virginia L. Filiaci: Dr. Filiaci is supported by institutional grants from NIH during the conduct of the study; Institutional contracts from GOG Foundation, Inc. outside the submitted work. Adrianne R. Mallen: Dr. Mallen reports no conflicts of interest. Kristina W. Thiel: Dr. Thiel is a co-founder of and holds equity in Immortagen, Inc. Eric J. Devor: Dr. Devor reports no conflict of interest. Katherine Moxley: Dr. Moxley attests that she has nothing to declare. Debra Richardson: Dr. Richardson reports that she serves on Advisory Boards for Genentech, Tesaro/GSK, AstraZeneca, Bayer, Deciphera, Mersana and Foundation Medicine. David Mutch: Dr. Mutch attests that he has no conflicts of interest. Angeles Alvarez Secord(:) Dr. Alvarez Secord discloses clinical trial grant funding received from AbbVie, Amgen, Astellas Pharma Inc., Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Eisai, Exelixis, Immutep Ltd., Incyte, Merck, PharmaMar, Roche/Genentech, Seattle Genetics, Inc., Tesaro/GSK, VBL Therapeutics and National Cancer Trial Network. Dr. Alvarez Secord has also received honoraria for Advisory Boards from Aravive, AstraZeneca, Clovis, Cordgenics, Eisai, Merck, Myriad, Oncoquest, Roche/Genentech and Tesaro/GSK within the past 24 months. Krishnansu S Tewari: Dr. Tewari served as a consultant and attended advisory boards for the manufacturers of bevacizumab (i.e., Genentech/Roche). Megan E McDonald: Dr. McDonald has no conflicts of interest to disclose. Cara Mathews: Dr. Mathews reports grants from National Institute of Health during the conduct of the study; grants from Syros, grants from Deciphera, grants from Astra Zeneca, grants from Astellas Pharma, grants from Tesaro/GSK, grants from Seattle Genetics and grants from Regeneron outside the submitted work. Casey Cosgrove: Dr. Cosgrove attests that she has no conflicts of interest. Summer Dewdney: Dr. Dewdney attests that she has nothing to declare. Yovanni Casablanca: Dr. Casablanca reports that spouse owns shares in Celsion (biotech company), but not related to this manuscript. Amanda Jackson: Peter G Rose: Dr. Rose attests that he has no conflicts of interest. Xun Clare Zhou: - Dr. Zhou attests that she has no conflicts of interest. Michael McHale: - Dr. McHale has no conflicts of interest to report. Heather Lankes: Dr. Lankes attests that she has no conflicts of interest. Douglas Levine: - Dr. Levine reports serving in a consulting/advisory role for Tesaro/GSK, Merck. Research funding to institution from Merck, Tesaro, Clovis Oncology, Regeneron, Agenus, Takeda, Immunogen, VBL Therapeutics, Genentech, Celsion, Ambry, Splash Pharmaceuticals. Founder Nirova BioSense, Inc. Carol Aghajanian: Dr. Aghajanian reports personal fees from Tesaro, personal fees from Immunogen, grants and personal fees from Clovis, grants from Genentech, grants from AbbVie, grants from Astra Zeneca, grants from Astra Zeneca, personal fees from Eisai/Merck, personal fees from Mersana Therapeutics, personal fees from Roche, personal fees from Abbvie, outside the submitted work., (Copyright © 2021. Published by Elsevier Inc.)

Advances in next generation sequencing have allowed for rapid and economical germline and tumor genomic profiling. Targeted therapies based on molecular tumor profiling are now integrated into treatment guidelines for many solid tumors. In epithelial ovarian cancer, 50% of tumors possess damaging mutations in homologous recombination repair genes (aka homologous recombination deficiency or HRD) which includes the BRCA genes. Deleterious BRCA mutations and HRD have recently emerged as predictive biomarkers for the use of PARP inhibitors in ovarian cancer. Every patient with ovarian cancer must be referred for genetic counseling and germline testing for BRCA mutations. Multigene panel genetic testing may be more informative and cost-effective than limited testing of cancer susceptibility genes. Patients without a germline deleterious BRCA mutation must be assessed for a somatic BRCA mutation. Assays for HRD may help guide treatment options in women who do not have a BRCA mutation. Currently, all patients with a germline or somatic BRCA mutation should be offered upfront maintenance therapy with a PARP inhibitor. During May 2020, options for maintenance therapy with a PARP inhibitor were expanded to patients with HRD and HR-proficient tumors., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To explore the relationship between tumor size and response to combined anti-vascular targeted therapy using the anti-angiogenesis inhibitor, bevacizumab, and the tubulin-binding vascular disrupting agent, fosbretabulin., Methods: An exploratory, post-hoc analysis of the randomized phase II trial, Gynecologic Oncology Group-0186I, was performed. One hundred and seven patients with recurrent ovarian carcinoma, treated with up to 3 prior regimens, were randomized to bevacizumab 15 mg/kg body weight with or without intravenous fosbretabulin 60 mg/m 2 body surface area every 21 days until progression or unacceptable toxicity. The primary analysis favored the combination (HR 0.69; 95% CI, 0.47-1.00; p = .049) [Monk BJ, et al. J Clin Oncol 2016;34:2279-86]. The Cox proportional hazards model was used to estimate the treatment effect in various subpopulations., Results: With extended follow-up, the median PFS for bevacizumab plus fosbretabulin was 7.6  months as compared to 4.8  months with bevacizumab alone (HR 0.74; 90% CI, 0.54-1.02). Overall survival was similar in the experimental and control arms (25.2 vs 24.4 mos, respectively, HR 0.85; 90% CI, 0.59-1.22; p = .461). Eighty-one patients had measurable disease and median tumor size was 5.7  cm. In the ≤5.7  cm subgroup, the HR for progression or death was 0.77 (90% CI 0.45-1.31). Patients with tumors >5.7  cm (n = 40) had a HR for progression or death of 0.55; 90% CI, 0.32-0.96; p = .075)., Conclusions: Although no significant survival benefit was observed, the trend showing a reduced HR for progression or death with increasing tumor size when fosbretabulin is added to bevacizumab compared to bevacizumab alone warrants further study., Competing Interests: Declaration of Competing Interest Dr. Krishnansu Tewari is a Steering Committee member and Principal Investigator and Study Chair for the FOCUS trial and reports having received an honorarium of $1000 from Mateon for consulting services. He has also attended advisory boards sponsored by Genentech in 2013, 2014, and 2016. Dr. Coleman reports grants and personal fees from AstraZeneca, grants from Merck, personal fees from Tesaro, personal fees from Medivation, grants and personal fees from Clovis, personal fees from Gamamab, grants and personal fees from Genmab, grants and personal fees from Roche/Genentech, grants and personal fees from Janssen, personal fees from Agenus, personal fees from Regeneron, personal fees from OncoQuest, outside the submitted work. Dr. Aghajanian reports personal fees from Tesaro, personal fees from Immunogen, grants and personal fees from Clovis, personal fees from Mateon Therapeutics, grants from Genentech, grants from AbbVie, grants from Astra Zeneca, grants from Astra Zeneca, personal fees from Eisai/Merck, personal fees from Mersana Therapeutics, personal fees from Roche, outside the submitted work. Dr. Mannel reports grants from The GOG/NRG NCI cooperative group system, during the conduct of the study; personal fees from Tesaro, outside the submitted work. Dr. Powell reports personal fees from Tesaro, personal fees from Merck, personal fees from Roche/ Genentech, personal fees from Clovis Oncology, personal fees from AstraZeneca, personal fees from Johnson & Johnson, personal fees from Eisai, outside the submitted work. Dr. Randall reports grants from Gynecologic Oncology Group, during the conduct of the study; personal fees from Genentech/Roche, outside the submitted work. Dr. Monk reports personal fees from Abbvie, personal fees from Advaxis, personal fees from Agenus, personal fees from Amgen, personal fees from Aravive, personal fees from AstraZeneca, personal fees from Asymmetric Therapeutics, personal fees from Boston Biomedical, personal fees from ChemoCare, personal fees from ChemoID, personal fees from Circulogene, personal fees from Clovis, personal fees from Conjupro, personal fees from Easai, personal fees from Geistlich, personal fees from Genmab/Seattle Genetics, personal fees from GOG Foundation, personal fees from ImmunoGen, personal fees from Immunomedics, personal fees from Incyte, personal fees from Janssen/Johnson&Johnson, personal fees from Laekna Health Care, personal fees from Mateon (formally Oxigene), personal fees from Merck, personal fees from Mersana, personal fees from Myriad, personal fees from Nucana, personal fees from Oncomed, personal fees from Oncoquest, personal fees from Oncosec, personal fees from Perthera, personal fees from Pfizer, personal fees from Precision Oncology, personal fees from Puma, personal fees from Regeneron, personal fees from Roche/Genentech, personal fees from Samumed, personal fees from Takeda, personal fees from Tesaro/GSK, personal fees from VBL, personal fees from Vigeo, outside the submitted work. All other co-authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cancer complicates 1 in 1000 pregnancies. Multidisciplinary consensus comprised of Gynecologic Oncology, Pathology, Neonatology, Radiology, Anesthesiology, Maternal Fetal Medicine, and Social Work should be convened. Pregnancy provides an opportunity for cervical cancer screening, with deliberate delays in treatment permissible for early stage carcinoma. Vaginal delivery is contraindicated in the presence of gross lesion(s) and radical hysterectomy with lymphadenectomy at cesarean delivery is recommended. Women with locally advanced and metastatic/recurrent disease should commence treatment at diagnosis with chemoradiation and systemic therapy, respectively; neoadjuvant chemotherapy to permit gestational advancement may be considered in select cases. Most adnexal masses are benign and resolve by the second trimester. Persistent, asymptomatic, benign-appearing masses can be managed conservatively; surgery, if indicated, is best deferred to 15-20 weeks, with laparoscopy preferable over laparotomy whenever possible. Benign and malignant germ cell tumors and borderline tumors are occasionally encountered, with unilateral adnexectomy and preservation of the uterus and contralateral ovary being the rule. Epithelial ovarian cancer is exceedingly rare. Ultrasonography and magnetic resonance imaging lack ionizing radiation and can be employed to evaluate disease extent. Tumor markers, including CA-125, AFP, LDH, inhibin-B, and even CEA and ßhCG may be informative. If required, chemotherapy can be administered following organogenesis during the second and third trimesters. Because platinum and other anti-neoplastic agents cross the placenta, chemotherapy should be withheld after 34 weeks to avoid neonatal myelosuppression. Bevacizumab, immune checkpoint inhibitors, and PARP inhibitors should be avoided throughout pregnancy. Although antenatal glucocorticoids to facilitate fetal pulmonary maturation and amniotic fluid index assessment can be considered, there is no demonstrable benefit of tocolytics, antepartum fetal heart rate monitoring, and/or amniocentesis. Endometrial, vulvar, and vaginal cancer in pregnancy are curiosities, although leiomyosarcoma and the dreaded twin fetus/hydatidiform mole have been reported. For gynecologic malignancies, pregnancy does not impart aggressive clinical behavior and/or worse prognosis., Competing Interests: Declaration of competing interest The authors have no relevant financial conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease., Methods: Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non‑platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations., Results: Non‑platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non‑platinum-based regimens., Conclusion: High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care., Competing Interests: Declaration of competing interest JW reports personal fees for serving on an advisory board for Tesaro in the past 36 months, not related to the submitted work. JB and RB have nothing to disclose. KM reports personal fees and other from Astra Zeneca, grants, personal fees and other from Genentech/Roche, grants, personal fees and other from Immunogen, grants, personal fees and other from Clovis, grants, personal fees and other from Tesaro, personal fees and other from Pfizer, personal fees from Janssen, personal fees from Aravive, personal fees from VBL Therapeutics, personal fees and other from Onco Med, personal fees from Samumed, grants and other from Lilly, personal fees from Eisai, all outside the submitted work; . BM reports personal fees from Abbvie, personal fees from Advaxis, personal fees from Agenus, personal fees from Amgen, personal fees from Aravive, personal fees from AstraZeneca, personal fees from Asymmetric Therapeutics, from Boston Biomedical, personal fees from ChemoCare, personal fees from ChemoID, personal fees from Circulogene, personal fees from Clovis, personal fees from Conjupro, personal fees from Easai, personal fees from Geistlich, personal fees from Genmab/Seattle Genetics, personal fees from GOG Foundation, personal fees from ImmunoGen, personal fees from Immunomedics, personal fees from Incyte, personal fees from Janssen/Johnson&Johnson, personal fees from Laekna Health Care, personal fees from Mateon (formally Oxigene), personal fees from Merck, personal fees from Mersana, personal fees from Myriad, personal fees from Nucana, personal fees from Oncomed, personal fees from Oncoquest, personal fees from Oncosec, personal fees from Perthera, personal fees from Pfizer, personal fees from Precision Oncology, personal fees from Puma, personal fees from Regeneron, personal fees from Roche/Genentech, personal fees from Samumed, personal fees from Takeda, personal fees from Tesaro/GSK, personal fees from VBL, personal fees from Vigeo, all outside the submitted work. KT reports personal fees and non-financial support from Genentech, personal fees and non-financial support from Merck, personal fees and non-financial support from Clovis, personal fees and non-financial support from Tesaro, non-financial support from Abbie, personal fees and non-financial support from Astra-Zeneca, non-financial support from Morphotek, personal fees and non-financial support from Genmab, all outside the submitted work., (Copyright © 2020. Published by Elsevier Inc.)

Objective: Early-phase data have demonstrated induction of antibody responses to a polyvalent vaccine conjugate (Globo-H, GM2, MUC1-TN, TF) with adjuvant OPT-821. We sought to determine if this combination decreases the hazard of progression or death compared to OPT-821 alone in patients with ovarian cancer in second/third clinical complete remission following chemotherapy. Secondary and translational objectives were overall survival (OS), safety, and immunogenicity., Methods: From 2010-2013, patients were randomized (1:1) to receive OPT-821±vaccine-KLH conjugate subcutaneously at weeks 1, 2, 3, 7, 11, and then every 12 weeks (total 11). Dose delay or reduction was not permitted. Patients were removed for pre-defined dose-limiting toxicity., Results: Of 171 patients randomized, 170 were treated. Most had disease of serous histology (85%), stage 3 disease at diagnosis (77%), and had received 2 prior regimens (68%). 32% received >6 treatment cycles [median 6, each arm (p = 0.33)]. 77% discontinued due to progression, 4% due to toxicity, and 1 due to myeloid dysplastic syndrome (MDS). Maximum toxicities included grade 4 MDS and depression/personality change (1 each, unlikely related), as well as grade 3 gastrointestinal disorders and others (n = 21, 4 related). Lesser adverse events were injection site reactions (82%) and fever (11%). Estimated HR for progression-free survival (PFS) of the vaccine + OPT-821 to OPT-821 arm was 0.98 (95% CI: 0.71-1.36). At a median follow-up of 60 months, median OS was 47 and 46 months, respectively., Conclusions: Vaccine + OPT-821 compared to OPT-821 alone was modestly immunogenic and did not prolong PFS or OS. Multi-remission patients are a viable, well-defined population for exploring innovative consolidation and maintenance approaches., Trial Registration: NCT00857545., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Bevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC)., Patients and Methods: Eligible OC patients had measurable (RECIST1.1) or detectable disease, 1-3 prior regimens, performance status (PS) 0-2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response., Results: 150 patients were randomized to BV with (n = 75) and without (n = 75) EV. Arms were well-balanced for age (median 63: range 28-92), PS (0: 73%, 1-2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (<6mos: 65%) and measurable disease (81%). The BV + EV vs BV median PFS was 5.9 vs 4.5 months (hazard ratio [HR] 0.95 (95% CI, 0.66-1.37, p = 0.39)). Median OS was 16.6 vs 17.3 months (HR 1.16 (95% CI, 0.72-1.87, p = 0.55). Objective measurable responses were higher with BV + EV (22% vs 12%). Study removal due to toxicity was higher with BV + EV (29% vs 12%). Toxicity (≥grade 3) from BV + EV were "other GI (mucositis)" (23 vs 1%) and "metabolic/nutrition" (19 vs. 7%); common ≥ grade 2 toxicities with BV + EV were cytopenia, nausea, fatigue and rash., Conclusion: The combination regimen (BV + EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy., Methods: In this randomized phase II trial, patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) endometrial cancer were randomly assigned to treatment with PC plus bevacizumab (Arm 1), PC plus temsirolimus (Arm 2) or ixabepilone and carboplatin (IC) plus bevacizumab (Arm 3). The primary endpoint was progression-free survival (PFS). Comparable patients on the PC Arm of trial GOG209 were used as historical controls. Secondary endpoints were response rate, overall survival (OS), and safety., Results: Overall, 349 patients were randomized. PFS duration was not significantly increased in any experimental arm compared with historical controls (p > 0.039). Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63-1.02), 1.22 (0.96-1.55) and 0.87 (0.68-1.11), respectively. Response rates were similar across arms (60%, 55% and 53%, respectively). Relative to controls, OS duration (with censoring at 36 months), was significantly increased in Arm 1 (p < 0.039) but not in Arms 2 and 3; the HRs (92% CIs) were 0.71 (0.55-0.91), 0.99 (0.78-1.26), and 0.97 (0.77-1.23), respectively. No new safety signals were identified. Common mutations and rates of mismatch repair protein loss are described by histotype. Potential predictive biomarkers for temsirolimus and bevacizumab were identified., Conclusion: PFS was not significantly increased in any experimental arm compared to historical controls. NRG Oncology/Gynecologic Oncology Group Study GOG-86P., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: We sought to determine the level of concordance among surgeons' assessment of residual disease (RD) and pre-treatment computed tomography (CT) findings among women who underwent optimal surgical cytoreduction for advanced stage ovarian cancer., Methods: This is a post-trial ad hoc analysis of a phase 3 randomized clinical trial evaluating the impact of bevacizumab in primary and maintenance therapy for patients with advanced stage ovarian cancer following surgical cytoreduction. All subjects underwent imaging of the chest/abdomen/pelvis to establish a post-surgical baseline prior to the initiation of chemotherapy. Information collected on trial was utilized to compare surgeon's operative assessment of RD, to pre-treatment imaging., Results: Of 1873 enrolled patients, surgical outcome was described as optimal (RD≤1cm) in 639 subjects. Twelve patients were excluded as they did not have a baseline, pretreatment imaging, leaving 627 participants for analysis. The average interval from surgery to baseline scan was 26days (range: 1-109). In 251 cases (40%), the post-operative scan was discordant with surgeon assessment, demonstrating RD>1cm in size. RD>1cm was most commonly identified in the right upper quadrant (28.4%), retroperitoneal para-aortic lymph nodes (RD>1.5cm; 28.2%) and the left upper quadrant (10.7%). Patients with RD>1cm on pre-treatment CT (discordant) exhibited a significantly greater risk of disease progression (HR 1.30; 95% CI 1.08-1.56; p=0.0059)., Conclusions: Among patients reported to have undergone optimal cytoreduction, 40% were found to have lesions >1cm on postoperative, pretreatment imaging. Although inflammatory changes and/or rapid tumor regrowth could account for the discordance, the impact on PFS and distribution of RD may suggest underestimation by the operating surgeon., (Copyright © 2018. Published by Elsevier Inc.)

Vascular endothelial growth factor (VEGF) has emerged as a therapeutic target in several malignancies, including cervical cancer. Chemotherapy doublets combined with the fully humanized monoclonal antibody, bevacizumab, now constitute first-line therapy for women struggling with recurrent/metastatic cervical carcinoma. Regulatory approval for this indication was based on the phase III randomized trial, GOG 240, which demonstrated a statistically significant and clinically meaningful improvement in overall survival when bevacizumab was added to chemotherapy: 17.0 vs 13.3 months; HR 0.71; 98% CI, 0.54-0.95; p = .004. Incorporation of bevacizumab resulted in significant improvements in progression-free survival and response. These benefits were not accompanied by deterioration in quality of life. GOG 240 identified vaginal fistula as a new adverse event associated with bevacizumab use. All fistulas occurred in women who had received prior pelvic radiotherapy, and none resulted in emergency surgery, sepsis, or death. Final protocol-specified analysis demonstrated continued separation of the survival curves favoring VEGF inhibition: 16.8 vs 13.3 months; HR 0.77; 95% CI, 0.62-9.95; p = .007. Post-progression survival was not significantly different between the arms in GOG 240. Moving forward, immunotherapy has now entered the clinical trial arena to address the high unmet clinical need for effective and tolerable second line therapies in this patient population. Targeting the programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) pathway using checkpoint inhibitors to break immunologic tolerance is promising. The immunologic landscape involving human papillomavirus-positive head and neck carcinoma and cutaneous squamous cell carcinoma can be informative when considering feasibility of checkpoint blockade in advanced cervical cancer. Phase II studies using anti-PD-1 molecules, nivolumab and pembrolizumab are ongoing, and GOG 3016, the first phase III randomized trial of a checkpoint inhibitor (cemiplimab) in cervical cancer, recently activated. Important considerations in attempts to inhibit the inhibitors include pseudoprogression and post-progression survival, abscopal effects, and immune-related adverse events, including endocrinopathies., (Copyright © 2018. Published by Elsevier Inc.)

Objective: Microscopic residual disease following complete cytoreduction (R0) is associated with a significant survival benefit for patients with advanced epithelial ovarian cancer (EOC). Our objective was to develop a prediction model for R0 to support surgeons in their clinical care decisions., Methods: Demographic, pathologic, surgical, and CA125 data were collected from GOG 182 records. Patients enrolled prior to September 1, 2003 were used for the training model while those enrolled after constituted the validation data set. Univariate analysis was performed to identify significant predictors of R0 and these variables were subsequently analyzed using multivariable regression. The regression model was reduced using backward selection and predictive accuracy was quantified using area under the receiver operating characteristic area under the curve (AUC) in both the training and the validation data sets., Results: Of the 3882 patients enrolled in GOG 182, 1480 had complete clinical data available for the analysis. The training data set consisted of 1007 patients (234 with R0) while the validation set was comprised of 473 patients (122 with R0). The reduced multivariable regression model demonstrated several variables predictive of R0 at cytoreduction: Disease Score (DS) (p<0.001), stage (p=0.009), CA125 (p<0.001), ascites (p<0.001), and stage-age interaction (p=0.01). Applying the prediction model to the validation data resulted in an AUC of 0.73 (0.67 to 0.78, 95% CI). Inclusion of DS enhanced the model performance to an AUC of 0.83 (0.79 to 0.88, 95% CI)., Conclusions: We developed and validated a prediction model for R0 that offers improved performance over previously reported models for prediction of residual disease. The performance of the prediction model suggests additional factors (i.e. imaging, molecular profiling, etc.) should be explored in the future for a more clinically actionable tool., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: This study evaluated single nucleotide polymorphisms (SNPs) associated with progression free (PFS) and overall survival (OS) in patients with advanced stage serous EOC., Methods: Patients enrolled in GOG-172 and 182 who provided specimens for translational research and consent were included. Germline DNA was evaluated with the Illumina's HumanOMNI1-Quad beadchips and scanned using Illumina's iScan optical imaging system. SNPs with allele frequency>0.05 and genotyping rate>0.98 were included. Analysis of SNPs for PFS and OS was done using Cox regression. Statistical significance was determined using Bonferroni corrected p-values with genomic control adjustment., Results: The initial GWAS analysis included 1,124,677 markers in 396 patients. To obtain the final data set, quality control checks were performed and limited to serous tumors and self-identified Caucasian race. In total 636,555 SNPs and 289 patients passed all the filters. The pre-specified statistical level of significance was 7.855e -08 . No SNPs met this criteria for PFS or OS, however, two SNPs were close to significance (rs10899426 p-2.144e - 08 ) (rs6256 p-9.774e -07 ) for PFS and 2 different SNPs were identified (rs295315 p-7.536e - 07 ; rs17693104 p-7.734e - 07 ) which were close to significance for OS., Conclusions: Using the pre-specified level of significance of 1×10 -08 , we did not identify any SNPs of statistical significance for OS or PFS, however several were close. The SNP's identified in this GWAS study will require validation and these preliminary findings may lead to identification of novel pathways and biomarkers., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients., Methods: Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response., Results: Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1-20). Seven (25%) patients had PFS >6months (90% CI: 7.3%-33.9%). Two (7%) (90% CI: 1.3%-20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1-4.4). The median overall survival was 7.9months (90% CI: 6.1-11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension., Conclusions: Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability., (Copyright © 2017. Published by Elsevier Inc.)

Objective: Gynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin., Methods: We analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer., Results: We first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin., Conclusions: Our findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To determine the relationship of the time from surgery to intraperitoneal (IP) chemotherapy (TSIC) initiation with survival of patients with stage III epithelial ovarian cancer (EOC) patients using ancillary data from cooperative group clinical trials., Methods: Data from 420 patients with stage III EOC treated with IP chemotherapy under GOG-0114 and 172 were reviewed. The Cox proportional hazards model was used to evaluate independent prognostic factors and estimate their covariate-adjusted effects on PFS and OS., Results: The median TSIC was 62.5days (interquartile range 28-83). The median TSIC was longer for patients in GOG-0114 vs those in GOG-172 (83 vs 26days, p<0.001). TSIC was significantly associated (p=0.049) with PFS: each 10% increase in TSIC (days) decreases the risk of progression by 3%. TSIC was not significantly associated with OS in this model. In a linear regression model, gross residual disease was significantly associated with shorter TSIC (R 2 -0.141, 95%CI -0.217, -0.064, p<0.001). When only data from GOG-172 were considered, no statistical significant association was found between TSIC and PFS or OS., Conclusions: In this ancillary data study, TSIC was not associated with improved OS in patients with stage III epithelial ovarian cancer. TSIC was significantly associated with PFS for the entire cohort, suggesting increase in PFS with longer TSIC. However, this was not found when only data from GOG 172 or GOG 114 were analyzed separately. Hence, the relationship between IP chemotherapy initiation and time from surgery needs to be studied further., Competing Interests: The authors report no conflicts of interest with the exception of Dr. Angeles Alvarez Secord who wishes to acknowledge that she received funds from Janssen, Clovis Oncology, Genentech and AstraZeneca. Additionally, Dr. Alvarez Secord reports research grant funding from Astellas Pharma Inc, Genentech, Amgen, Endocyte, Exelixis, Boehringher Ingelheim, Astex Pharmaceuticals Inc., Prima Biomed, Tesaro, Astra Zeneca, Eisai Morphotek, Bristol Myers Squibb and Incyte. These funds were distributed to Duke University Medical Center to support research including salary support for Dr. Secord. In the last 36 months, she has served on Advisory Boards for Janssen, Clovis Oncology, Genentech and AstraZeneca, outside the submitted work., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: We sought to analyze the clinicopathologic features, recurrence patterns and survival outcomes of women with high-grade uterine cancer (UC) enrolled on The Gynecologic Oncology Group (GOG) LAP2 trial., Methods: This is a post-hoc analysis of LAP-2 patients with grade 3 endometrioid adenocarcinoma (ENDO), uterine serous (USC), clear cell (CC) and carcinosarcoma (CS). Demographics, clinicopathologic features, and recurrence patterns, were compared by histology and surgical approach. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method., Results: Of the 2600 patients enrolled in LAP-2, 753 patients had high-grade UC: 350 had ENDO, 289 had USC, 42 had CC and 72 had CS. Compared with the ENDO cohort, those with other high-grade subtypes were older (p<0.001) and were more likely to have positive peritoneal cytology (p<0.001), positive lymph nodes (p=0.05) and higher disease stage on final pathology (p<0.001). With a median follow-up time of 60months, compared to patients with ENDO, those with USC, CCC and CS subtypes had higher recurrence rates (p<0.001), extra-pelvic recurrences (p<0.001) and poorer PFS (p<0.001) and OS (p<0.001). Those diagnosed with USC and CS experienced the worst survival outcomes (p=0.003). Patterns of recurrence and survival were not different in those staged with LSC vs LAP. On multivariable analysis, age, stage, pelvic washings and Type II histology were independently and adversely associated with survival., Conclusions: Women with apparent early-stage, USC and CS histologies have poorer outcomes than women with grade 3 endometrioid adenocarcinoma. Patterns of recurrence and survival were not impacted by surgical approach., Competing Interests: Dr. Nick Spirtos receives per capita reimbursement to the Women's Cancer Center, travel supplement as Gyn Onc Committee Chair, co-operative research funding on a per capita basis from GOG Foundation, Inc., and royalties from Wiley Health Services for Bonney's Gynaecological Surgery. Dr. Michael Pearl receives grant money from the GOG/NRG. He also serves as a consultancy for Ethicon, provided expert testimony for legal expert review, and has grants/grants pending from NIH, small foundations, as well as royalties from VitaTex. Dr. David O'Malley serves as a consultant for Yondelis on the Sarcoma Advisory Board, AstraZeneca on the Ovarian Cancer Advisory Board, Clovis on the Ovarian Cancer Advisory Board, Genentech/Roche on the Ovarian Cancer Advisory Board and Eisai on the Advisory Board. Dr. Robert Mannel receives grant monies from GOG-LAP2 grant. He also serves on the Advisory Board as a consultant for Medimmune, Oxigene, Endocyte, Bayer and Clovis. All other coauthors have no conflicts of interest to declare., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To determine the effect of age on completion of and toxicities following treatment of local regionally advanced cervical cancer (LACC) on Gynecologic Oncology Group (GOG) Phase I-III trials., Methods: An ancillary data analysis of GOG protocols 113, 120, 165, 219 data was performed. Wilcoxon, Pearson, and Kruskal-Wallis tests were used for univariate and multivariate analysis. Log rank tests were used to compare survival lengths., Results: One-thousand-three-hundred-nineteen women were included; 60.7% were Caucasian, 15% were age 60-70years and an additional 5% were >70; 87% had squamous histology, 55% had stage IIB disease and 34% had IIIB disease. Performance status declined with age (p=0.006). Histology and tumor stage did not significantly differ. Number of cycles of chemotherapy received, radiation treatment time, nor dose modifications varied with age. Notably, radiation protocol deviations and failure to complete brachytherapy (BT) did increase with age (p=0.022 and p<0.001 respectively). Only all grade lymphatic (p=0.006) and grade≥3 cardiovascular toxicities (p=0.019) were found to vary with age. A 2% increase in the risk of death for every year increase >50 for all-cause mortality (HR 1.02; 95% CI, 1.01-1.04) was found, but no association between age and disease specific mortality was found., Conclusion: This represents a large analysis of patients treated for LACC with chemo/radiation, approximately 20% of whom were >60years of age. Older patients, had higher rates of incomplete brachytherapy which is not explained by collected toxicity data. Age did not adversely impact completion of chemotherapy and radiation or toxicities., (Copyright © 2016. Published by Elsevier Inc.)

Background: Veliparib is a potent small molecule inhibitor of PARP-1/2, which is cytotoxic in tumor cells with deficiencies in BRCA1 or BRCA2. We studied the clinical activity and toxicity of veliparib in ovarian cancer patients carrying a germline BRCA1 or BRCA2 mutation (gBRCA)., Methods: Eligibility included three or fewer prior chemotherapy regimens, measurable disease and no prior use of a PARP inhibitor. Veliparib was administered at 400mg orally BID with one cycle being 28days. The two-stage Simon design was capable of detecting a 25% response probability with 90% power while controlling alpha=10% (at a 10% assumed null response probability)., Results: The median age of the 50 eligible patients was 57years (range 37-94) and 14, 18, and 18 patients had 1, 2, and 3 prior therapies respectively. Thirty patients (60%) were platinum-resistant. The median number of cycles administered was 6 (1-27). There was one grade 4 thrombocytopenia. Grade 3 adverse events were: fatigue (n=3), nausea (2), leukopenia (1), neutropenia (1), dehydration (1), and ALT (1). Grade 2 events >10% were: nausea (46%), fatigue (26%), vomiting (18%), and anemia (14%). The proportion responding was 26% (90% CI: 16%-38%, CR: 2, PR: 11); for platinum-resistant and platinum-sensitive patients the proportion responding was 20% and 35%, respectively. The most common reason for treatment discontinuation was progression (62%). Twenty-nine patients are alive; two with SD remain on veliparib. The median PFS is 8.18months., Conclusions: The single agent efficacy and tolerability of veliparib for BRCA mutation-associated recurrent ovarian cancer warrants further investigation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To evaluate the cost-effectiveness of bevacizumab in recurrent/persistent and metastatic cervical cancer using recently reported updated survival and toxicology data., Methods: A Markov decision tree based on the Gynecologic Oncology Group 240 randomized trial was created. The 2013 MediCare Services Drug Payment Table and Physician Fee Schedule provided costs. In the 5-year model subjects transitioned through the following states: response, progression, minor complications, severe complications, and death. Patients experiencing a health utility per month according to treatment effectiveness were calculated. Because cervical cancer survival is measured in months rather than years, results were reported in both quality adjusted cervical cancer life months and years (QALmonth, QALY), adjusted from a baseline of having advanced cervical cancer during a month., Results: The estimated total cost of therapy with bevacizumab is approximately 13.2 times that for chemotherapy alone, adding $73,791 per 3.5months (0.29year) of life gained, resulting in an incremental cost-effectiveness ratio (ICER) of $21.083 per month of added life. The ICER increased to $5775 per month of added life and $24,597/QALmonth ($295,164/QALY) due to the smaller difference in QALmonths. With 75% bevacizumab cost reduction, the ICER is $6737/QALmonth ($80,844/QALY), which translates to $23,580 for the 3.5month (0.29year) gain in OS., Conclusions: Increased costs are primarily related to the cost of drug and not the management of bevacizumab-induced complications. Cost reductions in bevacizumab result in dramatic declines in the ICER, suggesting that cost reconciliation in advanced cervical cancer may be possible through the availability of biosimilars, and/or less expensive, equally efficacious anti-angiogenesis agents., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Palliative care is recognized as an important component of oncologic care. We sought to assess the quality/quantity of palliative care education in gynecologic oncology fellowship., Methods: A self-administered on-line questionnaire was distributed to current gynecologic oncology fellow and candidate members during the 2013 academic year. Descriptive statistics, bivariate and multivariate analyses were performed., Results: Of 201 fellow and candidate members, 74.1% (n=149) responded. Respondents were primarily women (75%) and white (76%). Only 11% of respondents participated in a palliative care rotation. Respondents rated the overall quality of teaching received on management of ovarian cancer significantly higher than management of patients at end of life (EOL), independent of level of training (8.25 vs. 6.23; p<0.0005). Forty-six percent reported never being observed discussing transition of care from curative to palliative with a patient, and 56% never received feedback about technique regarding discussions on EOL care. When asked to recall their most recent patient who had died, 83% reported enrollment in hospice within 4 weeks of death. Fellows reporting higher quality EOL education were significantly more likely to feel prepared to care for patients at EOL (p<0.0005). Mean ranking of preparedness increased with the number of times a fellow reported discussing changing goals from curative to palliative and the number of times he/she received feedback from an attending (p<0.0005)., Conclusions: Gynecologic oncology fellow/candidate members reported insufficient palliative care education. Those respondents reporting higher quality EOL training felt more prepared to care for dying patients and to address complications commonly encountered in this setting., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To determine whether chemotherapy-induced neutropenia (C-iN) is associated with improved survival in a population of primary advanced ovarian cancer and peritoneal carcinoma patients treated with a carboplatin plus paclitaxel chemotherapy backbone., Methods: A post-hoc exploratory analysis of Gynecologic Oncology Group (GOG) protocol 182 was performed. Landmark analysis was conducted on all patients with progression-free survival >18weeks from the time of study entry. Neutropenia was defined as the absolute neutrophil count <1000mm(3). The occurrence of C-iN was analyzed according to demographic, clinicopathologic, and therapeutic intent, including age, body surface area, and treatment arm. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to evaluate independent prognostic factors and to estimate their effects on PFS and OS., Results: Neutropenic data was available for 3447 patients. Neutropenic (n=3196) and non-neutropenic groups (n=251) were similar in demographic and clinicopathologic characteristics. Neutropenic patients experienced significantly improved survival compared to non-neutropenic patients with the adjusted hazard ratio (HR) for death being 0.86 (95% confidence interval 0.74-0.99; p=0.041). There was no survival benefit associated with any of the treatment arms among patients with C-iN., Conclusion: These data suggest that C-iN may represent a clinical biomarker associated with a survival advantage for patients with untreated advanced ovarian cancer. The absence of C-iN may indicate under-dosing and ultimately attenuated anti-neoplastic effect in vulnerable populations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Despite survival gains achieved nearly two decades ago with combination platinum- and taxane-based intravenous chemotherapy, overall survival curves have remained relatively unchanged during the 21st century using newer cytotoxic agents. Although combined intravenous-intraperitoneal (IV-IP) chemotherapy is promising, tolerability remains a significant issue. An emphasis has been placed on exploring dose dense schedules and targeted agents. Vascular endothelial growth factor (VEGF) has emerged as an important therapeutic target in several solid tumors including ovarian carcinoma. The monoclonal antibody, bevacizumab, binds VEGF, thus preventing activation of the VEGF receptor (VEGFR) leading to inhibition of tumor angiogenesis. To date eight phase 3 randomized controlled trials incorporating anti-angiogenesis therapy in the treatment of newly diagnosed and recurrent ovarian carcinoma have met their primary endpoints. Four of these trials included bevacizumab and were reported from 2010 to 2012. During 2013, the other four studies were reported, each studying one of the following novel anti-angiogenesis agents: pazopanib, cediranib, trebananib, and nintedanib. Importantly, none of these drugs have been approved by the United States Food and Drug Administration (US FDA) for the treatment of ovarian cancer. The purpose of this review will be to highlight both VEGF-dependent and non-VEGF dependent angiogenic pathways in ovarian cancer and discuss the phase 3 experiences and regulatory implications of targeting the tumor microenviroment with anti-angiogenesis therapy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

During progression of cervical cancer, human papillomavirus genomes and cellular tumor suppressor genes can become methylated. Toward a better understanding of these biomarkers, we studied 104 samples with HPV16, 18, 31, and 45 representing five pathological categories from asymptomatic infection to cancer. We grouped all samples by HPV type and pathology and measured the overall methylation of informative amplicons of HPV late genes and the cellular DAPK gene. Methylation of all four HPV types as well as of the DAPK gene is lowest in asymptomatic infection and increases successively in all four pathological categories during progression to cancer. 27 out of 28 cancer samples showed methylation both in the L2/L1 genes as well as in DAPK, but a much lower fraction in all other pathological categories. We discuss the problem to develop diagnostic tests based on complex methylation patterns that make it difficult to classify amplicons as "methylated" or "unmethylated"., (© 2013 Published by Elsevier Inc.)

Background: A phase II trial was performed to evaluate the efficacy and safety of gefitinib in patients with persistent/recurrent endometrial cancer., Methods: Women with histologically confirmed persistent/recurrent endometrial cancer were treated with 500mg oral gefitinib daily until progression or severe toxicity, with progression-free survival (PFS) at six months as the primary endpoint. Tumor expression of total epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor A (PRA) and B (PRB), Ki67, pEGFR and activated extracellular signal-regulated kinase (pERK) were examined pre- and post-treatment. EGFR was sequenced, and serum concentrations of soluble EGFR (sEGFR) at baseline also were examined., Results: Of 29 patients enrolled, 26 were evaluable for efficacy and toxicity. Four patients experienced PFS ≥6 months, and one had a complete response which was not associated with an EGFR mutation. The concentration of sEGFR in pretreatment serum was positively correlated with overall survival (OS), but not with responsiveness to gefitinib in this small patient cohort. Expression of tumor biomarkers was not associated with PFS or OS. Co-expression of ER with PRA in primary and recurrent tumors, and pEGFR with pERK in primary tumors was observed., Conclusions: This treatment regimen was tolerable but lacked sufficient efficacy to warrant further evaluation in this setting. The possible association between serum sEGFR concentrations and OS, and temporal changes in expression of pEGFR and pERK and the documented CR of one patient are interesting and warrant additional investigation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To determine whether the number of positive pelvic nodes (PPN), cervical stromal involvement (CSI), and/or lymphovascular space involvement (LVSI) were prognostic factors among women with advanced endometrial carcinoma treated with adriamycin plus cisplatin (AP) or whole abdominal irradiation (WAI)., Methods: Data were abstracted from records of patients treated with adjuvant WAI or AP in a GOG randomized trial. Cox proportional hazards models were used to estimate the association of CSI and PPN with differences in PFS and OS while adjusting for treatment and previously studied factors., Results: WAI was randomly allocated to 202 and AP to 194 eligible patients. CSI (n=93 total) was associated with a 44% increase in risk of progression and a 33% increase in risk of death. There was a trend for increasing number PPN being associated with a 7% per positive node increase in risk of progression/death. For CSI, the estimated unadjusted treatment hazard ratios (HRs) were: PFS 0.85 (0.53, 1.38); OS 0.81 (0.50, 1.33). For metastatic disease limited to a single PPN (n=25), the unadjusted HRs were: PFS 0.96 (0.34, 2.74); OS 0.73 (0.24, 2.18). The test of homogeneity of treatment effect (ie., AP vs WAI) across subgroups (CSI, number of positive pelvic nodes) was not statistically significant for either endpoint, thus supporting the superiority of chemotherapy as reported in the original manuscript., Conclusions: The presence of CSI and increasing number of PPN were associated with poor prognosis. On average, patients with CSI experienced improved PFS and OS when treated with AP relative to WAI., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To compare progression-free survival (PFS), overall survival (OS) and toxicities of thalidomide versus tamoxifen and to evaluate serum vascular endothelial growth factor (VEGF) in biochemical-recurrent epithelial ovarian cancer, primary peritoneal cancer or fallopian tube carcinoma (EOC/PPC/FTC)., Methods: Biochemical recurrence was defined as a rising CA-125 exceeding twice the upper limit of normal without evidence of disease as defined by RECIST 1.0 criteria. Women with FIGO stages III and IV, histologically confirmed EOC/PPC/FTC who were free of disease following first-line chemotherapy were randomized to oral thalidomide 200mg daily with escalation to a maximum of 400 mg or tamoxifen 20mg orally twice daily for up to 1 year, progression or adverse effect prohibited further treatment. VEGF was quantified by ELISA in pre and post-treatment serum., Results: Of the 139 women randomized, 138 were eligible. Interim analysis showed that thalidomide did not reduce the recurrence rate relative to tamoxifen, and the trial was closed. Thalidomide versus tamoxifen was associated with a similar risk of progression (HR = 1.31, 95% confidence interval [CI] = 0.93-1.85), an increased risk of death (HR = 1.76, 95% CI = 1.16-2.68) and more grades 3 and 4 toxicities (55% versus 3%). The most common grades 3 and 4 toxicities were constitutional (12%), somnolence (12%), pulmonary (9%), venous thromboembolism (VTE) (6%) and peripheral neurologic (6%) for thalidomide, with VTE (1.4%) and gastrointestinal (1.4%) for tamoxifen. Serum VEGF was not associated with clinical characteristics, treatment, PFS or OS., Conclusion: Thalidomide was not more effective than tamoxifen in delaying recurrence or death but was more toxic. VEGF was not prognostic in this cohort., (Copyright © 2010 Elsevier Inc. All rights reserved.)

OBJECTIVE.: To identify patient characteristics which predict receipt of neoadjuvant chemotherapy (NCT) versus standard therapy (ST) in metastatic ovarian cancer. METHODS.: A retrospective matched case control study was conducted of 52 women treated with NCT compared to 104 women who received standard treatment from 1996 to 2007. The t test was used for comparison of means between the groups, and the chi(2) test was used for categorical data. Multivariable analysis was performed with logistic regression models and only two-tailed analyses with a P value <0.05 were considered statistically significant. RESULTS.: Age, employment and marital status, and insurance alone did not affect treatment allocation (P=NS). However, non-Hispanic White (NHW) patients were more as likely to receive ST (P<0.05). When insurance was stratified by ethnicity, NHW patients were twice as likely to have private insurance (OR=2.29, CI=1.16-4.53). Furthermore, medically compromised (MC) patients who were NHW were almost three times more likely to receive ST (OR=2.72, CI=1.02-5.00). In multivariate analysis, only MC and publically funded women were more likely to receive NCT (OR 3.83 CI=1.35-11.11); P=0.01). During surgery, patients receiving NCT were found to have smaller tumors and less ascites, and were more likely to be optimally debulked with lower estimated blood loss and shorter hospital stays. The median survival for ST was 55.8 months versus 26 months for NCT (P<0.001). CONCLUSIONS.: Non-clinical factors such as publically funded status and non-Hispanic White race may influence the allocation of NCT for women with metastatic ovarian cancer.

Objectives: Topotecan improves response rate (RR), progression-free survival (PFS) and overall survival (OS) when added to cisplatin in treating metastatic and recurrent cervical cancer. The objective of this study was to assess the feasibility of adding weekly topotecan to cisplatin in patients with primary, locally advanced carcinoma of the cervix receiving pelvic irradiation., Methods: Patients with primary, previously untreated, histologically confirmed invasive squamous cell, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, stages IB2-IVA were treated with external beam pelvic radiotherapy (45 Gy), intracavitary low dose rate brachytherapy (40 Gy) and a parametrial boost (5.4-9 Gy) with overall treatment time not to exceed 8 weeks. Concurrent chemotherapy was IV cisplatin 40 mg/m(2)plus IV topotecan 2 mg/m(2) on days 1, 8, 15, 22, 29 and once during parametrial boost for 6 cycles. Patients were monitored with history, physical examination, tumor measurement and laboratory evaluation before entering the study, before each cycle of chemotherapy, at study termination and every three months thereafter., Results: The study met its accrual goal of 12 patients. With a median follow-up of 22 months, eleven patients completed treatment and ten are in long term follow up without evidence of recurrent disease. The 12th patient developed progressive disease during therapy. All patients completed at least 4 cycles of chemotherapy, with the majority (82%) completing 5 or more. Grade 2 or higher neutropenia delayed treatment in 54% of cycles. The median treatment delay was 1.5 cycles (range: 1 to 5 cycles). Median treatment time was 59 days (range 46 to 81 days). The complete RR was 92% (95% confidence interval, 55%-100%)., Conclusions: The addition of weekly topotecan to cisplatin at this dose and schedule during pelvic irradiation for locally advanced cervical cancer appears to be feasible. Based on this primary treatment data and the activity of cisplatin-topotecan in the recurrent disease setting, phase II and III studies of this combination are warranted.

Infection with the human papillomavirus (HPV) is the most common sexually transmitted disease afflicting approximately 80% of the population. HPV infection is an essential factor in cervical carcinogenesis and cervical carcinoma is the second most common cause of cancer among women worldwide. In addition to cervical cancer, other malignancies in both men and women such as esophageal, oropharyngeal, and anal cancer have been causally associated with this virus. Other gender-specific HPV-related cancers include penile, vulvar and vaginal cancer. HPV-16 is the most common HPV type associated with a malignant phenotype regardless of organ of origin. HPV-16 together with HPV-18 accounts for approximately 70% of cervical cancers. Other non-oncogenic HPV types including HPV types 6 and 11 are associated with over 90% of benign HPV-related lesions such as genital warts and juvenile respiratory papillomatosis.

Purpose: To compare the in vitro drug resistance profiles of advanced stage primary and recurrent epithelial ovarian cancer specimens using the tritiated thymidine uptake assay., Methods: Extreme drug resistance (EDR) to cisplatin, paclitaxel, 4-hydroxycyclophosphamide, and topotecan was determined for an unselected population of primary and metastatic malignant ovarian tissues, synchronous tumors (primary and metastatic tissues obtained from the same patient at diagnosis), and metachronous lesions (specimens from the same patient before and after chemotherapy)., Results: For the large unselected population of malignant tissues (total, N = 6990; primary ovarian, N = 2031; metastatic ovarian, N = 4959), no statistically significant differences were discovered between primary tissues and metastatic lesions when a comparison was made between the percentage of tumors from each group that exhibited extreme drug resistance to the agents assayed. From the library of 6990 specimens, 119 synchronous pairings were identified. These synchronous lesions did not differ significantly in the %EDR between primary and metastatic sites in the same patient; approximately 10% shifted between low drug resistance and EDR. A total of 334 metachronous pairings were identified and the percentage of tissues that exhibited EDR also failed to show a significant difference when primary tumors were compared with matched recurrences in the same patient., Conclusions: For the agents studied, acquired resistance was not a function of disease site. In vitro drug resistance observed at recurrence was not influenced significantly by intervening therapy. It is possible that assay results at diagnosis could be used to guide subsequent therapy at relapse, especially when recurrent tissue is not available for analysis.