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During a career, which spanned nearly 60 years, Professor Philip J. DiSaia (1937–2018) trailblazed a path forward in academic medicine, which would become the standard by which Departments of Obstetrics and Gynecology and Gynecologic Oncology Divisions and Cancer Centers would be measured throughout the United States, in Europe and Japan. Following his discovery of fetal warfarin syndrome as a resident, DiSaia would serve in the U.S. Navy and successfully compete for an American Cancer Society Grant that would fund his Fellowship in Gynecologic Oncology under the instruction of Dr Felix N. Rutledge at the MD Anderson Hospital and Tumor Institute in Houston, Texas. Dr DiSaia's goal to establish a traditional academic department was realized at the University of California, Irvine, where he remained active in an unprecedented, uninterrupted 42‐year run, training many outstanding obstetrician‐gynecologists and gynecologic oncologists, future Division Directors, Cancer Center Directors and Department Chairpersons. His dedication to the field and inexhaustible work ethic fueled his many successes in tumor immunology and the clinical trials of the National Cancer Institute's Gynecologic Oncology Group. [ABSTRACT FROM AUTHOR]

The last 2 years have ushered in a new era in ovarian cancer therapy with the US Food and Drug Administration's (FDA) approval of poly-ADP ribose polymerase (PARP) inhibitors (PARPi). One of the deadliest cancers that women experience, ovarian cancer, is most often diagnosed in advanced stages. Although cytoreductive surgery and (platinum/taxane-based) chemotherapy can place the majority of patients into remission, most will experience a relapse of their disease in their lifetime. This has led to studies exploring the benefits and efficacy of maintenance treatment. This review will briefly discuss the history of maintenance therapy as well as focus on the FDA's approval of rucaparib and its companion tumor profiling test, in the US. It will describe how women with deleterious mutations in the BRCA gene, through their inherent deficiency in homologous recombination, presented scientists with a target to exploit through a concept known as synthetic lethality. Not only did this lead to a targeted treatment for BRCA mutation carriers but for other patients with deficiencies in homologous recombination and, more broadly, also in platinum-sensitive patients. The focus of this review will be on rucaparib in the US, approved for both maintenance of platinum-sensitive recurrent ovarian cancer and treatment in the third-line setting and beyond. It has the broadest indication amongst the three PARPi in ovarian cancer. Furthermore, the ongoing trials using rucaparib in ovarian cancer and other disease types will be discussed. [ABSTRACT FROM AUTHOR]

The article discusses the debate on the use of cisplatin plus paclitaxel to the patients with metastatic/recurrent cervical cancer in the U.S. It is stipulated that cisplatin plus paclitaxel provides a superior remissions of the recurrent and metastatic cervical cancer. Meanwhile, the quality of life of the patients would be enhanced by using the doublet. Also mentions is its availability to treat patients with recurrent cancer and those associated with some cures in select patients who had the history of metastatic disease.

Objective: To assess the presentation, characteristics, and prognostic significance of symptoms in patients with high-risk early-stage epithelial ovarian cancer.Methods: A retrospective chart review was performed on all patients enrolled in a phase III clinical trial (GOG 157). All patients had surgically staged, high-risk early-stage epithelial ovarian cancer (stage IA-IB and grade 3, any clear cell, stage IC or II). Chi-square and Kaplan-Meier estimates and Cox proportional hazards models were used for statistical analyses.Results: Of 419 patients evaluated for symptoms, 301 (72%) presented with one or more symptoms, and 118 (28%) were asymptomatic but had a mass found on examination. Forty percent had only one symptom, and 32% had more than one symptom. Among those with at least one symptom, the most common were abdominal and pelvic pain (31%), and increased girth or fullness (26%). Overall, 23% of patients with tumors 10 cm or smaller, 27% of patients with tumors larger than 10 cm to 15 cm, and 46% of patients with tumors larger than 15 cm had multiple symptoms (P<.001). There was no significant difference in presentation of symptoms based on age, stage, or histologic subtype. Symptoms at diagnosis were not associated with recurrence or survival.Conclusion: More than 70% of patients with high-risk early-stage, epithelial ovarian cancer present with one or more symptoms, with the most common being abdominal or pelvic pain. The proportion of women with symptoms and the number of symptoms increase with enlarging tumor size. [ABSTRACT FROM AUTHOR]

Background: GOG 240 was a practice-changing randomised phase 3 trial that concluded that chemotherapy plus bevacizumab for advanced cervical cancer significantly improves overall and progression-free survival, and the proportion of patients achieving an overall objective response, compared with chemotherapy alone. In this study, we aimed to analyse patient-reported outcomes in GOG 240.Methods: Eligible adult participants (aged ≥18 years) had primary stage IVB or recurrent or persistent carcinoma of the cervix with measurable disease and GOG performance status of 0-1. Participants were randomly assigned by web-based permuted block randomisation (block size 4) in a 1:1:1:1 ratio to the four treatment groups: cisplatin (50 mg/m(2) intravenously on day 1 or 2 of the treatment cycle) and paclitaxel (135 mg/m(2) intravenously over 24 h or 175 mg/m(2) intravenously over 3 h on day 1), with or without bevacizumab (15 mg/kg intravenously on day 1 or 2), or paclitaxel (175 mg/m(2) over 3 h on day 1) and topotecan (0·75 mg/m(2) for 30 min on days 1-3) with or without bevacizumab (15 mg/kg intravenously on day 1). Treatment assignment was concealed at randomisation (everyone was masked to treatment assignment, achieved by the use of a computer encrypted numbering system at the National Cancer Institute) and became open-label when each patient was registered to the trial. Treatment cycles were repeated every 21 days until disease progression or unacceptable toxicity, whichever occurred first. The coprimary endpoints of the trial were overall survival and safety; the primary quality-of-life endpoint was the score on the Functional Assessment of Cancer Therapy-Cervix Trial Outcome Index (FACT-Cx TOI). For our analysis of patient-reported outcomes, participants were assessed before treatment cycles 1, 2, and 5, and at 6 and 9 months after the start of cycle 1, with the FACT-Cx TOI, items from the FACT-GOG-Neurotoxicity subscale, and a worst pain item from the Brief Pain Inventory. All patients who completed baseline quality-of-life assessments and at least one further follow-up assessment were evaluable for quality-of-life outcomes. This study is registered with ClinicalTrials.gov, number NCT00803062.Findings: Between April 6, 2009, and Jan 3, 2012, a total of 452 patients were enrolled in the trial, of whom 390 completed baseline quality-of-life assessment and at least one further assessment and were therefore evaluable for quality-of-life outcomes. In these patients, patient-reported outcome completion declined from 426 (94%) of 452 (at baseline) to 193 (63%) of 307 (9 months post-cycle 1), but completion rates did not differ significantly between treatment regimens (p=0·78). The baseline FACT-Cx TOI scores did not differ significantly between patients who received bevacizumab versus those who did not (p=0·27). Compared with patients who received chemotherapy alone, patients who received chemotherapy plus bevacizumab reported FACT-Cx TOI scores that were an average of 1·2 points lower (98·75% CI -4·1 to 1·7; p=0·30).Interpretation: Improvements in overall survival and progression-free survival attributed to the incorporation of bevacizumab into the treatment of advanced cervical cancer were not accompanied by any significant deterioration in health-related quality of life. Patients responding to anti-angiogenesis therapy who maintain an acceptable quality of life could be suitable at progression for treatment with other novel therapies that might confer additional benefit.Funding: National Institutes of Health. [ABSTRACT FROM AUTHOR]

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.)

Purpose: To evaluate the impact of two different intraperitoneal (IP) chemotherapy regimens on progression-free survival (PFS) among women with newly diagnosed advanced ovarian carcinoma., Methods: Eligible patients were randomly assigned to six cycles of IV paclitaxel 80 mg/m 2 once per week with intravenous (IV) carboplatin area under the curve 6 (IV carboplatin) versus IV paclitaxel 80 mg/m 2 once per week with IP carboplatin area under the curve 6 (IP carboplatin) versus once every 3 weeks IV paclitaxel 135 mg/m 2 over 3 hours day 1, IP cisplatin 75 mg/m 2 day 2, and IP paclitaxel 60 mg/m 2 day 8 (IP cisplatin). All participants received bevacizumab 15 mg/kg IV every 3 weeks in cycles 2 to 22., Results: A total of 1,560 participants were enrolled and had 84.8 months of follow-up. The median PFS duration was 24.9 months in the IV carboplatin arm, 27.4 months in the IP carboplatin arm, and 26.2 months in the IP cisplatin arm. For the subgroup of 1,380 patients with stage II/III and residual disease of 1 cm or less, median PFS was 26.9 (IV-carboplatin), 28.7 (IP-carboplatin), and 27.8 months (IP cisplatin), respectively. Median PFS for patients with stage II/III and no residual disease was 35.9, 38.8, and 35.5 months, respectively. Median overall survival for all enrolled was 75.5, 78.9, and 72.9 months, respectively, and median overall survival for stage II/III with no gross residual disease was 98.8 months, 104.8 months, and not reached. Mean patient-reported Functional Assessment of Cancer Therapy neurotoxicity scores (Gynecologic Oncology Group) were similar for all arms, but the mean Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary scores during chemotherapy were statistically worse in the IP cisplatin arm., Conclusion: Compared with the IV carboplatin reference arm, the duration of PFS was not significantly increased with either IP regimen when combined with bevacizumab and was better tolerated than IP cisplatin.

Objective: To analyze clinical prognostic factors for survival after recurrence of high-grade, advanced-stage ovarian-peritoneal-tubal carcinoma and to develop a nomogram to predict individual survival after recurrence., Methods: We retrospectively analyzed patients treated in multicenter Gynecologic Oncology Group protocols for stage III and IV ovarian-peritoneal-tubal carcinoma who underwent primary debulking surgery, received chemotherapy with paclitaxel and a platinum compound, and subsequently developed recurrence. Prognostic factors affecting survival were identified and used to develop a nomogram, which was both internally and externally validated., Results: There were 4,739 patients included in this analysis, of whom, 84% had stage III and 16% had stage IV ovarian carcinoma. At a median follow-up of 88.8 months (95% CI 86.2-92.0 months), the vast majority of patients (89.4%) had died. The median survival after recurrence was 21.4 months (95% CI 20.5-21.9 months). Time to recurrence after initial chemotherapy, clear cell or mucinous histology, performance status, stage IV disease, and age were significant variables used to develop a nomogram for survival after recurrence, which had a concordance index of 0.67. The time to recurrence alone accounted for 85% of the prognostic information. Similar results were found for patients who underwent second look laparotomy and had a complete pathologic response or received intraperitoneal chemotherapy., Conclusion: For individuals with advanced-stage ovarian carcinoma who recur after standard first-line therapy, estimated survivals after recurrence are closely related to the time to recurrence after chemotherapy and prognostic variables can be used to predict subsequent survival., Clinical Trial Registration: ClinialTrials.gov, NCT00002568, NCT00837993, NCT00002717, NCT01074398, and NCT00011986.

The FDA approval of the PARP inhibitor olaparib for fourth-line therapy of germline BRCA1/2-mutated ovarian cancer represents the first registered indication for this class of drugs in any disease. PARP is a family of proteins involved in the repair of single-strand DNA breaks. High-grade serous ovarian carcinomas with BRCA deficiencies may be particularly vulnerable to both direct and indirect effects of PARP inhibition. This phenotype frequently arises as a consequence of defects in the repair of damaged DNA, rendering cancer cells susceptible to DNA-damaging platinum compounds and targeted therapies affecting homologous recombination repair (HRR). When cells already deficient in HRR are exposed to PARP inhibitors, apoptosis occurs by way of synthetic lethality. In this review, we trace the clinical development of olaparib for women with recurrent epithelial ovarian carcinoma harboring germline BRCA mutations, a biomarker for HRR deficiency present in 15% to 20% of cases. Clinical trials highlighted include not only those pivotal studies that have led to regulatory approval in the United States and in Europe, but also those in which olaparib was studied in novel combinations, including chemotherapy and antiangiogenesis agents., (©2015 American Association for Cancer Research.)

Cancer is a close second to heart disease for cause of death in the USA, and could soon surpass heart disease as the population ages and the incidence of cancer continues to increase. While heart disease can be addressed through behavior modification and education (e.g., smoking cessation, dietary changes, exercises that promote cardiovascular fitness), pharmacology and improved surgical devices and methods, cancer ultimately requires improved and novel drug treatments to bring mortality rates down. In 2014, the US FDA approved 17 drugs and/or drug combinations in 12 disease sites for a total of 19 indications in melanoma, hematologic malignancies, gastrointestinal carcinoma, non-small-cell lung cancer, gynecologic malignancies and lymphoma/lymphoproliferative disorders.