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PurposeThe efficacy, safety, and tolerability of cediranib plus olaparib (cedi/ola) were investigated in patients with nongermline-BRCA-mutated (non-gBRCAm) platinum-resistant recurrent ovarian cancer.Patients and methodsPARP inhibitor-naïve women aged ≥18 years with platinum-resistant non-gBRCAm ovarian cancer, ECOG performance status of 0-2, and ≥3 prior lines of therapy received cediranib 30 mg once daily plus olaparib 200 mg twice daily in this single-arm, multicenter, phase IIb trial. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using RECIST 1.1. Progression-free survival (PFS), overall survival (OS), and safety and tolerability were also examined.ResultsSixty patients received cedi/ola, all of whom had confirmed non-gBRCAm status. Patients had received a median of four lines of chemotherapy; most (88.3%) had received prior bevacizumab. ORR by ICR was 15.3%, median PFS was 5.1 months, and median OS was 13.2 months. Forty-four (73.3%) patients reported a grade ≥3 adverse event (AE), with one patient experiencing a grade 5 AE (sepsis), considered unrelated to the study treatment. Dose interruptions, reductions, and discontinuations due to AEs occurred in 55.0%, 18.3%, and 18.3% of patients, respectively. Patients with high global loss of heterozygosity (gLOH) had ORR of 26.7% [4/15; 95% confidence interval (CI), 7.8-55.1], while ORR was 12.5% (4/32; 95% CI, 3.5-29.0) in the low gLOH group.ConclusionsClinical activity was shown for the cedi/ola combination in heavily pretreated, non-gBRCAm, platinum-resistant patients with ovarian cancer despite failing to meet the target ORR of 20%, highlighting a need for further biomarker studies.

ObjectivePatients 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.MethodsData 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.ResultsOf 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.ConclusionsApproximately 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.

ObjectiveTo assess the presentation, characteristics, and prognostic significance of symptoms in patients with high-risk early-stage epithelial ovarian cancer.MethodsA 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.ResultsOf 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

BackgroundAge 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.MethodsWomen 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.ResultsOne-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).ConclusionsNon-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.

ObjectiveIn 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.MethodsWomen 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.Results1132 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.ConclusionsDD paclitaxel was tolerable and associated with longer PFS in the HR proficient and gBRCAwt groups, versus Q3W. gBRCA status did not impact safety.

PurposeIncreasing 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 methodsThere 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).ResultsIncreased 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.ConclusionHigh 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.

ObjectiveTo 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.MethodsAn 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/m2 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.ResultsWith 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).ConclusionsAlthough 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.

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.

PurposeGOG-0218, a double-blind placebo-controlled phase III trial, compared carboplatin and paclitaxel with placebo, bevacizumab followed by placebo, or bevacizumab followed by bevacizumab in advanced epithelial ovarian cancer (EOC). Results demonstrated significantly improved progression-free survival (PFS), but no overall survival (OS) benefit with bevacizumab. Blood samples were collected for biomarker analyses.Experimental designPlasma samples were analyzed via multiplex ELISA technology for seven prespecified biomarkers [IL6, Ang-2, osteopontin (OPN), stromal cell-derived factor-1 (SDF-1), VEGF-D, IL6 receptor (IL6R), and GP130]. The predictive value of each biomarker with respect to PFS and OS was assessed using a protein marker by treatment interaction term within the framework of a Cox proportional hazards model. Prognostic markers were identified using Cox models adjusted for baseline covariates.ResultsBaseline samples were available from 751 patients. According to our prespecified analysis plan, IL6 was predictive of a therapeutic advantage with bevacizumab for PFS (P = 0.007) and OS (P = 0.003). IL6 and OPN were found to be negative prognostic markers for both PFS and OS (P < 0.001). Patients with high median IL6 levels (dichotomized at the median) treated with bevacizumab had longer PFS (14.2 vs. 8.7 months) and OS (39.6 vs. 33.1 months) compared with placebo.ConclusionsThe inflammatory cytokine IL6 may be predictive of therapeutic benefit from bevacizumab when combined with carboplatin and paclitaxel. Aligning with results observed in patients with renal cancer treated with antiangiogenic therapies, it appears plasma IL6 may also define those patients with EOC more or less likely to benefit from the addition of bevacizumab to standard chemotherapy.

On 13 June 2018, Genentech, Inc. issued a press release announcing that the US FDA had approved the antiangiogenesis drug, bevacizumab, in combination with chemotherapy for frontline and maintenance therapy for women with newly diagnosed ovarian cancer. Regulatory approval was based on the National Cancer Institute-sponsored Gynecologic Oncology Group (GOG) protocol 0218, the Phase III, randomized, placebo-controlled, double-blind, multi-center and multi-national clinical trial that met its primary end point, progression-free survival. Bevacizumab is now approved in the frontline, platinum-sensitive recurrent and platinum-resistant recurrent settings for epithelial ovarian cancer. This review will address the broad range of clinical trials addressing the efficacy of bevacizumab use in ovarian cancer.

BackgroundSecondary surgical cytoreduction in women with platinum-sensitive, recurrent epithelial ovarian, primary peritoneal, or fallopian-tube ("ovarian") cancer is widely practiced but has not been evaluated in phase 3 investigation.MethodsWe randomly assigned patients with recurrent ovarian cancer who had received one previous therapy, had an interval during which no platinum-based chemotherapy was used (platinum-free interval) of 6 months or more, and had investigator-determined resectable disease (to no macroscopic residual disease) to undergo secondary surgical cytoreduction and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Adjuvant chemotherapy (paclitaxel-carboplatin or gemcitabine-carboplatin) and use of bevacizumab were at the discretion of the investigator. The primary end point was overall survival.ResultsA total of 485 patients underwent randomization, 240 to secondary cytoreduction before chemotherapy and 245 to chemotherapy alone. The median follow-up was 48.1 months. Complete gross resection was achieved in 67% of the patients assigned to surgery who underwent the procedure. Platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance was administered to 84% of the patients overall and was equally distributed between the two groups. The hazard ratio for death (surgery vs. no surgery) was 1.29 (95% confidence interval [CI], 0.97 to 1.72; P = 0.08), which corresponded to a median overall survival of 50.6 months and 64.7 months, respectively. Adjustment for platinum-free interval and chemotherapy choice did not alter the effect. The hazard ratio for disease progression or death (surgery vs. no surgery) was 0.82 (95% CI, 0.66 to 1.01; median progression-free survival, 18.9 months and 16.2 months, respectively). Surgical morbidity at 30 days was 9%; 1 patient (0.4%) died from postoperative complications. Patient-reported quality of life decreased significantly after surgery but did not differ significantly between the two groups after recovery.ConclusionsIn this trial involving patients with platinum-sensitive, recurrent ovarian cancer, secondary surgical cytoreduction followed by chemotherapy did not result in longer overall survival than chemotherapy alone. (Funded by the National Cancer Institute and others; GOG-0213 ClinicalTrials.gov number, NCT00565851.).

PurposeWe report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma.MethodsA total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry.ResultsMedian follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non-BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity.ConclusionNo survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

PurposeTo evaluate the impact of two different intraperitoneal (IP) chemotherapy regimens on progression-free survival (PFS) among women with newly diagnosed advanced ovarian carcinoma.MethodsEligible patients were randomly assigned to six cycles of IV paclitaxel 80 mg/m2 once per week with intravenous (IV) carboplatin area under the curve 6 (IV carboplatin) versus IV paclitaxel 80 mg/m2 once per week with IP carboplatin area under the curve 6 (IP carboplatin) versus once every 3 weeks IV paclitaxel 135 mg/m2 over 3 hours day 1, IP cisplatin 75 mg/m2 day 2, and IP paclitaxel 60 mg/m2 day 8 (IP cisplatin). All participants received bevacizumab 15 mg/kg IV every 3 weeks in cycles 2 to 22.ResultsA 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.ConclusionCompared 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.

ObjectiveTo 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.MethodsWe 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.ResultsThere 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.ConclusionFor 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 registrationClinialTrials.gov, NCT00002568, NCT00837993, NCT00002717, NCT01074398, and NCT00011986.

PurposeBevacizumab (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 methodsEligible 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.Results150 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 (

PurposeWe 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.MethodsThis 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.ResultsOf 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).ConclusionsAmong 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.

Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab.Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS).Results: Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-BRCA HRR mutations [HR = 0.73; 95% confidence interval (CI), 0.57-0.94; P = 0.01 for PFS; HR = 0.67; 95% CI, 0.50-0.90; P = 0.007 for OS] and BRCA1 mutations (HR = 0.80; 95% CI, 0.66-0.97; P = 0.02 for PFS; HR = 0.74; 95% CI, 0.59-0.94; P = 0.01 for OS) and were lowest for BRCA2 mutations (HR = 0.52; 95% CI, 0.40-0.67; P < 0.0001 for PFS; HR = 0.36; 95% CI, 0.25-0.53; P < 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations.Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status. Clin Cancer Res; 24(4); 777-83. ©2017 AACR.

Over the last decade, new therapeutics in the form of anti-angiogenic treatment, synthetic lethality, and checkpoint inhibition have offered new options for the treatment of ovarian cancer. This review summarizes studies related to these treatment modalities and additionally novel combinations that offer a veritable therapeutic matrix for clinicians to choose from.

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.

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

BackgroundThe purpose of this study was to determine the effect of retroperitoneal (RP) exploration on progression-free survival (PFS) and overall survival (OS) in epithelial ovarian cancer (EOC) patients with stage IIIC disease who underwent optimal debulking surgery.MethodsData were collected from records of the Gynecologic Oncology Group 182 (GOG-182) study of stage IIIC EOC patients cytoreduced to no gross residual disease (R0) or minimal gross residual ( 2 cm IP tumor without lymph node involvement (IP/RP-), 2) > 2 cm IP tumor with lymph node involvement (IP/RP+), and 3) > 2 cm IP tumor with no RP exploration (IP/RP?). The effects of disease distribution and RP exploration on PFS and OS were assessed using Kaplan-Meier and proportional hazards methods.ResultsThere were 1871 stage IIIC patients in GOG-182 who underwent optimal primary debulking surgery. Of these, 689 (36.8%) underwent RP exploration with removal of lymph nodes from at least 1 para-aortic site, and 1182 (63.2%) did not. There were 269 patients in the IP/RP- group, 420 patients in the IP/RP + group, and 1182 patients in the IP/RP? group. Improved PFS (18.5 vs 16.0 months; P

The Fifth Annual Advanced Course in Cytoreductive Surgery for Ovarian Cancer and Peritoneal Surface Malignancies was held at and sponsored by the Division of Gynecologic Oncology at the the University of California, Irvine on Friday and Saturday, October 9-10, 2015. The workshop was comprised of didactic modules, historical treatise, an impassioned tribute, a cadaver laboratory, and heated intraperitoneal chemotherapy demonstration. This was a not-for-profit workshop, and registration fees were used to support course faculty travel to U.C. Irvine and to pay for the cadavers. The original 56 available spots were filled within three weeks of the initial announcement, prompting procurement of two additional cadavers to satisfy registration overflow and accommodate the six U.C. Irvine fellows-in-training. While international participation in the Workshops continues to rise, we have also noted more U.S.-trained Gynecologic Oncologists among the registrants.

ObjectivesTo 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.MethodsData 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.ResultsThe 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

PurposeThe vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent.Patients and methodsPatients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m(2)) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%.ResultsThe study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm.ConclusionOn the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension.

Opinion statementInhibitors of poly (ADP-ribose) polymerase (PARP) have emerged as a new class of anti-cancer drugs, specifically for malignancies bearing aberrations of the homologous recombination pathway, like those with mutations in the BRCA 1 and BRCA 2 genes. Olaparib, a potent PARP1 and PARP2 inhibitor, has been shown to significantly increase progression-free survival (PFS) in women with recurrent ovarian cancer related to a germline BRCA mutation and is currently approved fourth-line treatment in these patients. PARP inhibitors (PARPi) target the genetic phenomenon known as synthetic lethality to exploit faulty DNA repair mechanisms. While ovarian cancer is enriched with a population of tumors with known homologous recombination defects, investigations are underway to help identify pathways in other gynecologic cancers that may demonstrate susceptibility to PARPi through synthetically lethal mechanisms. The ARIEL2 trial prospectively determined a predictive assay to identify patients with HRD. The future of cancer therapeutics will likely incorporate these HRD assays to determine the best treatment plan for patients. While the role of PARPi is less clear in non-ovarian gynecologic cancers, the discovery of a predictive assay for HRD may open the door for clinical trials in these other gynecologic cancers enriched with patients with HRD. Identification of patients with tumors deficient in homologous repair or have HRD-like behavior moves cancer treatment towards individualized therapies in order to maximize treatment effect and quality of life for women living with gynecologic cancers.

Epithelial ovarian cancer (EOC) is responsible for more cancer-related deaths than any other malignancy of the female reproductive system. The standard of care for advanced EOC involves a combination of cytoreductive surgery and platinum-based chemotherapy. Although a majority of patients respond to a platinum-containing regimen, many fail to respond to first-line treatment (platinum-refractory disease) or experience disease progression within 6 months of completing treatment (platinum-resistant disease). Even in patients who initially respond to platinum-based therapy, secondary development of platinum resistance is common. Many chemotherapeutic regimens with comparable efficacy and toxicities are available, leaving the determination of optimal therapy to the physician's discretion. There have been many efforts over the years to develop accurate predictors of outcomes in patients treated with chemotherapy to help inform treatment decisions. Predictive treatment markers are particularly relevant in a disease such as EOC, where a large number of similarly efficacious chemotherapy regimens are available. Chemosensitivity and resistance assays (CSRAs) are attractive approaches to interrogate the efficacy and complex biology of EOC. Some early predictive cellular tests, such as the early clonogenic assays, were limited by technical and logistical issues. Over time, changes in these assays have improved their prognostic and predictive value, but there is still a lack of widespread adoption due to methodological difficulties or limited clinical validation. Herein, we provide an overview of the evolution of CSRAs used to predict outcomes in patients treated with chemotherapy that have been evaluated for use in EOC, with a focus on the latest generation chemoresponse assay.

ObjectiveWe sought to investigate the impact of race, socioeconomic status (SES), and health care system characteristics on receipt of specific components of National Comprehensive Cancer Network guideline care for stage IIIC/IV ovarian cancer.Study designPatients diagnosed with stage IIIC/IV epithelial ovarian cancer between Jan. 1, 1996, through Dec. 31, 2006, were identified from the California Cancer Registry. Multivariate logistic regression analyses evaluated differences in surgery, chemotherapy, and treatment sequence according to race, increasing SES (SES-1 to SES-5), and provider annual case volume.ResultsA total of 11,865 patients were identified. Median age at diagnosis was 65.0 years. The overall median cancer-specific survival was 28.2 months. African American race (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.45-2.87) and care by a low-volume physician (OR, 19.72; 95% CI, 11.87-32.77) predicted an increased risk of not undergoing surgery. Patients with SES-1 (OR, 0.71; 95% CI, 0.60-0.85) and those treated at low-volume hospitals (OR, 0.88; 95% CI, 0.77-0.99) or by low-volume physicians (OR, 0.80; 95% CI, 0.70-0.92) were less likely to undergo debulking surgery. African American race (OR, 1.55; 95% CI, 1.24-1.93) and SES-1 (OR, 1.80; 95% CI, 1.35-2.39) were both significant predictors of not receiving chemotherapy. African American patients were also more likely than whites to receive no treatment (OR, 2.08; 95% CI, 1.45-2.99) or only chemotherapy (OR, 1.55; 95% CI, 1.10-2.18). Patients with low SES were more likely to receive no treatment (OR, 1.95; 95% CI, 1.44-2.64) or surgery without chemotherapy (OR, 1.67; 95% CI, 1.38-2.03).ConclusionAmong patients with advanced-stage ovarian cancer, African American race, low SES, and treatment by low-volume providers are significant and independent predictors of receiving no surgery, no debulking surgery, no chemotherapy, and nonstandard treatment sequences.

Drug discovery in the ovarian cancer arena continues to launch important new clinical trials. Many biologic agents are being studied in phase II and phase III clinical trials for recurrent disease. These agents include compounds that disrupt angiogenesis through a variety of mechanisms. Other oncogenic pathways are also specifically targeted such as PARP, MEK, and topoisomerase inhibitors which are currently being studied in phase III trials. Various cytotoxic agents, as well as therapeutic vaccines, are also under investigation, and continue to demonstrate promising new data. The relevant agents in the treatment of ovarian cancer which have demonstrated positive phase II activity will be discussed.

PurposeRisk-reducing salpingo-oophorectomy (RRSO) lowers mortality from ovarian/tubal and breast cancers among BRCA1/2 mutation carriers. Uncertainties persist regarding potential benefits of RRSO among high-risk noncarriers, optimal surgical age, and anatomic origin of clinically occult cancers detected at surgery. To address these topics, we analyzed surgical treatment arm results from Gynecologic Oncology Group Protocol-0199 (GOG-0199), the National Ovarian Cancer Prevention and Early Detection Study.Participants and methodsThis analysis included asymptomatic high-risk women age ≥ 30 years who elected RRSO at enrollment. Women provided risk factor data and underwent preoperative cancer antigen 125 (CA-125) serum testing and transvaginal ultrasound (TVU). RRSO specimens were processed according to a standardized tissue processing protocol and underwent central pathology panel review. Research-based BRCA1/2 mutation testing was performed when a participant's mutation status was unknown at enrollment. Relationships between participant characteristics and diagnostic findings were assessed using univariable statistics and multivariable logistic regression.ResultsInvasive or intraepithelial ovarian/tubal/peritoneal neoplasms were detected in 25 (2.6%) of 966 RRSOs (BRCA1 mutation carriers, 4.6%; BRCA2 carriers, 3.5%; and noncarriers, 0.5%; P < .001). In multivariable models, positive BRCA1/2 mutation status (P = .0056), postmenopausal status (P = .0023), and abnormal CA-125 levels and/or TVU examinations (P < .001) were associated with detection of clinically occult neoplasms at RRSO. For 387 women with negative BRCA1/2 mutation testing and normal CA-125 levels, findings at RRSO were benign.ConclusionClinically occult cancer was detected among 2.6% of high-risk women undergoing RRSO. BRCA1/2 mutation, postmenopausal status, and abnormal preoperative CA-125 and/or TVU were associated with cancer detection at RRSO. These data can inform management decisions among women at high risk of ovarian/tubal cancer.

Ovarian cancer is the leading cause of gynecologic cancer death in women. Our understanding of the treatment of ovarian cancer has evolved over the last decade, with the use neo-adjuvant chemotherapy, combined intravenous-intraperitoneal (IV-IP) chemotherapy, as well as dose dense paclitaxel. Despite significant improvements in overall survival, the majority of patients succumb to recurrent chemotherapy resistant disease. Given the above, an emphasis has been placed on exploring alternate therapeutics. Recent research efforts have improved our understanding of the molecular biology of ovarian cancer and novel targeted treatment strategies have emerged. With the discovery of BRCA1 and BRCA2 gene mutations, and a more comprehensive assessment of heredity ovarian cancer syndrome, targeted interventions exploiting this biologic susceptibility have emerged. To date, the most studied of these have been PARP inhibitors. The purpose of this review will be to discuss PARP inhibition in advanced stage ovarian cancer, highlighting recent scientific advancements.

ObjectiveTo 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.MethodsA 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

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.

Despite advances in cytotoxic chemotherapy and surgical cytoreduction, disease recurrence continues to be a troubling problem in patients with advanced-stage epithelial ovarian cancer (EOC). Malignant ascites affects approximately 10% of patients with recurrent EOC and is associated with troublesome symptoms, including abdominal pressure, distension, dyspnea, pelvic pain, and bowel/bladder dysfunction. To date, no effective therapy has been identified for the treatment of malignant ascites in patients with recurrent, advanced-stage ovarian cancer. Recently, immune modulation has gained attention as a novel approach to anti-cancer therapy. This review explores the role of epithelial cell-adhesion molecule (EpCAM)-directed immunotherapy, with a specific focus on the mechanism of action of the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3). In addition, clinical trials exploring the use of catumaxomab in the treatment of malignant ascites in patients with ovarian cancer are reviewed.

Ovarian cancer is the most deadly gynecologic cancer, with 15,000 anticipated deaths within the United States alone in 2012, and new treatment strategies are needed. Ovarian cancer tumors are known to host an immunosuppressive microenvironment. This suppression may be reversible via activation of the innate immune response. Toll-like receptor 8 activates innate immunity while simultaneously inhibiting the effects of regulatory T cells within the ovarian cancer tumors. VTX-2337 is a novel small molecule ligand of Toll-like receptor 8 and is currently the subject of a Phase II randomized, double-blind, placebo-controlled trial Gynecologic Oncology Group (GOG)-3003 for patients with recurrent platinum-resistant ovarian cancer. We look forward to the results of this trial as support for the paradigm of process therapy in the treatment of ovarian cancer.

Malignant ascites affects approximately 10% of patients with recurrent epithelial ovarian cancer and is associated with troublesome symptoms, including abdominal pressure and distension, dyspnea, bloating, pelvic pain, and bowel/bladder dysfunction. To date, no effective therapy has been identified for the treatment of malignant ascites in patients with recurrent, advanced ovarian cancer. In this article, we discuss currently existing options for the treatment of ascites associated with ovarian cancer, and review the literature as it pertains to novel, targeted therapies. Specifically, preclinical and clinical trials exploring the use of the antiangiogenic agents, bevacizumab and vascular endothelial growth factor-trap, as well as the nonangiogenic agent, catumaxomab, will be reviewed. Despite current limitations in treatment, knowledge regarding management options in the palliation of ascites is critical to practicing physicians. Ultimately, as with all novel therapies, symptom relief and treatment goals must be weighed against patient discomfort and potentially significant adverse events.

A proportion of reproductive age women are affected by gynecologic malignancies. This patient population is faced with difficult decisions, related to their cancer care and treatment, as well as future childbearing potential. Therefore, it is important for gynecologists to be familiar with fertility sparing management options in patients with cervical, ovarian, and endometrial cancer. In addition to understanding the surgical approaches available, providers should be able to counsel patients regarding their eligibility for and the indications and limitations of fertility sparing therapy for gynecologic cancer, allowing for appropriate referrals. A comprehensive PUBMED literature search was conducted using the key words "fertility preservation," "cervical cancer," "endometrial cancer," "ovarian cancer," "borderline tumor of the ovary," "germ cell tumor," "obstetrical outcomes," "chemotherapy," and "radiation." The following review summarizes fertility sparing options for patients with cervical, ovarian and endometrial cancer, with an emphasis on appropriate patient selection, oncologic, and obstetric outcomes.

PurposeTo 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).MethodsBiochemical 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.ResultsOf 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.ConclusionThalidomide was not more effective than tamoxifen in delaying recurrence or death but was more toxic. VEGF was not prognostic in this cohort.

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

PurposeTo compare the in vitro drug resistance profiles of advanced stage primary and recurrent epithelial ovarian cancer specimens using the tritiated thymidine uptake assay.MethodsExtreme 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).ResultsFor 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.ConclusionsFor 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.

Introduction: Approximately 300,000 women worldwide are diagnosed each year with ovarian cancer. Frequently diagnosed in late stages with ambiguous symptomatology, ovarian cancer has a low survival rate.Areas covered: Niraparib, a PARP inhibitor, was approved in 2020 for use in the maintenance treatment of ovarian cancer regardless of biomarker status. Included in the review are PRIMA (NCT02655016), NOVA (NCT01847274), AVANOVA2 (NCT02354131), and QUADRA (NCT02354586) trials which herald the advent of using maintenance oral therapies in the treatment of ovarian cancer. Additionally, with new combination drug trials, exciting avenues for treatment are also discussed with the FIRST (NCT03016338) trial.Expert opinion: Maintenance niraparib treatment regardless of genetic profile offers a new modality for the treatment of ovarian cancer with a low side effect profile and importantly oral dosing. New combinations of synergistic immunotherapeutics, and antiangiogenesis therapies with niraparib also offer exciting new frontiers for patients with ovarian cancer. [ABSTRACT FROM AUTHOR]

The American Society of Clinical Oncology (ASCO) meeting was held in Chicago, Ill, from May 31, 2013, to June 4, 2013, and focused on “Building Bridges to Conquer Cancer.” An estimated 25,500 oncology professionals, with a broad range of interests, attended the meeting. Cervical cancer, a gynecologic malignancy with a significant global burden, was prominently featured at this year’s meeting. In a mark of exemplary scientific accomplishment within our specialty, 2 of the 5 general session plenaries investigated advancements in cervical cancer care, extending from improved screening to treatment of metastatic disease. This was followed by the presentation of several important phase 2 and 3 clinical trials in the Gynecologic Oncology Tract, focusing on cervical, ovarian, uterine, and breast cancer, which will be discussed in this report. [ABSTRACT FROM AUTHOR]

The 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) was held in Chicago, June 1-5, 2011, and brought together more than 25,000 oncology professionals from a broad range of specialties to explore the theme, “Collaborating to Conquer Cancer”. The Gynecologic Oncology Track had a strong international presence, with important clinical trials being presented from Japan, Germany, Norway, the United States, and others. This meeting report will highlight several phase 3 and phase 2 clinical trials as well as notable translational research endeavors and other selected abstracts. [ABSTRACT FROM AUTHOR]

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. 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). 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]. g BRCA PVs observed in 24% younger vs 8% of older participants (p < 0.001); s BRCA in 8% vs 10% (p = 0.2559), and HRD (GIS ≥ 42) not due to g BRCA was 35% vs 31% (p = 0.36). HRD frequency was similar in participants aged < 70 and ≥ 70 years (35% vs 31%) when the contribution of g BRCA was excluded; rates of s BRCA 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. [Display omitted] • 48% of high grade serous ovarian cancers (HGSC) in older patients are homologous recombination deficient (HRD). • Somatic or germline BRCA1/2 pathogenic variants (PVs) contribute to almost half of HGSC tumors with HRD. • Excluding the contribution of germline BRCA PVs, the frequency of HRD is similar in younger vs older patients with HGSC. • The frequency of somatic BRCA1/2 PVs is independent of age (8% younger v 10% older participants). • HRD testing should not be restricted by patient age. [ABSTRACT FROM AUTHOR]

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). 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. 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. 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. • The formula used to estimate CrCl affects carboplatin dosing. • Estimated creatinine clearance (CrCl) <60 mL/min (by Jelliffe) did not accurately predict adverse events. • Our data do not support a minimum threshold CrCl <60 mL/min as exclusion criteria from clinical trials. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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 • Age ≥ 70 years was associated with an increased risk of both cancer-related and non-cancer related death. • Carboplatin and paclitaxel administration is well tolerated regardless of age. • Older age was associated with higher rates of grade 2 or higher peripheral neuropathy. • Risks of other chemotherapy related toxicities were equal between older compared to younger patients. [ABSTRACT FROM AUTHOR]

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. 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). 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). 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. • Normal baseline CA125 prior to chemotherapy is associated with better survival in high-risk early-stage ovarian cancer. • Normalization of CA125 after the first cycle of chemotherapy is associated improved survival in early-stage ovarian cancer. • Percent decline and absolute nadir normal value of CA125 were not predictive of outcome in early-stage ovarian cancer. [ABSTRACT FROM AUTHOR]

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). The OVAL (NCT03398655) study is an on-going study where patients are randomly assigned in a 1:1 ratio to weekly paclitaxel 80 mg/m2 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. 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%. 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. • OVAL is a Phase III trial using paclitaxel and VB-111 in recurrent ovarian cancer • VB-111 has a dual mechanism targeting tumor vasculature and anti-tumor immunity • CA-125 response in the VB-111 treated arm met the pre-specified interim criterion • Assuming balanced randomization, the response in the VB-111 arm was at least 58% • The OVAL study has been recommended to continue enrollment as planned [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Non‑platinum therapies are more cost-effective in comparison to bevacizumab and PARPi for platinum-resistant ovarian cancer. • Even when adjusting for quality of life, the non‑platinum chemotherapy proved to be the most cost-effective. • Primary expense of novel therapies lies in high developmental costs, rather than costs of infusions and complications. [ABSTRACT FROM AUTHOR]