Health-related quality of life in patients with newly diagnosed advanced ovarian cancer treated with niraparib vs placebo: Results from the phase 3 randomized PRIMA/ENGOT-OV26/GOG-3012 trial.

OBJECTIVE: To assess patient-reported health-related quality of life (HRQoL) in patients with ovarian cancer (OC) who received niraparib as first-line maintenance therapy. METHODS: PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) enrolled patients with newly diagnosed advanced OC who responded to first-line platinum-based chemotherapy. Patients were randomized (2:1) to niraparib or placebo once daily in 28-day cycles until disease progression, intolerable toxicity, or death. HRQoL was assessed as a prespecified secondary end point using patient-reported responses to the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30), the EORTC QLQ Ovarian Cancer Module (EORTC QLQ-OV28), the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), and EQ-5D-5L questionnaires. Assessments were collected at baseline and every 8 weeks (±7 days) for 56 weeks, beginning on cycle 1/day 1, then every 12 weeks (±7 days) thereafter while the patient received study treatment. RESULTS: Among trial participants (niraparib, n = 487; placebo, n = 246), PRO adherence exceeded 80% for all instruments across all cycles. Patients reported no decline over time in HRQoL measured via EORTC QLQ-C30 Global Health Status/QoL and FOSI overall scores. Scores for abdominal/gastrointestinal symptoms (EORTC QLQ-OV28) and nausea and vomiting, appetite loss, and constipation (EORTC QLQ-C30) were higher (worse symptoms) in niraparib-treated patients than placebo-treated patients; except for constipation, these differences resolved over time. Patients did not self-report any worsening from baseline of fatigue, headache, insomnia, or abdominal pain on questionnaires. CONCLUSIONS: Despite some early, largely transient increases in gastrointestinal symptoms, patients with OC treated with niraparib first-line maintenance therapy reported no worsening in overall HRQoL.

Carboplatin dosing in the treatment of ovarian cancer: An NRG oncology group study.

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(CrClJelliffe) 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.

The effect of older age on treatment outcomes in women with advanced ovarian cancer receiving chemotherapy: An NRG-Oncology/Gynecologic Oncology Group (GOG-0182-ICON5) ancillary study.

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.

Lifestyle intervention in ovarian cancer enhanced survival (LIVES) study (NRG/GOG0225): Recruitment, retention and baseline characteristics of a randomized trial of diet and physical activity in ovarian cancer survivors.

OBJECTIVE: The Lifestyle Intervention for oVarian cancer Enhanced Survival (LIVES) is a national study of a combined diet and physical activity intervention for stage II-IV ovarian cancer survival, an under-represented cancer in lifestyle behavioral intervention research. Here, we present the data on recruitment, retention, and baseline demographic, clinical and lifestyle behavior characteristics of the LIVES study participants. METHODS: The LIVES study (NRG Oncology/GOG 0225) is a Phase III diet plus physical activity intervention trial testing the hypothesis that ovarian cancer survivors in the lifestyle intervention will demonstrate better progression-free survival than those in the control condition. Study interventions were delivered via centralized telephone-based health coaching. Baseline descriptive statistics were computed for demographic, clinical, and lifestyle behavior characteristics. RESULTS: The LIVES study exceeded its recruitment goals, enrolling 1205 ovarian cancer survivors from 195 NRG/NCORP-affiliated oncology practices across 49 states from 2012 to 2018. The mean age of enrollees was 59.6 years; the majority (69.4%) with stage III disease; 89% White, 5.5% Hispanic; 64% overweight/obese. Baseline self-reported diet showed a mean daily intake of 6.6 servings of fruit and vegetables, 62.7 fat grams, and 21.7 g of fiber. Physical activity averaged 13.0 MET-hours/week of moderate to vigorous physical activity; 50.9 h/week of sedentary time. Retention rates exceeded 88%. CONCLUSION: The LIVES study demonstrates efficiency in recruiting and retaining ovarian cancer survivors in a 24-month study of diet and physical activity intervention with a primary endpoint of progression free survival that will be reported. TRIAL REGISTRATION: ClinicalTrials.govNCT00719303.

Beyond Sedlis-A novel histology-specific nomogram for predicting cervical cancer recurrence risk: An NRG/GOG ancillary analysis.

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.

Circulating Tumor Cells In Advanced Cervical Cancer: NRG Oncology-Gynecologic Oncology Group Study 240 (NCT 00803062).

To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin+/anti-CD45- cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0-18) and, at 36 days posttreatment, was 4 (range, 0-17). The greater the declination in CTCs between time points studied, the lower the risk of death [HR, 0.87; 95% confidence interval (CI), 0.79-0.95)]. Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32-1.03) and PFS (HR, 0.59; 95% CI, 0.36-0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker.

Long term survival outcomes of stage I mucinous ovarian cancer - A clinical calculator predictive of chemotherapy benefit.

OBJECTIVES: To determine the long-term potential benefit of adjuvant chemotherapy in subgroups of high-risk stage I mucinous ovarian cancer patients using a predictive scoring algorithm. METHODS: Data were collected from the National Cancer Database from 2004 to 2014. Based on demographic and surgical characteristics, a novel 10-year survival prognostic scoring system was developed using Cox regression. RESULTS: There were 2041 eligible patients with stage I mucinous ovarian cancer including 1362 (67%) with stage IA/IB disease, 598 (29%) with stage IC disease, and 81 (4%) with stage I disease not otherwise specified. Median age was 52 with a range of 13-90 years old. 737 (36%) patients were treated with adjuvant chemotherapy. Adjuvant chemotherapy was more common in patients with stage IC relative to stage IA/IB disease (69% vs. 21%, P < 0.001) or with poorly-differentiated relative to well-differentiated tumors (69% vs. 23%, P < 0.001). Unadjusted 10-year survival was 81% relative to 79% for patients treated with vs. without chemotherapy, respectively (P = 0.46). Patients were predicted to exhibit a low- or a high-risk of death using a multivariate Cox regression model with age, stage, grade, lymphovascular space invasion and ascites. Risk of death without vs. with adjuvant chemotherapy was similar in low-risk patients (88% vs. 84%; HR = 0.80, 95%CI = 0.56-1.15, P = 0.23) and worse in high-risk patients (51% vs. 74%; HR = 1.58, 95%CI: 1.05-2.38, P = 0.03) with stage I mucinous ovarian cancer. CONCLUSIONS: A predictive scoring algorithm may provide prognostic information on long-term survival and identify high-risk stage I mucinous ovarian cancer patients who might achieve a survival benefit from adjuvant chemotherapy.

Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma.

IMPORTANCE: Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. OBJECTIVE: To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. DESIGN, SETTING, AND PARTICIPANTS: The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to ≥23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019. INTERVENTIONS: The recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. MAIN OUTCOMES AND MEASURES: The primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis. RESULTS: Fourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. CONCLUSIONS AND RELEVANCE: Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02657889.

Randomized Trial of Intravenous Versus Intraperitoneal Chemotherapy Plus Bevacizumab in Advanced Ovarian Carcinoma: An NRG Oncology/Gynecologic Oncology Group Study.

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/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. 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.

Nomogram for Predicting Individual Survival After Recurrence of Advanced-Stage, High-Grade Ovarian Carcinoma.

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.

A Review of Gynecologic Oncology in the Global Setting: Educating and Training the Next Generation of Women's Health Providers.

IMPORTANCE: Women in low- and middle-income countries (LMICs) are responsible for the stability of their families. Child survival is directly linked to the health and well-being of their mother. Cancer is the leading cause of morbidity and mortality worldwide, and the incidence and mortality for women from cancer are projected to increase over the coming decades. Gynecologic cancer outcomes are improved when women are cared for by a gynecologic oncologist; however, there are limited specialized providers in LMICs. Increasing interest and involvement from specialists in the United States will improve partnerships abroad and the care of women worldwide. OBJECTIVE: To summarize the importance of global gynecologic oncology care and the current data for US trainees in obstetrics and gynecology to participate in clinical and capacity-building opportunities. EVIDENCE ACQUISITION: We performed a PubMed literature search for articles pertaining to the topic of global health education in obstetrics and gynecology and gynecologic oncology specifically. RESULTS: Many obstetric and gynecologic residency programs offer international opportunities, but these are less than those in other specialties and are more frequently focused in obstetrics. Many gynecologic oncology fellowship programs offer international experiences for fellows; however, the time and resources required are limited. Several US and international programs are ongoing to improve capacity building for gynecologic oncology in LMICs with local trainees. CONCLUSIONS AND RELEVANCE: Training and care in gynecologic oncology care worldwide are improving through efforts at multiple levels. Continued efforts are needed to improve US trainee international education and experience.

Evaluation of a Streamlined Oncologist-Led BRCA Mutation Testing and Counseling Model for Patients With Ovarian Cancer.

Purpose There is a growing demand for BRCA1/ 2 mutation ( BRCAm) testing in patients with ovarian cancer; however, the limited number of genetic counselors presents a potential barrier. To facilitate more widespread BRCAm testing in ovarian cancer, pretest counseling by the oncology team could shorten testing turnaround times and ease the pressure on genetic counselors. Patients and Methods The prospective, observational Evaluating a Streamlined Onco-genetic BRCA Testing and Counseling Model Among Patients With Ovarian Cancer (ENGAGE) study evaluated a streamlined, oncologist-led BRCAm testing pathway. The analysis population comprised 700 patients with ovarian cancer at 26 sites in the United States, Italy, and Spain. The primary objectives were to assess turnaround time and, using questionnaires, to evaluate stakeholder satisfaction (patients, oncologists, and geneticists or genetic counselors) with the oncologist-led BRCAm testing pathway. Results The median overall turnaround time was 9.1 weeks (range, 0.9 to 37.1 weeks), with median turnaround times in the United States, Italy, and Spain of 4.1 weeks (range, 0.9 to 37.1 weeks), 20.4 weeks (range, 2.9 to 35.4 weeks), and 12.0 weeks (range, 2.0 to 36.7 weeks), respectively. Patient satisfaction with the oncologist-led BRCAm testing pathway was high, with > 99% of patients expressing satisfaction with pre- and post- BRCAm test counseling. Oncologist satisfaction with the BRCAm testing pathway was also high, with > 80% agreeing that the process for performing BRCAm testing worked well and that counseling patients on BRCAm testing was an efficient use of their time. Oncologists expressed higher levels of satisfaction with the BRCAm testing pathway than did geneticists or genetic counselors. Conclusion The results of the ENGAGE study demonstrate that an oncologist-led BRCAm testing process is feasible in ovarian cancer. Development of local BRCAm testing guidelines similar to the one used in this study could allow faster treatment decisions and better use of resources in the management of patients with ovarian cancer.

Paclitaxel With and Without Pazopanib for Persistent or Recurrent Ovarian Cancer: A Randomized Clinical Trial.

IMPORTANCE: Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. Pazopanib is an oral, multitarget kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptors α and ß; and proto-oncogene receptor tyrosine kinase (c-KIT). OBJECTIVE: To estimate the progression-free survival (PFS) hazard ratio (HR) of weekly paclitaxel and pazopanib compared with weekly paclitaxel and placebo in women with recurrent ovarian cancer. Secondary objectives included frequency and severity of adverse events, proportion responding, and overall survival (OS) in each arm. Translational research objectives included exploring the association between possible biomarkers and single-nucleotide polymorphisms in vascular endothelial growth factor A, interleukin 8, and hypoxia-inducible factor 1α; and PFS, OS, and proportion responding. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled, double-blind phase 2 study was conducted at 26 participating institutions. Patients were enrolled between December 12, 2011, and April 22, 2013. Data were frozen on August 11, 2014. Participants were patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with 1 to 3 prior regimens and performance status of 0 to 2. One hundred six patients enrolled; 100 were evaluable for toxic effects. INTERVENTIONS: All patients received paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 every 28 days and were randomized 1:1 to pazopanib 800 mg orally daily or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was PFS. The study was designed to detect a 37.5% reduction in the hazard with 80% power (α = 10%). RESULTS: A total of 106 women (median age [range], 61 [35-87] years; 88 [83%] white) were enrolled. Study arms were well balanced for age, performance status, measurable disease, and prior bevacizumab. Proportion responding was 14 of 44 (31.8%) vs 10 of 44 (22.7%) for pazopanib plus paclitaxel vs paclitaxel alone. Median PFS was 7.5 vs 6.2 months for pazopanib plus paclitaxel vs paclitaxel alone, respectively (HR, 0.84; 90% CI, 0.57-1.22; P = .20). Median OS was 20.7 vs 23.3 months for pazopanib plus paclitaxel vs paclitaxel alone (HR, 1.04; 90% CI, 0.60-1.79; P = .90). Severe hypertension was more common on the pazopanib plus paclitaxel arm (relative risk, 12.0; 95% CI, 1.62-88.84). More patients discontinued treatment on the paclitaxel arm for disease progression (34 of 52 [65.4%] vs 17 of 54 [31.5%]), and more on the pazopanib plus paclitaxel arm for adverse events (20 of 54 [37%] vs 5 of 52 [9.6%]). No association was found between single-nucleotide polymorphisms (interleukin 8 and hypoxia-inducible factor 1α) and OS and proportion responding. Patients with VEGFA CC genotype may be more resistant to weekly paclitaxel than those with the AC or AA genotype, with 1 of 14 (7%), 3 of 15 (20%), and 4 of 8 (50%) responding, respectively. CONCLUSIONS AND RELEVANCE: The combination of pazopanib plus paclitaxel is not superior to paclitaxel in women with recurrent ovarian cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01468909.

Predictive modeling for determination of microscopic residual disease at primary cytoreduction: An NRG Oncology/Gynecologic Oncology Group 182 Study.

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.

Genome-wide association study evaluating single-nucleotide polymorphisms and outcomes in patients with advanced stage serous ovarian or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study.

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.

Association between hypoalbuminemia and surgical site infection in vulvar cancers.

OBJECTIVE: To determine if preoperative hypoalbuminemia is associated with postoperative wound complications among patients with vulvar cancer. METHODS: The National Surgical Quality Improvement Program database was queried for cases of vulvar cancer undergoing vulvectomy with or without lymphadenectomy (LND) from 2008 to 2013. Primary outcome was major wound complication. Secondary outcome was minor wound complication. Hypoalbuminemia was defined as albumin<3.5g/dL. Descriptive statistics and multivariable logistic regression were used for analysis. RESULTS: Of 777 vulvar cancer patients, 514 (66.2%) had vulvar surgery alone and 263 (30.3%) had a LND. Median age was 66 (range 20-90) and median BMI was 28.9kg/m(2) (range 14.3-65.5). The incidence of wound complication was 10.4% (81/777) with 48 minor and 39 major complications. There was no difference in major wound complications when a LND was performed (p=1.0). Preoperative albumin was recorded in 429 patients (55.2%). Patients with hypoalbuminemia were more likely to have a major wound complication (OR 2.9 95% CI 1.1-7.3, p=0.02), even after adjusting for BMI, age, preoperative hematocrit, and diabetes (aOR 2.7 95% CI 1.1-7.1, p=0.04). In bivariable analysis, age, diabetes, and BMI were not associated with wound complication. Patients with a wound infection had 10 times the odds of being readmitted within 30days (OR 9.5, 95% CI 4.9-18.4, p<0.01). CONCLUSIONS: Low preoperative albumin is associated with major postoperative wound complications in women undergoing surgery for vulvar cancer. When obtaining informed consent, patients with low albumin should be counseled regarding higher risks of postoperative wound complication.

Enhancing Care of the Survivor of Gynecologic Cancer: Managing the Menopause and Radiation Toxicity.

It is expected that there will be 290,000 cases of gynecologic cancers in 2016. Of these cancers, 60,000 will be endometrial and 22,000 will be ovarian-the two most common gynecologic cancers. Endometrial and ovarian cancers occur in menopausal women with mean ages of 60 and 63, respectively. The majority of endometrial cancers are early stage, and 5-year survival is considered good at upwards of 75%. For ovarian cancer, while survival rates have improved, the 5-year survival rate for the most common stage (stage III) is 40%. Thus, a substantial number of patients with gynecologic cancer are menopausal, and a significant number of patients are survivors, particularly of endometrial cancers. It will be important for survivors of gynecologic cancers to receive care tailored to their needs as women and to mitigate gender-specific side effects of their cancer treatment.

Technetium Tc 99m sulfur colloid phenotypic probe for the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin in women with ovarian cancer.

PURPOSE: Significant variability in the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin (PLD) exists. PLD undergoes clearance via the mononuclear phagocyte system (MPS). Technetium Tc 99m sulfur colloid (TSC) is approved for imaging MPS cells. We investigated TSC as a phenotypic probe of PLD pharmacokinetics and pharmacodynamics in women with epithelial ovarian cancer. METHODS: TSC 10 mCi IVP was administered and followed by dynamic planar and SPECT/CT imaging and blood pharmacokinetics sampling. PLD 30-40 mg/m(2) IV was administered with or without carboplatin, followed by plasma pharmacokinetics sampling. RESULTS: There was a linear relationship between TSC clearance and encapsulated doxorubicin clearance (R(2) = 0.61, p = 0.02), particularly in patients receiving PLD alone (R(2) = 0.81, p = 0.04). There was a positive relationship (ρ = 0.81, p = 0.01) between maximum grade palmar-plantar erythrodysesthesia toxicity developed and estimated encapsulated doxorubicin concentration in hands. CONCLUSIONS: TSC is a phenotypic probe for PLD pharmacokinetics and pharmacodynamics and may be used to individualize PLD therapy in ovarian cancer and for other nanoparticles in development.

Adjuvant Treatment and Clinical Trials in Elderly Patients With Endometrial Cancer: A Time for Change?

OBJECTIVES: The aim of the study were to evaluate the gap between recommended and received adjuvant therapy in elderly patients with endometrial cancer (EC) and to determine the percent of women 70 years and older who would meet enrollment criteria for representative Gynecologic Oncology Group (GOG) trials. METHODS AND MATERIALS: An institutional review board approved retrospective chart review of all EC cases from a tertiary care institution from 2005 to 2010 was performed. Clinical, surgical, and pathologic data were abstracted from electronic medical records. Gynecologic Oncology Group protocols 249, 209, and 229L were selected as representative national EC trials. Patients were evaluated for eligibility by each protocol's criteria. RESULTS: Twenty-six percent (280/1064) of patients with EC were older than 70 years. More than 60% (181/280) of elderly patients with EC were recommended to undergo adjuvant therapy. By therapy type, 64% (48/75) of elderly patients who were recommended adjuvant radiation received it, 53% (49/92) of elderly patients who were recommended combination chemotherapy and radiation received it, and 29% (4/14) of elderly patients who were recommended chemotherapy received it. In evaluating enrollment criteria for GOG 249, 30% (40/134) of pathologically eligible patients would have been eliminated for medical clearance; for GOG 209, 31% (26/86) would have been eliminated, and for GOG 229L, 9% (4/45) would have been eliminated purely for medical reasons. CONCLUSIONS: More adjuvant treatment is recommended in the elderly patients because of a higher incidence of advanced disease and aggressive histopathology. Approximately half of the elderly patients who were recommended treatment actually received it. In addition, clinical trial data are limited for elderly patients because approximately one third of the women aged 70 years and older who meet pathologic enrollment criteria for trials were excluded because of complex medical disease.

A phase II study of paclitaxel for the treatment of ovarian stromal tumors: An NRG Oncology/ Gynecologic Oncology Group Study.

OBJECTIVE: To estimate the probability of complete clinical response and toxicity of paclitaxel as second-line chemotherapy in measurable disease patients with malignant tumors of the ovarian stroma, and to evaluate the value of inhibin for predicting response. METHODS: Thirty-one patients with histologically confirmed ovarian stromal tumor were enrolled from 2000 to 2013. Patients were required to have measurable recurrent disease, and to have received only one prior chemotherapy regimen. Paclitaxel 175 mg/m2 was administered over a 3 hour infusion, cycling every 21 days. Inhibin levels were drawn within two weeks of initiation of treatment. RESULTS: Of 31 women enrolled, there was only one complete response (3.2%), and partial response in eight of 31 cases (25.8%). The pretreatment inhibin level for the single patient who had complete response was 88 pg/mL. Median progression-free survival was 10.0 months and overall survival was 73.6 months. Myelosuppression was common with 12 of 31 patients (38.7%) suffering grade 3 or 4 neutropenia, leukopenia, or anemia. CONCLUSION: There were too few complete responses to warrant continued evaluation of paclitaxel as a single agent treatment for women with recurrent malignant ovarian stromal tumors with measurable disease according to the primary objective of the study. Toxicity of the regimen was acceptable. Pretreatment inhibin is not a reliable tumor marker as it was not elevated in the majority of patients.