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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 31women 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 10.0months 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. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to identify patient and physician factors related to enrollment onto Gynecologic Oncology Group (GOG) trials. Methods Prospective study of women with primary or recurrent cancer of the uterus or cervix treated at a GOG institution from July 2010 to January 2012. Logistic regression examined probability of availability, eligibility and enrollment in a GOG trial. Odds ratios (OR) and 95% confidence intervals (CI) for significant (p < 0.05) results reported. Results Sixty institutions, 781 patients, and 150 physicians participated, 300/780 (38%) had a trial available, 290/300 had known participation status. Of these, 150 women enrolled (59.5%), 102 eligible did not enroll (35%), 38 (13%) were ineligible. Ethnicity and specialty of physician, practice type, data management availability, and patient age were significantly associated with trial availability. Patients with > 4 comorbidities (OR 4.5; CI 1.7-11.8) had higher odds of trial ineligibility. Non-White patients (OR 7.9; CI 1.3-46.2) and patients of Black physicians had greater odds of enrolling (OR 56.5; CI 1.1-999.9) in a therapeutic trial. Significant patient therapeutic trial enrollment factors: belief trial may help (OR 76.9; CI 4.9-> 1000), concern about care if not on trial (OR12.1; CI 2.1-71.4), pressure to enroll (OR .27; CI 0.12-.64), caregiving without pay (OR 0.13; CI .02-.84). Significant physician beliefs were: patients would not do well on standard therapy (OR 3.6; CI 1.6-8.4), and trial would not be time consuming (OR 3.3; CI 1.3-8.1). Conclusions Trial availability, patient and physician beliefs were factors identified that if modified could improve enrollment in cancer cooperative group clinical trials. [ABSTRACT FROM AUTHOR]

BACKGROUND The objective of the current study was to evaluate the effect of obesity on pretreatment quality of life (QoL) in gynecologic oncology patients. METHODS The authors analyzed collected data from an institution-wide cohort study of women with gynecologic cancers enrolled from August 2012 to June 2013. The Functional Assessment of Cancer Therapy-General, site-specific symptom scales, and the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) global mental and physical health tools were administered. Survey results were linked to clinical data abstracted from medical records (demographics and comorbid conditions). Bivariate tests and multivariate linear regression models were used to evaluate factors associated with QoL scores. RESULTS A total of 182 women with ovarian, uterine, cervical, and vulvar/vaginal cancers were identified; of these, 152 (84%) were assessed before surgery. Mean body mass index was 33.5 kg/m2 and race included white (120 patients [79%]), black (22 patients [15%]), and other (10 patients [6.5%]). A total of 98 patients (64.5%) were obese (body mass index ≥30). On multivariate analysis, subscales for functional (17 vs 19; P = .04), emotional (16 vs 19; P = .008), and social (22 vs 24; P = .02) well-being as well as overall Functional Assessment of Cancer Therapy-General scores (77 vs 86; P = .002) and Patient-Reported Outcomes Measurement Information System global physical health scores (45 vs 49; P = .003) were found to be significantly lower in obese versus nonobese patients. CONCLUSIONS Before cancer treatment, obese patients with gynecologic malignancies appear to have worse baseline QoL than their normal-weight counterparts. Emerging models of QoL-based cancer outcome measures may disproportionately affect populations with a high obesity burden. The potential disparate impact of cancer therapy on longitudinal QoL in the obese versus nonobese patients needs to be evaluated. Cancer 2015;121:395-402. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

To determine the utility of a clinical calculator to predict the benefits of chemotherapy and outcomes in women with early stage high risk ovarian cancer. Data from 2006-2015 was abstracted from the National Cancer Database. All patients had stage I, grade 3; stage IC, stage II, or clear cell carcinoma. Using a Cox regression model, based on demographic, surgico-pathologic, and laboratory characteristics, a clinical score was developed. Propensity score matching was used to reduce bias between patients who did and did not receive chemotherapy. The clinical calculator was validated by both bootstrapping and in an independent validation set. Of 8,289 patients with early stage high risk ovarian cancer, 6,990 (84%) did and 1,299 (16%) did not receive chemotherapy. Patients who underwent chemotherapy had a 5-year overall survival (OS) of 85% vs 80% in those without treatment (p<0.001). On univariate analysis, significant prognostic factors included older age (HR 1.71), larger tumor size (HR 1.13), malignant ascites (HR 1.32), decreased number of lymph nodes examined (HR 1.38), higher stage (HR 1.70), carcinosarcoma (HR 3.35), high grade histology (HR 2.23), lymphovascular invasion (HR 1.44), and elevated CA-125 (HR 1.17). To better define those who may have an increased benefit from chemotherapy, we designed a clinical calculator capable of dividing patients into low (n=2,518), moderate (n=3,361), and high-risk (n=2,410) groups with associated 5-year overall survival of 92%, 86% and 73%. Using the calculator, chemotherapy was associated with an improved 5-year overall survival in the high (58% to 75%, p<0.001) and moderate risk groups (82% to 86%, p=0.001), but did not benefit the low risk patients (92% to 92%, p=0.13). There was an interaction between increasing score and improved patient outcomes with the administration of chemotherapy (p<0.001). [Display omitted] Our results suggest a clinical calculator can help direct chemotherapy decision making for women with high risk early stage ovarian cancer. [ABSTRACT FROM AUTHOR]

To determine the utility of a clinical calculator to predict the benefits of chemotherapy and outcomes in women with early stage clear cell ovarian cancer. Data from 2006-2015 was abstracted from the National Cancer Database. All patients had stage I clear cell carcinoma. Using a Cox regression model based on demographic, surgico-pathologic and laboratory characteristics, a clinical score was developed. Propensity score weighting was used to reduce bias between patients who did and did not receive chemotherapy. Of 1,528 patients with stage I clear cell ovarian cancer, 1309 (85.7%) did receive and 219 (14.3%) did not receive chemotherapy. Patients who underwent chemotherapy had a 5-year overall survival (OS) of 85.6% vs. 84.0% in those without treatment (p=0.30). On univariate analysis, significant prognostic factors included older age (HR=1.021, 95% CI 1.002-1.021, p=0.03), malignant ascites (HR 1.608, 95% CI 1.054-2.453, p=0.03), and higher stage (1B or C) (HR 1.758, 95% CI 1.207-2.560, p=0.003). To better define those who may have an increased benefit from chemotherapy, we designed a clinical calculator capable of dividing patients into low (n=306), moderate (n=916), and high-risk (n=306) groups with associated 5-year overall survival of 90.3%, 86.8% and 76.1%, respectively (p<0.0001). Using the calculator, chemotherapy was associated with decreased hazard of death in the high-risk patients, (HR = 0.483, 95% CI 0.258-0.905, p=0.02), but did not benefit the moderate (HR= 1.551, 95% CI 0.752-3.199, p=0.57) or low-risk patients (HR = 0.751, 95% CI 0.281-2.006 p=0.24). [Display omitted] Our results suggest a clinical calculator can help direct chemotherapy decision making for women with early stage clear cell ovarian cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma. Background: Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy. Methods: We performed a randomized phase II trial of intravenous temsirolimus 25mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80mg bid for three weeks alternating with tamoxifen 20mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma. Results: There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded. Conclusions: Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy. [Copyright &y& Elsevier]

Abstract: Objective: To determine the radiographic characteristics of ovarian granulosa cell tumors (GCTs) and to evaluate the use of CA125 levels >35 in combination with imaging as an algorithm for preoperative diagnosis. Methods: A retrospective analysis of women from two academic medical centers who were diagnosed with ovarian GCT between January 1998 and August 2012 was conducted. Clinical data included tumor appearance on pre-operative imaging and CA125 levels. Ovarian cysts were defined as complex if imaging exhibited multicystic areas, hemorrhagic, solid, or cystic and solid components. A CA125 level >35 was abnormal. Results: One hundred and fifteen women were diagnosed with GCTs, of whom 63 underwent pre-operative imaging. Median age at surgery was 46years (12–87). Forty women had preoperative ultrasounds, 43 had CT scans and 20 underwent both modalities. GCTs were almost exclusively classified as complex cysts in 62 (98%) cases. The most common morphology was solid and cystic (n=44 (70%)). Forty-four (70%) patients had tumors >10cm. Forty-two patients had a pre-operative CA125 performed. Eighteen (43%) patients had complex masses and CA125 >35. Twenty-three (55%) had CA125 <35 with a complex mass, and one (2%) had a unilocular cyst with a CA125 >35. Conclusions: In this study, there was a near equal distribution of patients with complex masses and CA125 levels > or <35. If established strategies to predict malignancy are applied to GCTs, we will frequently fail to make the diagnosis pre-operatively. Additional research is necessary to generate an appropriate algorithm to guide pre-operative referral to a gynecologic oncologist. [Copyright &y& Elsevier]

Abstract: Objective: There is limited information concerning the role of relative dose intensity (RDI) on clinical outcomes in solid tumors. The objectives of our study were to evaluate the prognostic significance of RDI and predictors of reduced RDI in women with newly diagnosed advanced stage epithelial ovarian carcinoma (EOC) treated with platinum-based chemotherapy. Methods: A multi-center retrospective study of women with FIGO stage III–IV epithelial ovarian cancer treated postoperatively with multi-agent intravenous chemotherapy between 1995 and 2009 was conducted. Data were obtained to include the first four chemotherapy cycles administered. Outcomes included: (1) planned and delivered relative dose intensity (RDI), (2) progression-free (PFS) and overall (OS) survival. Survival estimates were based on Kaplan and Meier method, and multivariate analyses were based on logistic regression and Cox proportional hazards regression. Results: Evaluable subjects included 325 women. With median follow-up of 34months (range, 0.4–170), progression or recurrence was recorded in 241 (73.9%) and death in 179 (54.9%). In multivariate analysis, predictors of reduced planned RDI were: treatment off research protocols (odds ratio [OR]=4.3; P<0.001) and BSA >2m2 (OR=6.14; P<0.001); predictors of reduced delivered RDI were: BMI over 30kg/m2 (OR=2.35; P=0.008) and use of carboplatin (OR=2.71; P=0.008). In multivariate analysis, the following factors were independently associated with OS: delivered RDI <85% (hazard ratio [HR]=1.71; P=0.003) and elevated CA-125 at cycle 1 (HR=2.29; P=0.017). Conclusion: In this retrospective analysis, reduced chemotherapy RDI for ovarian cancer was associated with lower OS, but not PFS, despite adjustment for established prognostic factors. [Copyright &y& Elsevier]

Abstract: Objective: The aim of this study is to report recurrence-free and overall survival for women with endometrial adenocarcinoma who were surgically staged using robotic-assisted laparoscopy. Methods: A retrospective chart review was performed for all consecutive endometrial adenocarcinoma patients surgically staged with robotic-assisted laparoscopy at the University of North Carolina Hospital from 2005 to 2010. Demographic data, 5-year survival, and recurrence-free intervals were analyzed. Statistical analysis using Chi-square, t-test, and Kaplan–Meier curves were performed with SAS software. Study results were compared to endometrial cancer statistics from the Surveillance Epidemiology and End Results database from the National Cancer Institute. Results: A total of 499 patients were identified and included in the study. Recurrence-free intervals after robotic-assisted surgical staging were 85.2% for stage IA, 80.2% for stage IB, 69.8% for stage II, and 69% for stage III. Projected 5-year survival was 88.7% for all patients included in the study. Nearly 82% of cases were endometrioid adenocarcinoma, with papillary serous, clear cell or mixed histology comprising 17.4% of cases. Median follow up time was 23months, with a range of 0 to 80months. Among stage IA, IB, II, and III patients, projected overall survival was 94.2%, 85.9%, 77.4%, and 68.6%, respectively. Conclusions: The results from this study demonstrate that robotic-assisted surgical staging for endometrial cancer does not adversely affect rates of recurrence or survival. These findings provide further evidence that robotic-assisted laparoscopic surgical staging is not associated with inferior results when compared to laparotomy or traditional laparoscopy. [Copyright &y& Elsevier]

Abstract: Objective: To determine which patients with near midline lesions may safely undergo unilateral groin dissection based on clinical exam and lymphoscintigraphy (LSG) results. Methods: Patients participating in GOG-173 underwent sentinel lymph node (SLN) localization with blue dye, and radiocolloid with optional LSG before definitive inguinal–femoral lymphadenectomy (LND). This analysis interrogates the reliability of LSG alone relative to primary tumor location in those patients who had an interpretable LSG and at least one SLN identified. Primary tumor location was categorized as lateral (>2cm from midline), midline, or lateral ambiguous (LA) if located within 2cm, but not involving the midline. Results: Two-hundred-thirty-four patients met eligibility criteria. Sixty-four had lateral lesions, and underwent unilateral LND. All patients with LA (N=65) and midline (N=105) tumors underwent bilateral LND. Bilateral drainage by LSG was identified in 14/64 (22%) patients with lateral tumors, 38/65 (58%) with LA tumors and in 73/105 (70%) with midline tumors. At mapping, no SLNs were found in contralateral groins among those patients with LA and midline tumors who had unilateral-only LSGs. However, in these patients groin metastases were found in 4/32 patients with midline tumors undergoing contralateral dissection; none were found in 27 patients with LA tumors. Conclusion: The likelihood of detectable bilateral drainage using preoperative LSG decreases as a function of distance from midline. Patients with LA primaries and unilateral drainage on LSG may safely undergo unilateral SLN. [Copyright &y& Elsevier]

Abstract: Purpose: The Gynecologic Oncology Group (GOG) conducted a phase II trial to assess the efficacy and tolerability of the anti-EGFR antibody cetuximab, in persistent or recurrent carcinoma of the cervix. Patients and methods: Eligible patients had cervical cancer, measurable disease, and GOG performance status ≤2. Treatment consisted of cetuximab 400mg/m2 initial dose followed by 250mg/m2 weekly until disease progression or prohibitive toxicity. The primary endpoints were progression-free survival (PFS) at 6months and response. The study used a 2-stage group sequential design. Results: Thirty-eight patients were entered with 3 exclusions, leaving 35 evaluable for analysis. Thirty-one patients (88.6%) received prior radiation as well as either 1 (n=25, 71.4%) or 2 (n=10) prior cytotoxic regimens. Twenty-four patients (68.6%) had a squamous cell carcinoma. Grade 3 adverse events possibly related to cetuximab included dermatologic (n=5), GI (n=4), anemia (n=2), constitutional (n=3), infection (n=2), vascular (n=2), pain (n=2), and pulmonary, neurological, vomiting and metabolic (n=1 each). No clinical responses were detected. Five patients (14.3%; two-sided 90% CI, 5.8% to 30%) survived without progression for at least 6months. The median PFS and overall survival (OS) times were 1.97 and 6.7months, respectively. In this study, all patients with PFS at 6months harbored tumors with squamous cell histology. Conclusion: Cetuximab is well tolerated but has limited activity in this population. Cetuximab activity may be limited to patients with squamous cell histology. [Copyright &y& Elsevier]

Abstract: Background: The objective of this study was to estimate antitumor activity and toxicity of weekly docetaxel and gemcitabine as second-line chemotherapy for patients with recurrent uterine carcinosarcoma. Methods: Patients with recurrent carcinosarcoma of the uterus who had failed one regimen of chemotherapy, had a Gynecologic Oncology Group (GOG) performance status of 0–2 and had measurable disease were included. Treatment consisted of gemcitabine 600mg/m2 and docetaxel 35mg/m2 intravenously on days 1, 8 and 15 of a 28-day cycle until disease progression or intolerable adverse effects. This study employed an optimal but flexible two-stage design with an early stopping rule. If more than 3 out of 22–24 or more than 4 out of 25–29 patients responded, accrual to the second stage was to be initiated. Results: Twenty-eight patients were enlisted. Three patients were not eligible after pathology review. One patient was never treated. Twenty-four patients were evaluable. Nine patients had previous radiation therapy. There were no complete responses. Partial responses were seen in two patients (8.3%), stable disease in eight (33.3%) and progressive disease in 12 patients (50%). Two patients were not evaluable (8.3%). The median progression-free survival was 1.8months. The median survival was 4.9months. The treatment caused myelosuppression, mainly neutropenia, but also thrombocytopenia and anemia. Dose modifications became necessary in the majority of patients. In five patients, treatment was discontinued due to toxicity. Conclusions: This regimen of docetaxel and gemcitabine is not active in patients with recurrent carcinosarcoma of the uterus as second-line chemotherapy. [Copyright &y& Elsevier]

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., Competing Interests: Declaration of competing interest Dr. Pothuri reports institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Eisai, Genentech/Roche, GSK, I-Mab, Immunogen, Incyte, Karyopharm, Merck, Mersana, Onconova, Seagen, Sutro Biopharma, and Toray; consulting fees from AstraZeneca, GSK, GOG Foundation, Merck, and Seagen; support for attending meetings from GOG Partners; advisory board fees from Arquer Diagnostics, Atossa, Clovis Oncology, Deciphera, Eisai, Elevar Therapeutics, GOG Foundation, I-Mab, Immunogen, Lily, Merck, Mersana, Natera, Onconova, Regeneron, Sutro Biopharma, Tesaro/GSK, Toray, and VBL Therapeutic. Dr. Han has nothing to disclose. Dr. Chase reports consultant fees from AstraZeneca and GSK, and honoraria from AstraZeneca, GSK, Immunogen, and Seagen/Genmab. Dr. Heitz reports honoraria from AstraZeneca, GSK, Roche, and Tesaro; consulting fees from AstraZeneca, GSK, Roche, and Tesaro. Dr. Burger reports receiving travel support from Genentech and Mersana Therapeutics, stock from Genentech and Mersana Therapeutics, and is an employee of Genentech and Mersana Therapeutics. Dr. Gaba reports consulting fees, advisory board, and honoraria fees from AstraZeneca, Clovis Oncology, GSK, MSD, and PharmaMar, and support for attending meetings from AstraZeneca, Clovis Oncology, GSK, and MSD. Dr. Van Le has nothing to disclose. Dr. Guerra reports AstraZeneca, Clovis Oncology, GSK, Merck, Pharmamar, Roche, and Tesaro; honoraria from AstraZeneca, Clovis Oncology, GSK/Tesaro, and Merck; payment for expert testimony from AstraZeneca, Clovis Oncology, GSK, Merck, Tesaro; travel support from GSK, Roche, and Tesaro; advisory board participation for AstraZeneca, GSK, Merck, and Tesaro. Dr. Bender reports institutional grants from AbbVie, AstraZeneca, Clovis Oncology Inc., Genentech, MSD, and Tesaro. Dr. Korach serves in a leadership role for ISGO. Dr. Cloven reports advisory board fees from Aadii, GSK, Kartos 2022, Novita Pharmaceuticals 2023, Tarveda Therapeutics, Toray, Umoja 2022, and Zentalis. Dr. Churruca reports payment for expert testimony from PharmaMar and support for attending meetings from GSK, and MSD. Dr. Follana reports payment for expert testimony from AstraZeneca, Clovis, Daiichi, GSK, and Novartis; and support for attending meetings from AstraZeneca, Daiichi, GSK, and Novartis. Dr. DiSilvestro reports consulting fees from AstraZeneca, GSK, and Immunogen; travel support from AstraZeneca; and leadership roles in the GOG Foundation Board of Directors and NRG Oncology Board of Directors. Dr. Baurain reports consulting fees from AstraZeneca, Bristol-Myers Squibb, GSK, Immunocore, Merck, MSD, Novartis, Pfizer, Pierre-Fabre, Regeneron, Sanofi, and Sun Pharma. Dr. Jardon has nothing to disclose (deceased). Dr. Pisano has nothing to disclose. Dr. Peen has nothing to disclose. Dr. Mäenpää reports honoraria from AstraZeneca, Eisai, and GSK. Dr. Gupta was an employee of GSK at the time the analysis was conducted; currently an employee of Mersana Therapeutics. Dr. Bacqué was an employee of GSK at the time the analysis was conducted; currently an employee of Repare Therapeutics. Dr. Li was an employee of GSK at the time the analysis was conducted and reports GSK stock ownership; currently an employee of Adagio Therapeutics. Ms. Compton is a former employee of GSK and currently receiving consulting fees from GSK. Dr. Antonova is a former employee of GSK. Dr. Monk reports consulting fees from Agenus, Akeso Biopharma, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL; and speakers' bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK. Dr. González-Martín reports manuscript funding from GSK; research/grant funding from Roche and Tesaro/GSK; advisory/consulting fees from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, HederaDx, ImmunoGen, Illunina, MacroGenics, Mersana, MSD, Novartis, Novocure, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, Seagen, Sotio, Sutro, Takeda, and Tubuli; speaker bureau fees from AstraZeneca, Clovis Oncology, GSK, PharmaMar, and Roche; and support for attending meetings from AstraZeneca, GSK, PharmaMar, and Roche., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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

Purpose: The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN)., Methods: GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences., Results: From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL ( P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL., Conclusion: Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL., Competing Interests: Brian SlomovitzConsulting or Advisory Role: Clovis Oncology, AstraZeneca, Genentech, Incyte, Agenus, GlaxoSmithKline, GOG Foundation, Myriad Genetics, Merck, Eisai Ignace VergoteConsulting or Advisory Role: Amgen, AstraZeneca, Clovis Oncology, Carrick Therapeutics, Deciphera, Elevar Therapeutics, Genmab, GlaxoSmithKline, Immunogen, Jazz Pharmaceuticals, Mersana, MSD, Novocure, OCTIMET Oncology NV, Oncoinvent, Sotio, Verastem, Zentalis, Roche, MillenniumResearch Funding: Roche, Genmab, Amgen, OncoinventTravel, Accommodations, Expenses: Roche, AstraZeneca, Tesaro, Amgen, MSD/Merck Mats BrännströmStock and Other Ownership Interests: EUGIN Sweden Martin WidschwendterStock and Other Ownership Interests: Sola Diagnostics, BreOva HealthPatents, Royalties, Other Intellectual Property: Patents relevant for risk prediction or diagnosis of women's cancers Paul A. DiSilvestroConsulting or Advisory Role: AstraZeneca, AgenusResearch Funding: Janssen Oncology, Tesaro, AstraZeneca, Genentech, AbbVie Robert MannelConsulting or Advisory Role: Tesaro Dorry BollResearch Funding: AstraZeneca David CibulaConsulting or Advisory Role: AstraZeneca, Sotio, Roche, GlaxoSmithKline Diane ProvencherConsulting or Advisory Role: AstraZeneca, GlaxoSmithKlineResearch Funding: AstraZeneca, AbbVie Ingo B. RunnebaumConsulting or Advisory Role: AbbVie (I), Amgen, AstraZeneca, Clovis Oncology, GlaxoSmithKline, Oncgnostics, Tesaro Preben KjølhedeResearch Funding: Leo Pharma AB Katharina E. KieserHonoraria: AstraZenecaConsulting or Advisory Role: MerckResearch Funding: AstraZeneca Nicola M. SpirtosResearch Funding: AbbVie, AstraZeneca, Genentech/Roche, Clovis Oncology, Seattle GeneticsPatents, Royalties, Other Intellectual Property: Application No. PCT/US 2019/19465 Cannabis Based Therapeutic and Method of Use Application No, US Patent 0024098766 Compounds Cannabidiol and Flavanones 63/047550 (July 1, 2020) 63/055458 (July 23, 2020) David M. O'MalleyConsulting or Advisory Role: Janssen Oncology, AstraZeneca, Clovis Oncology, Tesaro, Novocure, AbbVie, Genentech/Roche, OncoQuest, Immunogen, GOG Foundation, Translational Genomics Research Institute, Agenus, Marker Therapeutics, Eisai, Genelux, Iovance Biotherapeutics, Ambry Genetics, Tarveda Therapeutics, Leap Therapeutics, Myriad Genetics, GlaxoSmithKline, Regeneron, Sorrento Therapeutics, Rubius Therapeutics, Elevar Therapeutics, Novartis, Seagen, BBI Healthcare, Arquer Diagnostics, Toray Medical, Takeda, InxMed, Celsion, Roche Diagnostics MSAResearch Funding: Amgen, AstraZeneca, Genentech/Roche, Regeneron, Immunogen, Janssen Research & Development, Clovis Oncology, EMD Serono, Ergomed, Ajinomoto, Cerulean Pharma, PharmaMar, Array BioPharma, Bristol Myers Squibb, Agenus, Tesaro, TRACON Pharma, Genmab, Seattle Genetics, Iovance Biotherapeutics, Leap Therapeutics, Merck, AbbVie/Stemcentrx, AbbVie, Mersana, Eisai, BBI Healthcare, Sumitomo Dainippon Pharma Oncology Mario M. LeitaoHonoraria: Intuitive SurgicalConsulting or Advisory Role: Intuitive Surgical, Ethicon/Johnson & Johnson, Medtronic, TakedaResearch Funding: KCITravel, Accommodations, Expenses: Intuitive Surgical Melissa A. GellerResearch Funding: Tesaro, Genentech, FATE Therapeutics, Morphotek, Bayer Karl TamussinoOther Relationship: Medtronic Daniel H. TobiasConsulting or Advisory Role: Ethicon Jayanthi S. LeaConsulting or Advisory Role: Roche Brynhildur EyjolfsdottirOther Relationship: Intuitive Surgical Krishnansu S. TewariHonoraria: Tesaro, Clovis OncologyConsulting or Advisory Role: Roche/Genentech, Tesaro, Clovis Oncology, AstraZenecaSpeakers' Bureau: Roche/Genentech, AstraZeneca, Merck, Tesaro, Clovis OncologyResearch Funding: AbbVie, Genentech/Roche, Morphotek, Merck, RegeneronTravel, Accommodations, Expenses: Roche/Genentech Ranjit ManchandaHonoraria: AstraZeneca Linda Van LeConsulting or Advisory Role: EyePoint Pharmaceuticals, Novartis, Advarum, Neurotech, Iveric, Gemini Therapeutics, NaegisResearch Funding: GOG Partners Trial Bradley J. MonkLeadership: US OncologyHonoraria: AbbVie, Advaxis, Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Asymmetric Therapeutics, Boston Biomedical, ChemoID, Clovis Oncology, Deciphera Pharmaceuticals, Eisai, Geistlich Pharma, Genmab/Seattle Genetics, ImmunoGen, Immunomedics, Incyte, Iovance Biotherapeutics, Laekna Health Care, Merck, Mersana, Myriad Pharmaceuticals, Nucana, Oncomed, Oncoquest, Oncosec, Perthera, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, Senti Biosciences, Takeda, Tarveda Therapeutics, Tesaro/GSK, Vavotar Life Sciences, Vascular Biogenics, Vigeo Therapeutics, GOG Foundation, Starton Therapeutics, Elevar Therapeutics, Novocure, Gradalis, Karyopharm TherapeuticsConsulting or Advisory Role: AbbVie, Advaxis, Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Asymmetric Therapeutics, Boston Biomedical, ChemoCare, ChemoID, Clovis Oncology, Deciphera Pharmaceuticals, Eisai, Geistlich Pharma, Genmab/Seattle Genetics, GOG Foundation, ImmunoGen, Immunomedics, Incyte, Iovance Biotherapeutics, Laekna Health Care, Merck, Mersana, Myriad Pharmaceuticals, Nucana, Oncomed, Oncoquest, Oncosec, Perthera, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, Senti Biosciences, Takeda, Tarveda Therapeutics, Tesaro/GSK, Vavotar Life Sciences, Vascular Biogenics, Vigeo Therapeutics, Gradalis, Karyopharm Therapeutics, Sorrento Therapeutics, NovocureSpeakers' Bureau: Roche/Genentech, AstraZeneca, Clovis Oncology, Eisai, Tesaro/GSK, MerckResearch Funding: Novartis, Amgen, Genentech, Lilly, Janssen, Array BioPharma, Tesaro, Morphotek, Pfizer, Advaxis, AstraZeneca, Immunogen, Regeneron, Nucana Carien L. CreutzbergConsulting or Advisory Role: MerckResearch Funding: Elekta, Varian Medical SystemsNo other potential conflicts of interest were reported.

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., (©2020 American Association for Cancer Research.)

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

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.

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 β; 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.

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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.

Purpose: Risk-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 Methods: This 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., Results: Invasive 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., Conclusion: Clinically 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., (© 2014 by American Society of Clinical Oncology.)

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer., (© 2012 Wiley Periodicals, Inc.)

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer., Competing Interests: The authors have declared that no competing interests exist.