Antibody-Drug Conjugates in Gynecologic Cancers.

OPINION STATEMENT: Antibody-drug conjugates (ADCs) are a novel class of targeted cancer therapies with the ability to selectively deliver a cytotoxic drug to a tumor cell using a monoclonal antibody linked to a cytotoxic payload. The technology of ADCs allows for tumor-specificity, improved efficacy, and decreased toxicity compared to standard chemotherapy. Common toxicities associated with ADC use include ocular, pulmonary, hematologic, and neurologic toxicities. Several ADCs have been approved by the United States Food and Drug Administration (FDA) for the management of patients with recurrent or metastatic gynecologic cancers, a population with poor outcomes and limited effective treatment options. The first FDA-approved ADC for recurrent or metastatic cervical cancer was tisotumab vedotin, a tissue factor-targeting agent, after demonstrating response in the innovaTV 204 trial. Mirvetuximab soravtansine targets folate receptor alpha and is approved for use in patients with folate receptor alpha-positive, platinum-resistant, epithelial ovarian cancer based on results from the SORAYA trial. While there are no FDA-approved ADCs for the treatment of uterine cancer, trastuzumab deruxtecan, an anti-human epidermal growth factor receptor 2 (HER2) agent, is actively being investigated. In this review, we will describe the structure and mechanism of action of ADCs, discuss their toxicity profiles, review ADCs both approved and under investigation for the management of gynecologic cancers, and discuss mechanisms of ADC resistance.

Implementing guidelines for risk-stratified thromboprophylaxis among gynecologic oncology patients: A quality improvement initiative.

OBJECTIVE(S): Risk-stratified thromboprophylaxis is recommended for oncology patients with a Khorana risk score (KS) ≥ 2 receiving cancer-directed therapy. We describe a quality improvement (QI) initiative designed to increase adherence to thromboprophylaxis guidelines for patients with gynecologic malignancies initiating outpatient treatment. METHODS: Provider awareness and documentation of venous thromboembolism (VTE) risk assessment and thromboprophylaxis eligibility were identified as key QI drivers. Starting May 2021, a KS calculator and thromboprophylaxis algorithm were incorporated into outpatient documentation templates. Patients with gynecologic malignancies initiating outpatient therapy from January - December 2021 were eligible. The primary process measure was the percentage of patients with KS eligibility documented each month during the baseline (Jan - Apr) versus implementation (May - Dec) periods. Rate of appropriate thromboprophylaxis initiation and incidence of VTE served as outcome measures. Incidence of adverse bleeding events served as the balancing measure. RESULTS: 337 patients accounted for the initiation of 383 treatment regimens, including 128 in the baseline period and 255 in the implementation period. KS documentation increased significantly between the baseline and implementation periods (7% vs 62.4%, p < 0.001). 73 of the 177 eligible patients (46.2%; 166 unique patients) had appropriate documentation; of these, 57 initiated thromboprophylaxis. There was no difference in VTE rates or adverse bleeding events between eligible patients who initiated thromboprophylaxis compared with those who did not (12.3% vs 15.6%; p = 0.65 and 7.0% vs 8.2%; p = 1.0, respectively). CONCLUSION(S): This QI initiative resulted in greater adherence to risk-stratified thromboprophylaxis guidelines. No bleeding signals were identified. Studies addressing cost, medication adherence, and long-term outcomes are necessary.

Guidelines for goals of care discussions in patients with gynecologic cancer.

This article represents a distillation of literature to provide guidance for goals of care discussions with patients who have gynecologic malignancies. As clinicians who provide surgical care, chemotherapy, and targeted therapeutics, gynecologic oncology clinicians are uniquely positioned to form longitudinal relationships with patients that can enable patient-centered decision making. In this review, we describe optimal timing, components, and best practices for goals of care discussions in gynecologic oncology.

"You start feeling comfortable, you just start sharing:" A qualitative study of patient distress screening in Black and White patients with endometrial cancer.

OBJECTIVES: Black patients with endometrial cancer are less likely to express distress and receive referrals for support services compared to White patients. We aim to characterize patient perceptions of the National Comprehensive Cancer Network Distress Thermometer and Problem List (NCCN DT & PL), a common distress screening tool, among Black and White patients with endometrial cancer and determine strategies to improve equity in referral to appropriate support services. METHODS: We conducted semi-structured interviews with 15 Black and 15 White patients with endometrial cancer who reported varying levels of distress on the NCCN DT & PL. Interviews were audio-recorded, transcribed, evaluated through staged content analysis, and salient themes were compared by patient race. RESULTS: The NCCN DT & PL was generally considered understandable, however the word "distress" could be alienating to participants who considered their stress to be less "drastic." Black participants mentioned fewer negative emotions such as worry and sadness in describing distress and spoke more often of a positive outlook. Additionally, Black participants emphasized the importance of relationship-building with clinicians for open communication on the NCCN DT & PL and clinical encounter. Finally, participants were divided on whether they would alter the way they completed the NCCN DT & PL given more information on cut off scores for referrals, but generally expressed a desire for more direct offers of support services. CONCLUSIONS: Relationship-building, open communication around emotion, and longitudinal direct offers of support emerged as avenues to reduce inequities in referral to supportive services for patients with endometrial cancer.

Understanding the spectrum of malignant bowel obstructions in gynecologic cancers and the application of the Henry score.

OBJECTIVE: Malignancy-associated bowel obstruction (MBO) is a potential sequela of advanced gynecologic cancers, adversely impacting both quality of life and prognosis. The Henry score (HS) was developed in a gastrointestinal cancer-predominant population to predict 30-day mortality. We aim to characterize MBO in gynecologic cancers and assess the utility of the HS in this population. METHODS: This is a retrospective review of patients with gynecologic cancer and MBO admitted to a single academic institution from 2016 to 2021. The primary outcome is to characterize malignant small and large bowel obstructions in primary and recurrent gynecologic cancer using readmission and mortality rates. Secondary outcomes are to assess the Henry score and inpatient MBO management. RESULTS: 179 patients totaling 269 were admissions identified, most commonly affecting patients with ovarian cancer. The majority (89.4%) were managed non-operatively while 10.6% were managed surgically. No significant differences were observed in survival for medical versus surgical management. Thirty-day mortality increased with increasing HS (0%, 0-1; 14.3%, 2-3; 40.9%, 4-5). Over 1/3 (34.1%) of patients were readmitted for recurrent or persistent MBO. Goals of care conversations were documented for 56.8% of patients with HS 4-5. Mortality rates across the entire cohort were high-20.1% and 60.9% had died by 1 and 6 months, respectively. CONCLUSIONS: Survival rates following an initial MBO admission are poor. The HS has utility in gynecologic cancers for assessing 30-day mortality and may be a useful tool to aid in the management and counseling of patients with gynecologic cancer and MBO.

Radical hysterectomy case volume and cervical cancer treatment in the era of COVID-19: A multi-site analysis of National Cancer Institute-designated Comprehensive Cancer Centers.

OBJECTIVE: To compare radical hysterectomy case volume, cancer stage, and biopsy-to-treatment time of invasive cervical cancer diagnosed before and after onset of the COVID-19 pandemic. METHODS: In a multi-institution retrospective cohort study conducted at 6 large, geographically diverse National Cancer Institute-designated cancer centers, patients treated for newly diagnosed invasive cervical cancer were classified into 2 temporal cohorts based on date of first gynecologic oncology encounter: (1) Pre-Pandemic: 3/1/2018-2/28/2020; (2) Pandemic & Recovery: 4/1/2020-12/31/2021. The primary outcome was total monthly radical hysterectomy case volume. Secondary outcomes were stage at diagnosis and diagnosis-to-treatment time. Statistical analyses used chi-squared and two sample t-tests. RESULTS: Between 3/1/2018-12/31/2021, 561 patients were diagnosed with cervical cancer. The Pre-Pandemic and Pandemic & Recovery cohorts had similar age, race, ethnicity, smoking status, and Body Mass Index (BMI). During Pandemic & Recovery, the mean monthly radical hysterectomy case volume decreased from 7[SD 2.8] to 5[SD 2.0] (p = 0.001), the proportion of patients diagnosed with Stage I disease dropped from 278/561 (49.5%) to 155/381 (40.7%), and diagnosis of stage II-IV disease increased from 281/561 (50.1%) to 224/381 (58.8%). Primary surgical management was less frequent (38.3% Pandemic & Recovery versus 46.7% Pre-Pandemic, p = 0.013) and fewer surgically-treated patients received surgery within 6 weeks of diagnosis (27.4% versus 38.9%; p = 0.025). CONCLUSIONS: Lower radical hysterectomy case volume, a shift to higher cervical cancer stage, and delay in surgical therapy were observed across the United States following the COVID-19 outbreak. Decreased surgical volume may result from lower detection of early-stage disease or other factors.

Treatments and outcomes in high-risk gestational trophoblastic neoplasia: A systematic review and meta-analysis.

BACKGROUND: High-risk gestational trophoblastic neoplasia (GTN) is rare and treated with diverse approaches. Limited published institutional data has yet to be systematically reviewed. OBJECTIVES: To compile global high-risk GTN (prognostic score ≥7) cohorts to summarise treatments and outcomes by disease characteristics and primary chemotherapy. SEARCH STRATEGY: MEDLINE, Embase, Scopus, ClinicalTrials.gov and Cochrane were searched through March 2021. SELECTION CRITERIA: Full-text manuscripts reporting mortality among ≥10 high-risk GTN patients. DATA COLLECTION AND ANALYSIS: Binomial proportions were summed, and random-effects meta-analyses performed. MAIN RESULTS: From 1137 records, we included 35 studies, representing 20 countries. Among 2276 unique high-risk GTN patients, 99.7% received chemotherapy, 35.8% surgery and 4.9% radiation. Mortality was 10.9% (243/2236; meta-analysis: 10%, 95% confidence interval [CI] 7-12%) and likelihood of complete response to primary chemotherapy was 79.7% (1506/1890; meta-analysis: 78%, 95% CI: 74-83%). Across 24 reporting studies, modern preferred chemotherapy (EMA/CO or EMA/EP) was associated with lower mortality (overall: 8.8 versus 9.5%; comparative meta-analysis: 8.1 versus 12.4%, OR 0.42, 95% CI: 0.20-0.90%, 14 studies) and higher likelihood of complete response (overall: 76.6 versus 72.8%; comparative meta-analysis: 75.9 versus 60.7%, OR 2.98, 95% CI: 1.06-8.35%, 14 studies), though studies focused on non-preferred regimens reported comparable outcomes. Mortality was increased for ultra-high-risk disease (30 versus 7.5% high-risk; meta-analysis OR 7.44, 95% CI: 4.29-12.9%) and disease following term delivery (20.8 versus 7.3% following molar pregnancy; meta-analysis OR 2.64, 95% CI: 1.10-6.31%). Relapse rate estimates ranged from 3 to 6%. CONCLUSIONS: High-risk GTN is responsive to several chemotherapy regimens, with EMA/CO or EMA/EP associated with improved outcomes. Mortality is increased in patients with ultra-high-risk, relapsed and post-term pregnancy disease.

Reducing non-surgical readmissions on a gynecologic oncology service.

OBJECTIVE: To assess the effects of a quality improvement (QI) initiative designed to reduce non-surgical readmissions on a gynecologic oncology service. METHODS: A two-phase QI initiative was implemented on an inpatient gynecologic oncology service to reduce non-surgical 30-day readmissions. Phase 1, from July 2018 to June 2020, included trainee education, frequent physical therapy consultation, pharmacy discharge medication review, 72-h post-discharge telephone call, and standardized 10-day clinic follow-up after discharge. Phase 2, from July 2020 to December 2020, incorporated a nurse practitioner to perform discharge navigation and arrange outpatient follow-up. The incidence of non-surgical readmissions during these phases was compared to that of a baseline period (July 2017-June 2018). We also assessed readmissions to identify common indications and evaluate potential demographic and clinical risk factors. RESULTS: Of 390 total non-surgical gynecologic oncology admissions, 100 were readmitted within 30 days (25.6%). Gastrointestinal tract (GI) obstruction, malignancy-associated pain and infection were the most common symptomatic diagnoses at the index admission, and 30% of readmitted patients had an identical indication for readmission. Compared to the baseline period, we observed a reduction in non-surgical readmissions from 34.1% to 22.6% in Phase 1 and to 18.9% in Phase 2 (p < 0.03) based on internal review, and a reduction from 13.9% to 11.9% in Phase 1 and to 4.7% in Phase 2 (p = 0.04) based on healthcare performance tracking data. CONCLUSIONS: 30-day hospital readmission among non-surgical gynecologic oncology patients is common. Implementation of a multifaceted readmissions reduction QI initiative significantly improved readmission rates.

Cost-effectiveness of management strategies for patients with recurrent ovarian cancer and inoperable malignant bowel obstruction.

OBJECTIVES: Patients with recurrent platinum-resistant ovarian cancer often present with inoperable malignant bowel obstruction (MBO) from a large burden of abdominal disease. Interventions such as total parenteral nutrition (TPN) and chemotherapy may be used in this setting. We aim to describe the relative cost-effectiveness of these interventions to inform clinical decision making. METHODS: Four strategies for management of platinum-resistant recurrent ovarian cancer with inoperable MBO were compared from a societal perspective using a Monte Carlo simulation: (1) hospice, (2) TPN, (3) chemotherapy, and (4) TPN + chemotherapy. Survival, hospitalization rates, end-of-life (EOL) setting, and MBO-related utilities were obtained from literature review: hospice (survival 38 days, 6% hospitalization), chemotherapy (42 days, 29%), TPN (55 days, 25%), TPN + chemotherapy (74 days, 47%). Outcomes were the average cost per strategy and incremental cost-effectiveness ratios (ICERs) in US dollars per quality-adjusted life year (QALY) gained. RESULTS: In the base case scenario, TPN + chemotherapy was the most costly strategy (mean; 95% CI) ($49,741; $49,329-$50,162) and provided the highest QALYs (0.089; 0.089-0.090). The lowest cost strategy was hospice ($14,591; $14,527-$14,654). The TPN alone and chemotherapy alone strategies were dominated by a combination of hospice and TPN + chemotherapy. The ICER of TPN + chemotherapy was $918,538/QALY compared to hospice. With a societal willingness to pay threshold of $150,000/QALY, hospice was the strategy of choice in 71.6% of cases, chemotherapy alone in 28.4%, and TPN-containing strategies in 0%. CONCLUSIONS: TPN with or without chemotherapy is not cost-effective in management of inoperable malignant bowel obstruction and platinum-resistant ovarian cancer.

Malnutrition as a risk factor for post-operative morbidity in gynecologic cancer: Analysis using a national surgical outcomes database.

OBJECTIVE: To assess, using a national surgical outcomes database, the association of various malnutrition definitions with post-operative morbidity in three gynecologic malignancies. METHODS: Patients undergoing resection of ovarian, uterine, or cervical cancer between 2005 and 2019 were identified using the National Surgical Quality Improvement Program (NSQIP) database. Patients were classified based on specific, pre-defined malnutrition criteria: severe malnutrition (Body Mass Index (BMI) <18.5 + 10% weight loss), European Society for Clinical Nutrition and Metabolism ((ESPEN1); BMI 18.5-22 + 10% weight loss), ESPEN2 (BMI < 18.5), American Cancer Society ((ACS); normal/overweight BMI + 10% weight loss), mild malnutrition (BMI 18.5-22), or albumin (<3.5 g/dL). Outcomes included 30-day major complications, readmission, reoperation. Modified Poisson regression estimated associations between definitions and outcomes. RESULTS: Of 76,290 total patients undergoing surgery, those meeting malnutrition definitions were: severe-98 (0.1%), ESPEN1-148 (0.2%), ESPEN2-877 (1.1%), ACS-1028 (1.3%), mild-2853 (3.7%), and albumin (11.1%). Complication rates were: unplanned readmission-5.5%, reoperation-1.7%, major complications-13.5%. For ovarian cancer, ESPEN2 malnutrition was associated with higher readmissions (risk ratio 1.69; 95% confidence interval 1.29-2.20), reoperations (2.53; 1.70-3.77), and complications (1.36; 1.20-1.54). For uterine cancer, ACS malnutrition was associated with readmissions (2.74; 2.09-3.59), reoperations (3.61; 2.29-5.71) and complications (3.92; 3.40-4.53). For cervical cancer, albumin<3.5 g/dL was associated with readmissions (1.48; 1.01-2.19), reoperations (2.25; 1.17-4.34), and complications (2.59; 2.11-3.17). Albumin<3.5 was associated with adverse outcomes in ovarian and uterine cancer. CONCLUSIONS: Preoperative risk assessments might be tailored using cancer-specific malnutrition criteria. Major complications, readmissions, and reoperations are all associated with the ESPEN2 definition for ovarian cancer, the ACS definition for uterine cancer, and with albumin<3.5 for all cancers.

Distress screening in endometrial cancer leads to disparity in referral to support services.

OBJECTIVES: Racial disparities in survival from endometrial cancer (EC) are well known. Cancer distress has also been associated with worse clinical outcomes. We characterized the association between race/ethnicity, patient distress reported on the National Comprehensive Cancer Network Distress Thermometer and Problem List (NCCN DT & PL), referral to support services, time to surgery, and acceptance of adjuvant therapy in patients with EC. METHODS: We included patients presenting at an academic gynecologic oncology practice from 1/2013-6/2020 who had not received prior EC-directed treatment. Demographics, NCCN DT scores, and treatment details were abstracted from the electronic medical record. Difference in initial DT scores by race/ethnicity and treatment type was tested using general linear modeling. The significance of interaction effects was tested using linear mixed models and logistic regression. RESULTS: 393 non-Hispanic White (NHW) and 134 non-Hispanic Black (NHB) patients were included. Median distress scores were higher in NHW patients compared to NHB patients (4 vs. 2, p < 0.001); 51% of NHW patients qualified for referral to support services compared to 40% of NHB patients (p = 0.03). Distress scores were highest at initial appointment and declined over time in NHW patients regardless of treatment, but were initially low and remained low over time in NHB patients. There was no association of initial distress score with time to surgery or acceptance of adjuvant treatment (p-values >0.25). CONCLUSIONS: An observed difference in NCCN DT leads to racial disparities in referral to support services. The NCCN DT may not adequately measure distress in NHB women with EC.

Promoting timely goals of care conversations between gynecologic cancer patients at high-risk of death and their providers.

OBJECTIVE: We designed a multi-faceted intervention to increase the rate of outpatient goals of care (GOC) conversations in women with gynecologic cancers who are at high-risk of death. METHODS AND MATERIALS: A multidisciplinary team developed an educational program around GOC conversations at end-of-life and chose criteria to prospectively identify patients at high-risk of death who might benefit from timely GOC conversations: recurrent or metastatic endometrial, cervical or vulvar cancer or platinum-resistant ovarian cancer. Gynecologic oncology provider consensus was built regarding the need to improve the quality and timing of GOC conversations. Eligible outpatients were prospectively identified and providers alerted pre-encounter; timely GOC documentation within 3 visits of high-risk identification was tracked. Our institution concurrently and subsequently tracked GOC documentation during the last 6 months of life among all established oncology patients. RESULTS: Of 220 pilot period high-risk patients (96 pre- and 124 during pilot period 2017-2018), timely GOC discussion documentation increased from 30.2% to 88.7% (p < 0.001) and this increase was sustained over time. In the post-pilot period (2019-2020), among patients seen by oncologists during last 6 months of life, compared to other cancer types, gynecologic cancer patients had a higher rate of GOC documentation (81% versus 9%; p < 0.001), a lower rate of receiving chemotherapy during the last 14 days of life (2% vs 5%; p = 0.051), and no difference in end-of-life admissions (29% vs 31%; p = NS). CONCLUSIONS: Implementation of systematic outpatient identification of high-risk gynecologic oncology patients is feasible, sustainable, and increases the timely conduct of GOC conversations.

Chemotherapy discontinuation processes in a gynecologic oncology population.

OBJECTIVE: We sought to categorize the processes by which gynecologic oncology patients stop chemotherapy and to evaluate associations between these processes and end-of-life outcome metrics. METHODS: A cohort of patients with metastatic or recurrent gynecologic cancer in an outpatient setting from January 2016 to May 2018 was identified. All deceased patients in this cohort were included for analysis. Processes of discontinuing chemotherapy were categorized as: 1) definitive decision inpatient; 2) definitive decision outpatient; 3) delayed decision (eg: treatment break and never resumed chemotherapy); 4) no decision. Associations between patient characteristics and clinical outcomes of those who made a definitive outpatient decision versus those who made any other type of decision were assessed. RESULTS: 220 patients were identified; 205 patients were deceased at time of analysis. Of these, 36.6% made a definitive decision to stop chemotherapy as an outpatient, while 41.5% never made a decision to discontinue chemotherapy. Making a definitive decision as an outpatient, when compared to all other decision types, was associated with significantly lower incidence of death in the hospital (5.6% vs 21.1%, p < 0.004) and hospitalization within 30 days of death (20.8% vs 56.6%, p < 0.001), and significantly increased median time from last chemotherapy to death (135.5 vs 62 days, p < 0.001). CONCLUSION: Only one in three women in this cohort of patients deceased from gynecologic cancer made a definitive decision to discontinue chemotherapy in an outpatient setting, and this process was associated with improved end-of-life outcomes. Future efforts should examine the impact of interventions designed to increase the proportion of patients who transition away from chemotherapy via shared decision making in the outpatient setting.

The preferences of women with ovarian cancer for oral versus intravenous recurrence regimens.

OBJECTIVE: To assess preferences of women with ovarian cancer regarding features of available anti-cancer regimens for platinum-resistant, biomarker-positive disease, with an emphasis on oral PARP inhibitor and standard intravenous (IV) chemotherapy regimens. METHODS: A discrete-choice-experiment preferences survey was designed, tested, and administered to women with ovarian cancer, with 11 pairs of treatment profiles defined using seven attributes (levels/ranges): regimen (oral daily, IV weekly, IV monthly); probability of progression-free (PFS) at 6 months (40%-60%); probability of PFS at 2 years (10%-20%); nausea (none, moderate); peripheral neuropathy (none, mild, moderate); memory problems (none, mild); and total out-of-pocket cost ($0 to $10,000). RESULTS: Of 123 participants, 38% had experienced recurrence, 25% were currently receiving chemotherapy, and 18% were currently taking a PARP inhibitor. Given attributes and levels, the relative importance weights (sum 100) were: 2-year PFS, 28; cost, 27; 6-month PFS, 19; neuropathy,14; memory problems, nausea, and regimen, all ≤5. To accept moderate neuropathy, participants required a 49% (versus 40%) chance of PFS at 6 months or 14% (versus 10%) chance at 2 years. Given a 3-way choice where PFS and cost were equal, 49% preferred a monthly IV regimen causing mild memory problems, 47% preferred an oral regimen causing moderate nausea, and 4% preferred a weekly IV regimen causing mild memory and mild neuropathy. CONCLUSIONS: These findings challenge the assumption that oral anti-cancer therapies are universally preferred by patients and demonstrate that there is no "one size fits all" regimen that is preferable to women with ovarian cancer when considering recurrence treatment regimens.

Standardization of lower extremity quantitative lymphedema measurements and associated patient-reported outcomes in gynecologic cancers.

Practice changing standardization of lower extremity lymphedema quantitative measurements with integrated patient reported outcomes will likely refine and redefine the optimal risk-reduction strategies to diminish the devastating limb-related dysfunction and morbidity associated with treatment of gynecologic cancers. The National Cancer Institute (NCI), Division of Cancer Prevention brought together a diverse group of cancer treatment, therapy and patient reported outcomes experts to discuss the current state-of-the-science in lymphedema evaluation with the potential goal of incorporating new strategies for optimal evaluation of lymphedema in future developing gynecologic clinical trials.

Primary cytoreductive surgery for advanced stage endometrial cancer: a systematic review and meta-analysis.

OBJECTIVE: Endometrial cancer uncommonly presents at an advanced stage and little prospective evidence exists to guide the management thereof. We aimed to summarize the evidence about primary cytoreductive surgery in the treatment of advanced stage endometrial cancer. DATA SOURCES: MEDLINE, Embase, and Scopus databases were searched from inception to September 11, 2020, using search terms representing the themes "endometrial cancer," "advanced stage," and "primary cytoreductive surgery." STUDY ELIGIBILITY CRITERIA: We included full-text, English reports that included ≥10 patients undergoing primary cytoreductive surgery for advanced stage endometrial cancer and that reported on the outcomes of primary cytoreductive surgery and survival rates based on the residual disease burden. METHODS: Two reviewers independently screened the studies and with disagreements between the reviewers resolved by a third reviewer. Data were extracted using a standardized form. The percentage of cases reaching maximal (no gross residual disease) and optimal (<1 cm or <2 cm residual disease) cytoreduction were assessed by summing binomials proportions, and the association with survival was assessed using an inverse variance-weighted meta-analysis of logarithmic hazard ratios. RESULTS: From 1219 unique records identified, 34 studies were selected for inclusion. Studies consisted of single or multi-institutional cohorts of patients collected over a period of 6 to 24 years and included various mixes of histologies (endometrioid, serous, clear cell, and carcinosarcoma) and disease stages (III or IV). In a meta-analysis of the extent of residual disease after primary cytoreductive surgery, we found that 52.1% of cases reached no gross residual disease status (n=18 studies; 1329 patients) and 75% reached <1 cm residual disease status (n=27 studies; 2343 patients). The proportion of cytoreduction for both thresholds was lower for studies of stage IV vs stage III to IV disease (41.4% vs 69.8% for no gross residual disease; 63.2% vs 82.2% for <1 cm residual disease) but did not vary notably by histology. In a meta-analysis of the reported hazard ratios, submaximal (any gross residual disease vs no gross residual disease) and suboptimal (≥1 cm vs <1 cm) cytoreduction thresholds were associated with worse progression-free survival (submaximal hazard ratio, 2.16; 95% confidence interval, 1.45-3.21; I2=68%; suboptimal hazard ratio, 2.55; 95% confidence interval, 1.93-3.37; I2=63%) and overall survival rates (submaximal hazard ratio, 2.57; 95% confidence interval, 2.13-3.10; I2=1%; suboptimal hazard ratio, 2.62; 95% confidence interval, 2.20-3.11; I2=15%). Sensitivity analyses limited to high-quality studies demonstrated consistent results. CONCLUSION: Among cases of advanced stage endometrial cancer undergoing primary cytoreductive surgery, a significant proportion of patients are left with residual disease, which is associated with worse survival outcomes. Further investigations about the roles of neoadjuvant chemotherapy and primary cytoreductive surgery in prospective trials is warranted in this population.

Management of high, moderate, and low penetrance ovarian cancer susceptibility mutations: an assessment of current risk reduction practices.

OBJECTIVE: Limited information exists regarding risk reduction strategies for women with moderate and low penetrance ovarian cancer susceptibility mutations. We sought to assess current risk reduction practice patterns for carriers of these mutations through a survey of members of the Society of Gynecologic Oncology. METHODS: Society of Gynecologic Oncology members were emailed a survey consisting of two vignettes: (1) a 35-year-old premenopausal woman; (2) a 55-year-old postmenopausal woman with comorbidities. Each vignette contained sub-scenarios in which the patient had either a BRCA1 (relative risk (RR)=30-60), RAD51C (RR=5.0), or ATM (RR=1.5-2.0) mutation. Respondents were queried about their preferred management approach. Summary statistics were performed to describe results of the survey. We used χ2 testing for statistical analyses, comparing results according to mutation type and demographic information. RESULTS: A total of 193 (15%) of 1284 Society of Gynecologic Oncology members responded. For the premenopausal woman, 99%, 80%, and 40% would perform a risk reducing salpingo-oophorectomy prior to menopause in the setting of a BRCA1, RAD51C, and ATM mutation, respectively. For the postmenopausal woman, 98%, 85%, and 42% would proceed with risk reducing salpingo-oophorectomy in the setting of a BRCA1, RAD51C, and ATM mutation, respectively. Response distribution for carriers of RAD51C and ATM mutations were different from BRCA1 in both vignettes (p<0.001). CONCLUSIONS: Respondents were more likely to perform risk reducing salpingo-oophorectomy, in the setting of a BRCA1, RAD51C, and ATM mutation, earlier and more frequently in the setting of a BRCA1 mutation. However, there was a lack of consensus about management of the moderate and low penetrance mutations, suggesting that more data regarding age specific risks and appropriate risk reduction strategies for these alterations are needed.

Place of death by region and urbanization among gynecologic cancer patients: 2006-2016.

OBJECTIVE: To evaluate associations between US region of residence and urbanization and the place of death among women with gynecologic malignancies in the United States. METHODS: A retrospective cross-sectional study was performed using publicly available death certificate data from the National Center for Health Statistics. All gynecologic cancer deaths were included from 2006 to 2016. Comparisons among categories were performed with a two-tailed chi-square test, with p-values <0.05 considered significant. RESULTS: From 2006 to 2016, 328,026 women died from gynecologic malignancies in the US. Of these deaths, 40.1% (n = 134,333) occurred in the patient's home, 24.9%(n = 81,823) in the hospital, and 11.3% (37,188) in an inpatient hospice facility. Place of death varied by geographic region. The Northeast had the largest percentage of gynecologic cancer patients (31.3%) die as a hospital inpatient. The West had the highest percentage of deaths (49.3%) at home. Deaths in a hospice facility were the highest (14.1%) in the South. Place of death varied by urbanization; patients residing in large central metro or rural counties were the most likely to die during hospital admission (28.7% and 27.1%, respectively). Patients living in medium-sized metro areas were the least likely to die in hospitals (21.8%) and most likely to die in a hospice facility (14.3%). All comparisons were significant by study definition. CONCLUSION: The place of death for patients with gynecologic malignancies varies by US region and urbanization. These disparities are multifactorial in nature, likely influenced by both sociodemographic factors and regional resource availability. In this study, however, rural and central metro areas are identified as regions that may benefit from further hospice development and advocacy.

Gender variation in Medicare utilization and payments in gynecologic oncology.

OBJECTIVES: The Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File (POSPUF) and Medicare Physician and Other Supplier National Provider Identifier (POS NPI) Aggregate Report are publicly available files from the Center for Medicare and Medicaid Services that include payments to providers who care for fee-for-service Medicare recipients. The aim of this study was to analyze variability in gynecologic oncologists' Medicare reimbursements, with attention to differences in provider gender and time in practice. METHODS: The 2015 POSPUF and POS NPI were analyzed with respect to gynecologic oncologists. We searched external publicly available data sources to confirm subspecialty and to determine each provider's number of years in practice. Evaluation and management (E&M) and procedure/surgery codes were analyzed; drug delivery codes were excluded due to variability in billing by facility/hospital. RESULTS: The POS NPI file included 733 gynecologic oncologist providers receiving $55,626,739 in total payments. Female providers comprised 39% of gynecologic oncologists and received 31% of reimbursements (30% of E&M reimbursements and 24% of surgical reimbursements). During the first ten years in practice, female providers comprised 58% of providers and accounted for 52% of reimbursed services, compared to 38% of providers/26% of reimbursed services (11-20 years), and 18% of providers/19% of reimbursed services (>20 years). CONCLUSION: Male gynecologic oncologists perform more Medicare services than their female counterparts. There is a comparable number of services performed between genders among both the most senior and the most junior providers, with a gender gap in services and reimbursements among mid-career providers.

Phase II trial of nintedanib in patients with bevacizumab-resistant recurrent epithelial ovarian, tubal, and peritoneal cancer.

BACKGROUND: Bevacizumab provides benefit in epithelial ovarian cancer (EOC), yet resistance to bevacizumab often occurs. We determined if nintedanib, a tyrosine kinase inhibitor of VEGF, FGF, and PDGF receptors has antitumor activity in bevacizumab-resistant recurrent EOC, tubal, and peritoneal cancer. METHODS: This phase II study evaluated nintedanib 200 mg/day until disease progression or unacceptable toxicity. The primary objective was 6-month progression free survival (PFS6m). Secondary objectives were response rate and toxicity. Simon two-stage optimal design was used. Baseline angiogenic plasma biomarkers were measured. RESULTS: 27 patients were enrolled evaluable for PFS; 26 were evaluable for PFS6m. The median age was 65 years (range 44-73); 89.9% had high-grade serous EOC; 70% received at least >2 prior chemotherapies; and 81% (22/27) had chemoresistant disease. With median follow up of 15.6 months (range 2-38) the PFS6m rate was 11.5% (3/26). Three participants had long duration of disease control (8-16 months). Median PFS and overall survival were 1.8 and 16 months, respectively. Response rate was 7.4% (2/27 PR). Thirty-seven percent (10/27) had stable disease, while 56% (15/27) had progressive disease. Adverse events included Grade 3 liver enzyme elevation (15%), Grade 3 diarrhea (7%), Grade 2 fatigue (7%), and Grade 2 nausea/vomiting (15%). PD patients exhibited higher levels of CD73, IL6, and VEGFD (p < 0.05) compared to PR/SD patients. IL6 was associated with worse PFS (p = 0.03). CONCLUSIONS: Single-agent nintedanib has minimal activity in an unselected bevacizumab-resistant EOC population. Nintedanib was tolerable and toxicities were manageable. Plasma CD73, IL6, and VEGFD were identified as prognostic markers for progressive disease, and IL6 was associated with worse PFS confirming similar observations made in patients treated with other anti-angiogenic agents.