Association of allostatic load with overall survival in epithelial ovarian cancer.

OBJECTIVE: Elevated allostatic load (AL), an integrated, cumulative marker of physiologic damage due to socioenvironmental stress, is associated with increased mortality in patients with breast, lung, and other cancers. The relationship between allostatic load and mortality in ovarian cancer patients remains unknown. We examined the relationship between allostatic load and overall survival in ovarian cancer patients. METHODS: This cross-sectional study used data from 201 patients enrolled in a prospective observational ovarian cancer cohort study at a National Cancer Institute-designated Comprehensive Cancer Center from October 2012 through June 2022. All patients underwent debulking surgery and completed a full course of standard-of-care platinum-based chemotherapy. Follow-up was completed through January 2024. Allostatic load was calculated as a summary score by assigning one point to the worst sample quartile for each of ten biomarkers measured within 45 days before the ovarian cancer diagnosis. High allostatic load was defined as having an allostatic load in the top quartile of the summary score. A Cox proportional hazard model with robust variance tested the association between allostatic load and overall survival. RESULTS: There were no associations between allostatic load and ovarian cancer clinical characteristics. After accounting for demographic, clinical, and treatment factors, high allostatic load was associated with a significant increase in mortality (hazard ratio 2.17 [95%CI, 1.13-4.15]; P = 0.02). CONCLUSION: Higher allostatic load is associated with worse survival among ovarian cancer patients. Allostatic load could help identify patients at risk for poorer outcomes who may benefit from greater socioenvironmental support during treatment.

Concurrent RB1 Loss and BRCA-Deficiency Predicts Enhanced Immunological Response and Long-Term Survival in Tubo-Ovarian High-Grade Serous Carcinoma.

PURPOSE: To evaluate RB1 expression and survival across ovarian carcinoma histotypes, and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 primary HGSC to characterize tumors with concurrent BRCA-deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC, but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared to patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA-deficiency correlated with transcriptional markers of enhanced interferon response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA-deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

The role of obesity in treatment planning for early-stage cervical cancer.

OBJECTIVES: Optimal management of obese patients with early-stage cervical cancer is debated despite evidence of non-inferior survival in obese patients undergoing radical hysterectomy with pelvic lymphadenectomy (RH) compared to primary radiation with or without radiosensitizing chemotherapy (RT). Objectives included describing patient factors affecting disposition to RH versus RT; comparing RH outcomes for obese (BMI >30 mg/m2) and non-obese patients; and comparing differences in recurrence free survival (RFS) and overall survival (OS). METHODS: This was a single institution cohort study of all cervical cancer patients who underwent RH or were candidates for RH based on clinical stage. Demographic, clinicopathologic and treatment outcomes were collected and analyzed. RESULTS: RT patients (n = 39, 15%) had a higher BMI (p = 0.004), older age (p < 0.001), more life-limiting comorbidities (LLC) (p < 0.001), larger tumor size (p = 0.001), and higher clinical stage (p = 0.013) compared to RH patients (n = 221, 85%). On multivariable survival analysis there was no difference in OS based on treatment modality; significant predictors of worse OS were larger tumor size, higher number of LLC and recurrence. Among the RH group, obese patients had a longer operative time (p = 0.01) and more LLC (p = 0.02); there were no differences in demographic or clinicopathologic characteristics, operative outcomes, RFS or OS compared to non-obese patients. CONCLUSION: In this cohort of RH-eligible cervical cancer patients, BMI was independently associated with disposition to RT. Studies demonstrate that RH is feasible and safe in obese patients with no difference in RFS or OS when compared to non-obese patients. Thus, the decision for disposition to RT should not be based on obesity alone.

Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Background: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. Patients and methods: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. Results: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Ovarian serous borderline tumor with mural nodules of anaplastic carcinoma and omental involvement: A case report.

Mural nodules are rarely identified in cystic ovarian neoplasms, and have been categorized into sarcoma-like, sarcomatous, and anaplastic carcinomatous types. Most reports of these mural nodules have been described in mucinous ovarian tumors. In this case report, we describe an ovarian serous borderline tumor with mural nodules composed of high-grade carcinoma with anaplastic features and necrosis, including the morphologic features, immunoprofile, and results of tumor DNA sequencing. Omental involvement was also identified. Recognition of this phenomenon in serous tumors is important, so that thickened areas of cyst wall in ovarian serous tumors will be thoroughly examined.

Is Substantial Lymphovascular Space Invasion Prognostic in Patients With Pathologically Lymph Node-Negative Endometrial Cancer?

PURPOSE: Lymphovascular space invasion (LVSI) predicts for higher rates of recurrence and increased mortality in endometrial cancer. Using 3-tier LVSI scoring, a PORTEC-1 and -2 trials analysis demonstrated that substantial LVSI was associated with worse locoregional (LR-DFS) and distant metastasis disease-free survival (DM-DFS), and these patients possibly benefited from external beam radiation therapy (EBRT). Furthermore, LVSI is a predictor for lymph node (LN) involvement, but the significance of substantial LVSI is unknown in patients with a pathologically negative LN assessment. We aimed to evaluate clinical outcomes of these patients in relation to the 3-tier LVSI scoring system. METHODS AND MATERIALS: We performed a single-institutional retrospective review of patients with stage I endometrioid-type endometrial cancer who underwent surgical staging with pathologically negative LN evaluation from 2017 to 2019 with 3-tier LVSI scoring (none, focal, or substantial). Clinical outcomes (LR-DFS, DM-DFS, and overall survival) were analyzed using the Kaplan-Meier method. RESULTS: A total of 335 patients with pathologically LN-negative stage I endometrioid-type endometrial carcinoma were identified. Substantial LVSI was present in 17.6% of patients; 39.7% of patients received adjuvant vaginal brachytherapy and 6.9% of patients received EBRT. Adjuvant radiation treatment varied by LVSI status. In patients with focal LVSI, 81.0% received vaginal brachytherapy. Among patients with substantial LVSI, 57.9% received vaginal brachytherapy alone, and 31.6% of patients received EBRT. The 2-year LR-DFS rates were 92.5%, 98.0%, and 91.4% for no LVSI, focal LVSI, and substantial LVSI, respectively. The 2-year DM-DFS rates were 95.5%, 93.3%, and 93.8% for no LVSI, focal LVSI, and substantial LVSI, respectively. CONCLUSIONS: In our institutional study, patients with pathologically LN-negative stage I endometrial cancer with substantial LVSI had similar rates of LR-DFS and DM-DFS compared with patients with none or focal LVSI. These findings highlight the need for multi-institutional studies to validate the prognostic value of substantial LVSI in this patient population.

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study.

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study.

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Clinical factors associated with failed sentinel lymph node mapping in endometrial cancer.

Objective: Sentinel lymph node (SLN) mapping is a highly accurate surgical technique for detecting metastases in endometrial cancer. The objective of this study was to identify clinical factors associated with failed mapping. Methods: All patients with endometrial cancer undergoing minimally-invasive staging and planned SLN biopsy from 1/1/2017 to 12/31/2020 at a single institution were identified retrospectively. Demographic, clinicopathologic and treatment data were obtained. Data were compared using descriptive statistics. Univariate and multivariable logistic regression were performed to identify predictors of failed mapping. Results: 819 patients were identified with a mean age of 64.6 years (range 26-93) and mean BMI of 35.6 kg/m2 (range 18-68). Most (88.5 %, 725/819) had early-stage disease and endometrioid histology (82.3 %, 674/819). A majority (74.2 %, 608/819) had successful bilateral mapping, and 54 (6.6 %) had unsuccessful bilateral mapping. Increasing BMI was significantly associated with unsuccessful bilateral mapping: patients with BMI > 30 were more likely to have unsuccessful SLN mapping (p = 0.033). Among patients with known lymph node status (799/819), patients with macrometastases and micrometastases were more likely to have failed bilateral mapping compared to those with negative SLNs or isolated tumor cells (p = 0.013). On multivariable analysis, higher BMI and histology were associated with failed bilateral mapping (OR = 1.023, 95 % CI (1.005, 1.041) and OR = 1.678, 95 % CI (1.177, 2.394), respectively). Conclusion: SLN mapping has a high success in patients undergoing minimally-invasive surgical staging for endometrial cancer. Increasing BMI, high risk histology, and lymph node metastases are risk factors for failed mapping.

Phase I trial of ribociclib with platinum chemotherapy in ovarian cancer.

BACKGROUNDNew therapeutic combinations to improve outcomes of patients with ovarian cancer are clearly needed. Preclinical studies with ribociclib (LEE-011), a CDK4/6 cell cycle checkpoint inhibitor, demonstrate a synergistic effect with platinum chemotherapy and efficacy as a maintenance therapy after chemotherapy. We tested the safety and initial efficacy of ribociclib in combination with platinum-based chemotherapy in recurrent ovarian cancer.METHODSThis phase I trial combined weekly carboplatin and paclitaxel chemotherapy with ribociclib, followed by ribociclib maintenance in patients with recurrent platinum-sensitive ovarian cancer. Primary objectives were safety and maximum tolerated dose (MTD) of ribociclib when given with platinum and taxane chemotherapy. Secondary endpoints were response rate (RR) and progression-free survival (PFS).RESULTSThirty-five patients were enrolled. Patients had a mean of 2.5 prior lines of chemotherapy, and 51% received prior maintenance therapy with poly(ADP-ribose) polymerase inhibitors and/or bevacizumab. The MTD was 400 mg. The most common adverse events included anemia (82.9%), neutropenia (82.9%), fatigue (82.9%), and nausea (77.1%). The overall RR was 79.3%, with a stable disease rate of 18%, resulting in a clinical benefit rate of 96.6%. Median PFS was 11.4 months. RR and PFS did not differ based on the number of lines of prior chemotherapy or prior maintenance therapy.CONCLUSIONThis work demonstrates that the combination of ribociclib with chemotherapy in ovarian cancer is feasible and safe. With a clinical benefit rate of 97%, this work provides encouraging evidence of clinical efficacy in patients with recurrent platinum-sensitive disease.TRIAL REGISTRATIONClinicalTrials.gov NCT03056833.FUNDINGThis investigator-initiated trial was supported by Novartis, which provided drugs and funds for trial execution.

Same-day Hospital Discharge after Minimally Invasive Hysterectomy in a Gynecologic Oncology Practice: Feasibility, Safety, Predictors of Admission, and Adverse Outcomes.

STUDY OBJECTIVES: (1) Determine the feasibility and safety of same-day hospital discharge (SDHD) after minimally invasive hysterectomy (MIH) in a gynecologic oncology practice and (2) detail predictors of immediate postoperative hospital admission and multiple 30-day adverse outcomes. DESIGN: Retrospective cohort study. SETTING: University of Pittsburgh Medical Center Magee-Womens Hospital. PATIENTS: MIH by a gynecologic oncologist between January 2017 and July 2019. INTERVENTIONS: Clinicopathologic, operative, and medical characteristics, as well as 30-day postoperative complications, emergency department (ED) encounters, and hospital readmissions were extracted. Admitted and SDHD patients were compared using descriptive, chi-square, Fisher's exact, t test, and logistic regression analyses. Univariate and multivariable analyses (MVA) revealed predictors of postoperative hospital admission, 30-day readmission, and a 30-day composite adverse event variable (all-reported postoperative complications, ED encounter, and/or readmission). MEASUREMENTS AND MAIN RESULTS: A total of 1124 patients were identified, of which 77.3% had cancer or precancer; 775 patients (69.0%) underwent SDHD. On MVA, predictors of postoperative admission included older age, distance from hospital, longer procedure length, operative complications, start time after 2 PM, radical hysterectomy, minilaparotomy, adhesiolysis, cardiac disease, cerebrovascular disease, venous thromboembolism, diabetes, and neurologic disorders (p <.05). Moreover, 30-day adverse outcomes were rare (complication 8.7% National Surgical Quality Improvement Program/11.9% all-reported; ED encounter 5.0%; readmission 3.6%). SDHD patients had fewer all-reported complications (10.3% vs 15.5%, p = .01), no difference in ED encounters (4.6% vs 5.7%, p = .44), and fewer observed readmissions (2.8% vs 5.2%, p = .05). Predictors of readmission were identified on univariate; MVA was not feasible given the low number of events. Longer procedure length and cardiac and obstructive pulmonary disease were predictors of the composite adverse event variable (p <.05). CONCLUSION: SDHD is feasible and safe after MIH within a representative gynecologic oncology practice. Clinicopathologic, medical, and surgical predictors of multiple adverse outcomes were comprehensively described. By identifying patients at high risk of postoperative adverse events, we can direct SDHD selection in the absence of standardized institutional and/or national consensus guidelines and identify patients for prehabilitation and increased perioperative support.

Intensive Daily Symptom and Function Monitoring Is Feasible and Acceptable to Women Undergoing First-Line Chemotherapy for Gynecologic Cancer.

BACKGROUND: Women receiving chemotherapy for gynecologic cancer (GC) experience severe symptoms with associated functional changes. Understanding day-to-day symptom and function variation within and across chemotherapy treatment cycles could inform improved symptom management, but such studies are rare and may be infeasible in clinical care. OBJECTIVE: The aim of this study was to evaluate feasibility and acceptability of daily symptom monitoring combined with objective and self-reported functional assessments every 21 days during active chemotherapy for GC. METHODS: Thirty women enrolled in a prospective observational study during first-line chemotherapy completed a daily symptom and falls diary during their entire chemotherapy treatment period. Patient-reported outcomes and objective symptom and function testing were assessed before each chemotherapy appointment. Study outcomes included accrual and attrition rates, completion of study assessments, and qualitative perceptions of study participation. RESULTS: Participants were 92% White, 60% had high school or higher education, 68% were married/partnered, and 62% had stage III or IV cancer at diagnosis. The study had an 83% accrual rate, 6.6% early withdrawal rate, and 17% total attrition rate. Missing assessments for prechemotherapy patient-reported outcomes and objective assessments ranged from 27% to 35% and 35% to 47% respectively, with a general decrease across cycles. Daily diary completion rate was 83% overall. Participants rated study participation positively. CONCLUSIONS: Intensive daily symptom and function monitoring was feasible and acceptable to GC patients and may provide a sense of symptom controllability. IMPLICATIONS FOR PRACTICE: Daily symptom and function monitoring in research studies may provide patients with information to support symptom discussions with the clinical team. Future work should develop proactive symptom management interventions using personalized symptom trajectories.

Do air gaps with image-guided vaginal cuff brachytherapy impact failure rates in patients with high-intermediate risk FIGO Stage I endometrial cancer?

PURPOSE: The aim of this study was to assess the impact of air gaps at the cylinder surface on the rate of vaginal cuff failure (VCF) after image-guided adjuvant vaginal cuff brachytherapy (VCBT) in the treatment of high-intermediate risk (HIR) FIGO (Fédération Internationale de Gynécologie et d'Obstétrique (International Federation of Gynecology and Obstetrics)) Stage I endometrial cancer. METHODS AND MATERIALS: A retrospective review of patients treated with image-guided VCBT from 2009 to 2016 for HIR FIGO Stage I endometrial cancer was performed. Air gaps present at the applicator surface on the first postinsertion CT were contoured. Vaginal cuff failure-free survival (VCFFS) was measured from the first fraction of VCBT to VCF. RESULTS: A total of 234 patients were identified. Air gaps were present on the first postinsertion CT scan in 82% of patients. The median number of air gaps was 2 (interquartile range [IQR] 1-3), median depth of the largest air gap was 2.7 mm (IQR 2.1-3.4 mm), and the median cumulative volume of air gaps was less than 0.1 cm3 (range < 0.1-0.7 cm3). At a median followup of 56 months (IQR 41-69), 12 patients (5%) experienced VCF, of which 4 had isolated VCF and 8 had synchronous pelvic or distant failure. Five-year VCFFS and isolated VCFFS were 96% (95% confidence interval 93-98%) and 98% (95% confidence interval 96-100%), respectively. On univariate analysis, no factors, including the presence, number, maximum depth, or cumulative volume of air gaps, were predictive for VCFFS. CONCLUSIONS: In this population, VCFFS remained high despite most patients having air gaps present on postinsertion CT scan.

Dose-escalated intensity modulated radiation therapy in patients with locally-advanced vulvar cancer - does it increase response rate?

PURPOSE: GOG 205 safely increased clinical (cCR) and pathologic complete response (pCR) in locally-advanced vulvar cancer through dose escalation using three-dimensional radiotherapy (RT). The aim of this study is to assess the response of dose-escalated intensity modulated radiotherapy (IMRT) in locally-advanced vulvar cancer. METHODS: A retrospective review of patients treated with dose-escalated (≥ 55Gy) IMRT from 2012 to 2018 for locally-advanced vulvar cancer was performed. Patients treated with preoperative or definitive intent were included. Rates of cCR and pCR were assessed, and predictors of disease-free survival (DFS) were analyzed using the Kaplan Meier method with log rank test between groups and a parsimonious multivariate Cox model. RESULTS: Median dose to the vulva was 66.0 Gy (Interquartile Range [IQR]: 66.0-68.0) for definitive and 59.4 Gy (IQR: 58.0-59.4) for preoperative IMRT. The overall rates of cCR and pCR were 76% and 70%, respectively. DFS at two years was 65% (95% Confidence Interval [CI] 50-80%) for all patients, 81% (95% CI 63% - 98%) for definitive IMRT, and 55% (95% CI 35% - 76%) for preoperative IMRT. On multivariate analysis, cCR predicted for disease-free survival (HR 0.21; 95% CI 0.06-0.76; p = 0.02), and pCR predicted for OS (HR 0.12; 95% CI 0.02-0.60; p = 0.01). Grade 3 acute and late RT toxicity was seen in 14 (29%) and 3 (6%) of patients, respectively. CONCLUSION: Dose-escalated IMRT for locally-advanced vulvar cancer is well tolerated, with rates of cCR and pCR that compare favorably with published data.

Validation of the surprise question in gynecologic oncology: A one-question screen to promote palliative care integration and advance care planning.

OBJECTIVE: The "surprise question" ("Would you be surprised if this patient died in the next year?") has been shown to be predictive of 12-month mortality in multiple populations, but has not been studied in gynecologic oncology (GO) patients. We sought to evaluate the prognostic performance of the surprise question in GO patients among physician and non-physician providers. METHODS: GO providers at two tertiary care centers were asked the surprise question about a cohort of their patients undergoing chemotherapy or radiation. Demographic and clinical information was chart abstracted. Mortality data were collected at one year; relative risk of death at one year based on response to the surprise question was then calculated. RESULTS: 32 providers (12 MDs, 7 APPs, 13 RNs) provided 942 surprise question assessments for 358 patients. Fifty-seven % had ovarian cancer and 54% had recurrent disease. Eighty-three (24%) patients died within a year. Patients whose physician answered "No" to the surprise question had a 43% one-year mortality (compared to 10% for "Yes"). Overall RR of 12-month mortality for "No" was 3.76 (95% CI 2.75-5.48); this association remained significant in all provider types. Among statistically significant predictors of 12-month mortality (including recurrent disease and >2 prior lines of chemotherapy), the surprise question had the highest RR. CONCLUSIONS: The surprise question is a simple, one question tool that effectively identifies GO patients increased risk of 12-month mortality. The surprise question could be used to identify patients for early referral to palliative care and initiation advance care planning.

Magnetic resonance imaging response in patients treated with definitive radiation therapy for medically inoperable endometrial cancer-Does it predict treatment response?

PURPOSE: Many patients with endometrial cancer cannot undergo surgery and instead receive definitive radiation therapy (RT). We investigate the correlation between MRI response to RT and clinical outcomes. METHODS AND MATERIALS: Women with inoperable, clinical Stage I endometrial cancer were treated with definitive brachytherapy (BT) with/without pelvic RT (PRT). Patients underwent MRI with functional diffusion-weighted imaging before and after RT. A radiologist retrospectively classified cases as complete, partial, or indeterminate response (CR, PR, or IR, respectively) vs. disease progression. Local control was clinicopathologically defined. RESULTS: From 2007 to 2017, 50 women underwent definitive RT. Thirty-five (70%) received BT alone (median dose 37.5 Gy). For combined therapy, the median PRT and BT doses were 45 and 25 Gy, respectively. Median gross tumor volume and high-risk clinical target volume were 7.1 cc and 90.0 cc, respectively. Median followup among living patients was 20 months. All patients underwent post-RT MRI with T1/T2 sequencing at a median of 3.2 months after RT; 40 patients (80%) underwent functional diffusion-weighted imaging sequences. On initial post-RT MRI, CR was documented in 42 patients (84%), IR in 1 patient (2%), and PR in seven patients (14%). At median followup of 16.3 months, no CR patients had uterine failure. Among eight patients with initial PR/IR, all were found to be clinicopathologically no evidence of disease at the uterus on further evaluation. CONCLUSIONS: Definitive RT with BT or BT + PRT is associated with high response rates on MRI. Overall, initial CR predicted for excellent outcome with no infield failure.

Neoadjuvant Chemoradiation Therapy Followed by Extrafascial Hysterectomy in Locally Advanced Type II Endometrial Cancer Clinically Extending to Cervix.

PURPOSE: The role of neoadjuvant chemoradiation therapy in locally advanced type II endometrial cancer is controversial. We thus aimed to present our experience with the hypothesis that neoadjuvant chemoradiation therapy is associated with similarly high rates of downstaging and locoregional control for type II endometrial cancer and type I endometrial cancer. METHODS AND MATERIALS: Thirty-four patients with type II endometrial cancer with clinical evidence of cervical ± parametrium involvement treated with neoadjuvant external beam radiation therapy (45-50.4 Gy in 25-28 fractions) and high-dose-rate brachytherapy with a median total dose of 20 Gy (range, 15-27.5) in 4 fractions (range, 3-5) and concurrent platinum chemotherapy ± adjuvant chemotherapy from 2008 to 2018 were retrospectively reviewed. Patients with type I pathologic diagnoses and those treated with definitive (rather than preoperative) intent were excluded. RESULTS: Pathologic characteristics were as follows: 38% were carcinosarcoma, 18% serous, and 24% clear cell. Ninety-four percent of patients were downstaged to an extrafascial hysterectomy, and 94% had negative surgical margins. The 2-year local control, regional control, distant control, disease-free survival, and overall survival were 87.8%, 81.3%, 76.3%, 52.5%, and 63.7%, respectively. There was 1 subacute grade 3 and 1 late grade 3 small bowel obstruction, directly attributable to radiation therapy. CONCLUSIONS: Neoadjuvant chemoradiation therapy effectively downstages the majority of locally advanced type II endometrial cancers, thereby increasing the likelihood of achieving complete resection with negative margins.

The Prognostic Significance of p16 Status in Patients With Vulvar Cancer Treated With Vulvectomy and Adjuvant Radiation.

PURPOSE: Vulvar squamous cell carcinoma (VSCC) is a relatively rare malignancy. Human papillomavirus has been implicated as a causative factor for a subset of these patients. The purpose of this study was to evaluate whether p16-positivity (a human papillomavirus surrogate) predicts for better response rates in women who undergo surgery followed by adjuvant radiation therapy (RT). METHODS AND MATERIALS: We retrospectively analyzed data from women with VSCC who were treated with adjuvant RT. p16-Positivity was defined as diffuse strong immunoreactivity within the tumor. Time to event outcomes was performed with Kaplan-Meier and cumulative incidence methodologies. RESULTS: Thirty-nine women were identified. Ten had positive results for p16 (p16+), and 29 had negative results (p16-). The median follow-up was 25.7 months. The median age at diagnosis was 59 years for women with p16+ tumors and 74 years for women with p16- tumors (P = .022). The distribution of stage did not differ by p16 status. The indications for adjuvant RT were close/positive margins in 19 women, positive nodes in 9 women, and both in 11 women. There were 21 recurrences: 15 vulvar, 3 isolated nodal, 2 synchronous vulvar/nodal, and 1 distant metastasis. In-field relapse rates at 3 years were lower in p16+ patients (32.5%) than in p16- patients (59.1%, P = .072). This trend was also observed in progression-free survival (P = .062). A p16+ status and a lower International Federation of Gynecology and Obstetrics stage were associated with fewer in-field relapses and improved progression-free survival in multivariable analyses. The p16 status was not a predictor of overall survival. CONCLUSIONS: p16-Positivity appears to be a prognostic factor for in-field relapse rates in patients with VSCC appropriately treated with adjuvant RT.

Chemotherapy in older adult gynecologic oncology patients: Can a phenotypic frailty score predict tolerance?

OBJECTIVE: Evaluate the ability of an office-administered phenotypic frailty assessment to predict chemotherapy tolerance in older adult gynecologic oncology patients, and describe practice patterns for chemotherapy administration in this population. METHODS: Prospective, single-institution cohort study of gynecologic oncology patients 65 or older initiating chemotherapy. Phenotypic frailty testing at an office visit encompassed components of two validated frailty assessments: Fried Score (physical testing and patient response) and FRAIL Scale (patient response only). Patients were followed through three cycles of neoadjuvant chemotherapy or six cycles of adjuvant chemotherapy. Standard statistics examined the relationship of frailty to chemotherapy regimen, ability to complete chemotherapy, and complications. RESULTS: Eighty patients were included, 65% with ovarian and 34% with endometrial cancer. On average 57% of patients were fit, 32% intermediately frail, and 11% frail. 68% received adjuvant chemotherapy versus 32% neoadjuvant. The majority (81%) received IV chemotherapy on a 21-day cycle and 81% initially received a regimen consistent with standard-of-care chemotherapy (SOCC). Age was not associated with receiving SOCC, or tolerance or completion of chemotherapy. Frailty was associated with non-initiation of SOCC in all patients and inability to complete SOCC in adjuvant patients. Complications and regimen alterations were common but were not associated with frailty. CONCLUSIONS: There is a need to develop tools to help physicians predict chemotherapy tolerance among older adult gynecologic oncology patients in order to prevent both under- and over-treatment while minimizing morbidity. However, in this study phenotypic frailty assessment had limited predictive utility. Among adjuvant chemotherapy patients, frailty was associated with inability to complete SOCC and thus may be helpful in selecting patients appropriate for less aggressive chemotherapy regimens.

Unplanned postoperative intensive care unit admission for ovarian cancer cytoreduction is associated with significant decrease in overall survival.

OBJECTIVES: Previous studies have identified age, nutritional status, and hematocrit as risk factors for unplanned ICU admission in gynecologic oncology patients. We sought to identify additional perioperative factors that can be predictive of unplanned ICU admission and its impact on outcomes in women with ovarian cancer undergoing ovarian cancer cytoreductive procedures. METHODS: This was a case-control study of patients with unplanned ICU admission after primary surgery for ovarian cancer from January 2007 to December 2013. Controls were selected in a 2:1 ratio matching for primary surgeon and date of surgery. Clinical data was abstracted and compared between cases and controls using conditional logistic regression. RESULTS: The dataset consisted of 324 patients (108 ICU admissions, 216 controls). On multivariable analysis, failure to optimally cytoreduce (p = 0.001, OR 3.76) and higher EBL (p < 0.001, OR 1.20 per 100 cm3) remained significant predictors of unplanned ICU admission. On multivariable analysis of outcomes, ICU admission was independently associated with increased length of stay (12 days vs. 6 days, p < 0.001), increased number of postop complications (2 vs. 0, p < 0.001), and increased risk of readmission within 30 days (p = 0.041, OR 2.46). Even controlling for debulking status, ICU admission remained associated with a worse median OS (27.3 vs 57.9 months, p < 0.001). CONCLUSIONS: ICU admission for women undergoing cytoreductive surgery for ovarian cancer is associated with a significant decrease in OS and increase in number of postoperative complications. For this inherently high-risk population, this information is critical when counseling patients about peri-operative risks in primary cytoreductive surgery.