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

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

Prognostic significance of ethnicity and age in advanced stage epithelial ovarian cancer: An NRG oncology/gynecologic oncology group study.

BACKGROUND: Age and ethnicity are among several factors that influence overall survival (OS) in ovarian cancer. The study objective was to determine whether ethnicity and age were of prognostic significance in women enrolled in a clinical trial evaluating the addition of bevacizumab to front-line therapy. METHODS: Women with advanced stage ovarian, primary peritoneal, or fallopian tube cancer were enrolled in a phase III clinical trial. All women had surgical staging and received adjuvant chemotherapy with one of three regimens. Cox proportional hazards models were used to evaluate the relationship between OS with age and race/ethnicity among the study participants. RESULTS: One-thousand-eight-hundred-seventy-three women were enrolled in the study. There were 280 minority women and 328 women over the age of 70. Women age 70 and older had a 34% increase risk for death when compared to women under 60 (HR = 1.34; 95% CI 1.16-1.54). Non-Hispanic Black women had a 54% decreased risk of death with the addition of maintenance bevacizumab (HR = 0.46, 95% CI:0.26-0.83). Women of Asian descent had more hematologic grade 3 or greater adverse events and a 27% decrease risk of death when compared to non-Hispanic Whites (HR = 0.73; 95% CI: 0.59-0.90). CONCLUSIONS: Non-Hispanic Black women showed a decreased risk of death with the addition of bevacizumab and patients of Asian ancestry had a lower death rate than all other minority groups, but despite these clinically meaningful improvements there was no statistically significant difference in OS among the groups.

Correlation of imaging and plasma based biomarkers to predict response to bevacizumab in epithelial ovarian cancer (EOC).

PURPOSE: Increasing measures of adiposity have been correlated with poor oncologic outcomes and a lack of response to anti-angiogenic therapies. Limited data exists on the impact of subcutaneous fat density (SFD) and visceral fat density (VFD) on oncologic outcomes. This ancillary analysis of GOG-218, evaluates whether imaging markers of adiposity were predictive biomarkers for bevacizumab (bev) use in epithelial ovarian cancer (EOC). PATIENTS AND METHODS: There were 1249 patients (67%) from GOG-218 with imaging measurements. SFD and VFD were calculated utilizing Hounsfield units (HU). Proportional hazards models were used to assess the association between SFD and VFD with overall survival (OS). RESULTS: Increased SFD and VFD showed an increased HR for death (HR per 1-SD increase 1.12, 95% CI:1.05-1.19 p = 0.0009 and 1.13, 95% CI: 1.05-1.20 p = 0.0006 respectively). In the predictive analysis for response to bev, high VFD showed an increased hazard for death in the placebo group (HR per 1-SD increase 1.22, 95% CI: 1.09-1.37; p = 0.025). However, in the bev group there was no effect seen (HR per 1-SD increase: 1.01, 95% CI: 0.90-1.14) Median OS was 45 vs 47 months in the VFD low groups and 36 vs 42 months in the VFD high groups on placebo versus bev, respectively. CONCLUSION: High VFD and SFD have a negative prognostic impact on patients with EOC. High VFD appears to be a predictive marker of bev response and patients with high VFD may be more likely to benefit from initial treatment with bev.

Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer.

OBJECTIVE: Platinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Preclinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) are synergistic. CAPRI (NCT03462342) is an investigator-initiated study of olaparib plus ceralasertib in recurrent HGSOC. Herein, we present results from the platinum-resistant cohort. METHODS: A Simon 2-stage design was utilized. Platinum-resistant HGSOC patients received ceralasertib 160 mg orally daily, days 1-7 and olaparib 300 mg orally twice daily, days 1-28 of a 28-day cycle until toxicity or progression. Primary endpoints were toxicity and efficacy including objective response rate (ORR) by RECIST. Secondary endpoint was progression-free survival (PFS). The null hypothesis (≤5% ORR) would be rejected if there were ≥ 1 responses in 12 patients. RESULTS: Fourteen PARPi-naïve patients were evaluable for toxicity; 12 were evaluable for response. Three had BRCA1 mutations (1 germline, 2 somatic). Adverse events possibly related to treatment were primarily grade (G) 1/2. G3 toxicities included nausea (14.3%), fatigue (7.1%), anorexia (7.1%), and anemia (7.1%). No objective responses occurred. Best response was stable disease in 9 patients and progressive disease in three. Five patients had a ≥ 20% to <30% reduction in disease burden, including 3 with BRCA1 mutations. Three of 11 patients (27%; 2 with BRCA1 mutations) evaluable by Gynecologic Cancer Intergroup criteria had >50% CA-125 decline, including 2 with CA-125 normalization. Median PFS was 4.2 months overall (90% CI:3.5-8.2) and 8.2 months (3.6 months-not determined) for patients with BRCA1 mutations. CONCLUSIONS: Olaparib plus ceralasertib is well-tolerated. No objective responses occurred, though a signal of activity was seen particularly in disease associated with BRCA1. Further evaluation of this combination should include alternate dosing strategies in genomically-selected populations.

The "Far Left" of the Morphologic Spectrum of Ovarian High-grade Serous Carcinoma: Case Report of a Purely Noninvasive High-grade Serous Carcinoma Mimicking an Ovarian Serous Borderline Tumor.

High-grade serous carcinoma has a variety of different growth patterns, but is typically easily recognizable to pathologists and rarely confused with serous borderline tumors. We report a case of a 71-yr-old woman with a unilateral 5.1 cm ovarian cyst with small papillary projections on contrast-enhanced magnetic resonance imaging of the pelvis. Histologic examination showed a noninvasive papillary neoplasm with hierarchical branching and epithelial proliferation, and thus, at low magnification, bearing a striking resemblance to a serous borderline tumor. However, a more careful examination demonstrated high-grade cytologic features, nuclear pleomorphism, and abundant mitotic activity, suggestive of high-grade serous carcinoma. The morphology and immunohistochemical profile of this lesion is consistent with a rare, purely noninvasive growth pattern of high-grade serous carcinoma. This lesion represents the "far left" of the high-grade ovarian serous carcinoma morphologic spectrum and can mimic a serous borderline tumor.

Bevacizumab-associated thrombotic microangiopathy treated with eculizumab: A case series and systematic review of the literature.

BACKGROUND: Bevacizumab is a recombinant monoclonal antibody against the vascular endothelial growth factor A (VEGF-A) ligand that is used in the management of various solid malignancies. The adverse effect profiles of angiogenesis inhibitors, such as bevacizumab, have become increasingly well characterized and include renal manifestations such as hypertension, proteinuria, and thrombotic microangiopathy. Eculizumab inhibits terminal-complement activation and is used to treat atypical hemolytic uremic syndrome. There has been growing usage of eculizumab to treat bevacizumab-associated thrombotic microangiopathy. MATERIALS AND METHODS: We performed a systematic review of the literature to identify full-text articles that describe the use of eculizumab for bevacizumab-associated thrombotic microangiopathy. RESULTS: Our systematic review identified 522 unique articles of which 5 were included in the final review. 9 cases, including 2 new cases presented in this review, were identified in which eculizumab was used in the management of bevacizumab-associated thrombotic microangiopathy. Hematologic parameters and kidney function stabilized or improved in all cases, and the 2 patients who required renal replacement therapy were able to discontinue dialysis. CONCLUSIONS: Given the findings of this systematic review, the use of eculizumab in the treatment of bevacizumab-associated thrombotic microangiopathy warrants further study, particularly in severe cases.

Performance of lymphadenectomy for apparent early stage malignant ovarian germ cell tumors in the era of platinum-based chemotherapy.

OBJECTIVES: To investigate the patterns of use and impact of lymphadenectomy (LND) on overall survival (OS) of patients with apparent early stage malignant ovarian germ cell tumors (MOGCTs). METHODS: Patients with apparent stage I MOGCT diagnosed between 2004 and 2015 were drawn from the National Cancer Database. The performance of LND was assessed from the pathology report. OS was evaluated using Kaplan-Meier curves, and compared with the log-rank test. A multivariate Cox analysis was performed to control for confounders. RESULTS: A total of 2774 patients were identified; 1426 (51.4%) underwent LND. The median number of lymph nodes (LN) removed was 9 (range 1-81); 48.3% of patients had at least 10 lymph nodes removed. The rate of regional lymph node metastasis was 10.3% (147 patients). There was no difference in OS, between patients who did (n = 1287) and did not (n = 1210) undergo LND, p = 0.81; 5-yr OS rates were 96.5% and 97.6% respectively. After controlling for patient age, insurance status, histology, presence of medical comorbidities, and receipt of chemotherapy, the performance of LND was not associated with better survival (HR: 1.33, 95% CI: 0.82, 2.14). CONCLUSIONS: While LN metastasis is common in apparent early stage MOGCTs, the performance of LND was not associated with a survival benefit.

Radical hysterectomy is not associated with a survival benefit for patients with stage II endometrial carcinoma.

OBJECTIVE: To evaluate the role of radical hysterectomy in the management of patients with stage II endometrial carcinoma. MATERIALS: Patients diagnosed between 2004 and 2015, with stage II (based on the revised FIGO staging) endometrial carcinoma who had hysterectomy and regional lymph node surgery were identified in the National Cancer Database. Those who had radical or modified radical (RH), or total hysterectomy (TH) were selected. Overall survival (OS) was assessed with Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to evaluate survival after controlling for confounders. RESULTS: A total of 7552 patients who met the inclusion criteria were identified. Rate of RH was 10.5%. Those who underwent RH had longer hospital stay (median 3 vs 2 days, p < 0.001) and a higher 90-day (1.6% vs 0.8%, p = 0.05) mortality. There was no difference in OS between patients who had RH (n = 712) and SH (n = 5955) (p = 0.62); 5-year survival rates were 77.4% and 76.9%, respectively. After controlling for patient age (<65, ≥65 years), race (white, black, other/unknown), insurance status, presence of comorbidities, tumor size (<5, ≥5 cm, unknown), histology (endometrioid, non-endometrioid), performance of adequate lymphadenectomy, and receipt of adjuvant chemotherapy and radiation therapy, performance of radical hysterectomy was not associated with better survival (HR: 1.01, 95% CI: 0.85, 1.21). CONCLUSIONS: Radical hysterectomy was not associated with a survival benefit in a cohort of patients with stage II endometrial carcinoma.

Advanced stage primary mucinous ovarian carcinoma. Where do we stand ?

OBJECTIVE: To evaluate factors associated with survival of patients with advanced stage mucinous ovarian carcinoma (MOC) using a large multi-institutional database. METHODS: Patients diagnosed between 2004 and 2014 with advanced stage (III-IV) MOC were identified within the National Cancer Database. Those without a personal history of another primary tumor who received cancer-directed surgery with a curative intent were selected for further analysis. Overall survival (OS) was evaluated with Kaplan-Meier curves, and compared with the log-rank test. Multivariate Cox analysis was performed to identify independent predictors of survival. RESULTS: A total of 1509 patients with a median age of 59 years (IQR 20) met the inclusion criteria: stage III (n = 1045, 69.3%) and stage IV disease (n = 464, 30.7%). Patients who received chemotherapy (n = 1065, 70.6%) had better OS compared to those who did not (n = 385, 25.5%), (median OS 15.44 vs 5.06 months, p < 0.001). The type of reporting facility (p = 0.65) and the year of diagnosis (p = 0.27) were not associated with OS. Presence of residual disease was strongly associated with OS (p < 0.001). After controlling for confounders, the administration of chemotherapy (HR 0.63, 95% CI 0.55, 0.72) was associated with better survival. CONCLUSION: Advanced stage MOC has an extremely poor prognosis. Patients who received chemotherapy had a small improvement in survival. Every effort to achieve complete gross resection should be performed. Given no improvement in survival outcomes over time, there is an eminent need for novel treatment options.

Adjuvant chemotherapy is not associated with a survival benefit for patients with early stage mucinous ovarian carcinoma.

OBJECTIVE: Primary mucinous ovarian carcinoma (MOC) is a rare histologic subtype of ovarian cancer. The benefit of adjuvant chemotherapy for patients with MOC is unclear. PATIENTS AND METHODS: Patients diagnosed with stage I mucinous ovarian cancer (MOC) between 2004 and 2015 were identified from the U.S National Cancer Database. Those with a history of another primary tumor were excluded. Factors independently associated with the receipt of chemotherapy were identified using logistic regression. Impact of chemotherapy on overall survival (OS) for patients diagnosed between 2004 and 2014 was assessed using was Kaplan-Meier curves, and compared with the log-rank test. A multivariate Cox analysis was performed to control for confounders. RESULTS: We identified 4811 patients with a median age at diagnosis of 51 years (IQR: 21). Chemotherapy was administered to 1488 (30.9%) patients; 20.2% and 60.2% for those with stage IA/IB and IC respectively, p < 0.001. Stage IC, larger tumor size, and high tumor grade, were associated with the receipt of chemotherapy. There was no difference in OS between patients who did (n = 1322) and did not (n = 2920) receive chemotherapy, p = 0.17; 5-year OS rate was 86.8% vs 89.7%, respectively. No difference was noted following stratification by substage (p = 0.46 for IA/IB and p = 0.11 for IC). After controlling for substage, patient age, type of insurance, tumor grade, performance of lymphadenectomy and the presence of co-morbidities, the administration of chemotherapy was not associated with better survival (HR:1.18, 95% CI: 0.85, 1.64). CONCLUSIONS: In a large cohort of patients with stage I MOC, receiving chemotherapy was not associated with a survival benefit.