Search

ObjectivesIn a prospective study of platinum-resistant ovarian cancer patients, we examined whether the Disease-related Symptoms-Physical (DRS--P) scale of the NCCN/FACT-Ovarian Cancer Symptom Index-18 (NFOSI-18) is responsive to clinical change in patients estimated by their provider to survive at least six months.MethodsThe NFOSI-18, and other FACT measures, was collected at study entry and 3 and 6 months post-enrollment. Measures were compared for those who died or dropped off study prior to 3 months or prior to 6 months (assumed as health deterioration over time), or those who stayed on study through 6 months (presumed as stable disease over time). Statistical analyses included a fitted linear mixed model for estimating the group differences over time, Cox regression to assess the probability of survival with patient-reported outcomes, and effect size.ResultsDRS-P scores of patients who completed only one assessment were significantly lower compared to patients who were able to complete two assessments [5.9 points lower (2.0-9.8); p

Abstract Background Malignant ascites often develops in advanced stages of ovarian carcinoma, consisting of single and aggregated tumor cells, or spheroids. Spheroids have commonly been used as tumor models to study drug efficacy, and have shown resistance to some chemotherapies and radiation. However, little is known about the adhesive or invasive capabilities of spheroids, and whether this particular cellular component of the ascites can contribute to dissemination of ovarian cancer. Here, we examined the invasive ability of ascites spheroids recovered from seven ovarian carcinoma patients and one primary peritoneal carcinoma (PPC) patient. Methods Ascites spheroids were isolated from patients, purified, and immunohistochemical analyses were performed by a pathologist to confirm diagnosis. In vitro assays were designed to quantify spheroid disaggregation on a variety of extracellular matrices and dissemination on and invasion into normal human mesothelial cell monolayers. Cell proliferation and viability were determined in each assay, and statistical significance demonstrated by the student's t-test. Results Spheroids from all of the patients' ascites samples disaggregated on extracellular matrix components, with the PPC spheroids capable of complete disaggregation on type I collagen. Additionally, all of the ascites spheroid samples adhered to and disaggregated on live human mesothelial cell monolayers, typically without invading them. However, the PPC ascites spheroids and one ovarian carcinoma ascites spheroid sample occasionally formed invasive foci in the mesothelial cell monolayers, suggestive of a more invasive phenotype. Conclusion We present here in vitro assays using ascites spheroids that imitate the spread of ovarian cancer in vivo. Our results suggest that systematic studies of the ascites cellular content are necessary to understand the biology of ovarian carcinoma.

PURPOSE: GOG-0218, a double-blind placebo-controlled phase III trial, compared carboplatin and paclitaxel with placebo, bevacizumab followed by placebo, or bevacizumab followed by bevacizumab in advanced epithelial ovarian cancer (EOC). Results demonstrated significantly improved progression-free survival (PFS), but no overall survival (OS) benefit with bevacizumab. Blood samples were collected for biomarker analyses. EXPERIMENTAL DESIGN: Plasma samples were analyzed via multiplex ELISA technology for seven prespecified biomarkers [IL6, Ang-2, osteopontin (OPN), stromal cell-derived factor-1 (SDF-1), VEGF-D, IL6 receptor (IL6R), and GP130]. The predictive value of each biomarker with respect to PFS and OS was assessed using a protein marker by treatment interaction term within the framework of a Cox proportional hazards model. Prognostic markers were identified using Cox models adjusted for baseline covariates. RESULTS: Baseline samples were available from 751 patients. According to our prespecified analysis plan, IL6 was predictive of a therapeutic advantage with bevacizumab for PFS (P = 0.007) and OS (P = 0.003). IL6 and OPN were found to be negative prognostic markers for both PFS and OS (P < 0.001). Patients with high median IL6 levels (dichotomized at the median) treated with bevacizumab had longer PFS (14.2 vs. 8.7 months) and OS (39.6 vs. 33.1 months) compared with placebo. CONCLUSIONS: The inflammatory cytokine IL6 may be predictive of therapeutic benefit from bevacizumab when combined with carboplatin and paclitaxel. Aligning with results observed in patients with renal cancer treated with antiangiogenic therapies, it appears plasma IL6 may also define those patients with EOC more or less likely to benefit from the addition of bevacizumab to standard chemotherapy.

PurposeGOG-0218, a double-blind placebo-controlled phase III trial, compared carboplatin and paclitaxel with placebo, bevacizumab followed by placebo, or bevacizumab followed by bevacizumab in advanced epithelial ovarian cancer (EOC). Results demonstrated significantly improved progression-free survival (PFS), but no overall survival (OS) benefit with bevacizumab. Blood samples were collected for biomarker analyses.Experimental designPlasma samples were analyzed via multiplex ELISA technology for seven prespecified biomarkers [IL6, Ang-2, osteopontin (OPN), stromal cell-derived factor-1 (SDF-1), VEGF-D, IL6 receptor (IL6R), and GP130]. The predictive value of each biomarker with respect to PFS and OS was assessed using a protein marker by treatment interaction term within the framework of a Cox proportional hazards model. Prognostic markers were identified using Cox models adjusted for baseline covariates.ResultsBaseline samples were available from 751 patients. According to our prespecified analysis plan, IL6 was predictive of a therapeutic advantage with bevacizumab for PFS (P = 0.007) and OS (P = 0.003). IL6 and OPN were found to be negative prognostic markers for both PFS and OS (P < 0.001). Patients with high median IL6 levels (dichotomized at the median) treated with bevacizumab had longer PFS (14.2 vs. 8.7 months) and OS (39.6 vs. 33.1 months) compared with placebo.ConclusionsThe inflammatory cytokine IL6 may be predictive of therapeutic benefit from bevacizumab when combined with carboplatin and paclitaxel. Aligning with results observed in patients with renal cancer treated with antiangiogenic therapies, it appears plasma IL6 may also define those patients with EOC more or less likely to benefit from the addition of bevacizumab to standard chemotherapy.

PurposeWe report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma.MethodsA total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry.ResultsMedian follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non-BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity.ConclusionNo survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

ObjectivesThe goals of treating recurrent platinum-resistant ovarian cancer are palliative, aimed at reducing symptoms and improving progression free survival. A prospective trial was conducted to determine the prevalence and severity of symptoms, and associated care needs.MethodsEligible women included those with persistent or recurrent platinum-resistant ovarian cancer with an estimated life expectancy of at least 6 months. The Needs at the End-of-Life Screening Tool (NEST), FACIT-Fatigue (FACIT-F), NCCN-FACT Ovarian Symptom Index [NFOSI-18]; Disease Related Symptoms (DRS), Treatment Side Effects (TSE), and Function/Well Being (F/WB) were collected at study entry, 3 and 6 months.ResultsWe enrolled 102 evaluable patients. Initiation of Do Not Resuscitate (DNR) discussions increased over time from 28% at study entry to 37% at 6 months. At study entry, the most common disease-related symptoms were fatigue (92%), worry (89%), and trouble sleeping (76%); 73% reported being "bothered by treatment side effects", which included nausea (41%) and hair loss (51%) neither of which changed over time. The most common NEST unmet needs were in the symptom dimension. The social dimension was associated with F/WB (p = 0.002) and FACIT-F (p = 0.006); symptoms were associated with DRS (p = 0.04), TSE (p = 0.03), and FACIT-F (p = 0.04); existential was not associated with any of the patient-reported symptoms; therapeutic was associated with F/WB (p = 0.02).ConclusionsIn patients nearing the end of life, there are significant associations between disease and treatment related symptoms and unmet patient needs, which do not change substantially over time. Careful exploration of specific end-of-life care needs can improve patient-centered care and QOL.