Deanna Teoh

Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers

OBJECTIVE To compare the clinico-pathologic characteristics and survival of women with clear cell versus other epithelial ovarian cancers. METHODS Data were obtained from the Surveillance, Epidemiology and End Results Program between 1988 and 2001 and analyzed using Kaplan-Meier and Cox proportional hazards models. RESULTS Of 28,082 women with epithelial ovarian cancer, 1411 (5%) had clear cell, 13,835 (49.3%) papillary serous, 3655 (13%) endometrioid, 2711 (9.7%) mucinous, and 6470 (23%) had unspecified histologies. The median age of overall patients was 64 years; with clear cell patients presenting at younger age (55 years). The proportion of clear cell histology was significantly higher in Asians versus Whites, Blacks, and others (11.1% versus 4.8%, 3.1%, and 5.5%; p<0.001). Clear cell carcinoma is more likely to be diagnosed at early-stage (67.3%) compared to 19.2% in serous, 61.6% endometrioid, and 61.3% in mucinous carcinomas (p<0.005). Retroperitoneal lymph node metastases were found in 13.6% of serous carcinomas, 7.9% clear cell, 7.3% endometrioid, and 3.8% of mucinous (p<0.001). Adjusted for stage, the 5-year disease-specific survival of patients with clear cell carcinoma is worse compared to serous: 85.3% vs. 86.4% for stage I, 60.3% vs. 66.4% stage II, 31.5% vs. 35.0% stage III, and 17.5% vs. 22.2% for stage IV, respectively (p<0.001). On multivariate analysis, age, stage, grade, histology, and surgical treatment were independent predictors of disease-specific survival. CONCLUSIONS Our data suggest that women with clear cell ovarian cancer present at a younger age, are more likely to be Asian, and have a poorer prognosis compared to serous cancers.

Antiangiogenic agents in combination with chemotherapy for the treatment of epithelial ovarian cancer.

Objective The purpose of this review was to provide an overview of angiogenesis, including the rationale for targeting angiogenesis as a treatment strategy for epithelial ovarian cancer (EOC) and to discuss available clinical trial data with antiangiogenic agents in EOC, with a focus on combinations with chemotherapy. Methods This was a literature review of clinical studies evaluating select antiangiogenic agents in combination with traditional cytotoxic chemotherapy for the treatment of EOC. Results Several therapies that target angiogenesis-specific pathways are undergoing clinical development for EOC. Although some of these agents have demonstrated single-agent activity for EOC, there is considerable interest in combining this treatment strategy with chemotherapy in an effort to potentially improve treatment benefits in this patient population. Bevacizumab, an anti–vascular endothelial growth factor (VEGF) monoclonal antibody, is the most studied antiangiogenic agent in EOC and has shown efficacy as monotherapy and combined with chemotherapy in both the relapsed/recurrent and first-line settings. However, results from recent phase 3 trials raise questions regarding patient selection and optimal dose, schedule, and duration of bevacizumab therapy. Other agents in various phases of testing include aflibercept (VEGF Trap), a fusion protein that binds all isoforms of VEGF; multitargeted antiangiogenic tyrosine kinase inhibitors (eg, BIBF 1120, cediranib, pazopanib, sorafenib); and AMG 386, a selective angiopoietin inhibitor. Toxicities associated with VEGF inhibition are also a concern with antiangiogenic therapy, including hypertension, proteinuria, thromboses, and gastrointestinal perforation. Conclusions Results from recently completed and ongoing clinical trials combining antiangiogenic agents with chemotherapy are awaited in hopes of expanding therapeutic options for patients with EOC.

Antiangiogenic therapies in epithelial ovarian cancer.

BACKGROUND Angiogenesis is a critical component of tumor development and proliferation, and increased angiogenesis has been associated with a worse clinical outcome in a number of solid tumors, including ovarian cancer. Therefore, agents that target the angiogenic process are of considerable interest in the treatment of ovarian cancer. METHODS Studies evaluating the efficacy of antiangiogenic agents in ovarian cancer are reported. Antiangiogenic agents examined include vascular endothelial growth factor (VEGF) pathway inhibitors, including monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and a soluble receptor decoy, as well as inhibitors of other angiogenic factors and vascular disrupting agents. RESULTS The VEGF inhibitor bevacizumab has been shown to have efficacy in ovarian cancer in phase II trials and a progression-free survival advantage in one phase III trial. TKIs block the VEGF receptors and secondary angiogenic pathways and have shown activity in phase I and II trials. Alternative angiogenesis inhibitors include EphA2 inhibitors and a selective angiopoietin 1/2-neutralizing peptibody. Another strategy is to destroy the existing tumor vasculature, and a number of vascular disrupting agents are being studied in preclinical and phase I trials. Antiangiogenic agents have a unique side effect profile, likely due to inhibition of normal physiologic angiogenesis. CONCLUSIONS Phase II and early phase III trials have demonstrated that antiangiogenic therapies have significant activity in ovarian cancer. The results of phase III trials in the front-line and recurrent settings will determine the extent of clinical benefit of antiangiogenic therapies in combination with chemotherapy. Antiangiogenic agents have a distinct side effect profile, and further studies are necessary to evaluate how to minimize the incidence of these events and to identify women most likely to benefit from these therapies.

Survival after recurrence in early-stage high-risk epithelial ovarian cancer: A Gynecologic Oncology Group study

OBJECTIVE This study aimed to evaluate the clinical outcome of recurrent early-stage high-risk epithelial ovarian cancer patients. METHODS Demographic and clinicopathological data were collected from women enrolled in GOG 157 who underwent surgical staging and had recurrent disease. Survival probability was estimated using Kaplan-Meier method, and hazard ratio of death was analyzed using Cox regression model. RESULTS Of 74 women with recurrent early-stage high-risk ovarian cancer, the median age at recurrence was 63 years; 93% were White, 2.7% were Black, 2.7% were Asian, and 1.4% were Others. Fifty-eight percent had stage I, and the remainder had stage II disease. Clear cell, serous, endometrioid, mucinous, and other tumors consisted of 28.4%, 25.7%, 24.3%, 16.2%, and 5.4% of patients, respectively; in addition, 36.5% had ascites, 33.8% had positive cytology, and 43.2% had ruptured tumors. Fifty-eight percent underwent three cycles, and 42% had six cycles of adjuvant chemotherapy with paclitaxel and carboplatin. Recurrence was diagnosed clinically in 46% and radiographically in 54% of women. The median time from completion of primary chemotherapy to recurrence (treatment-free interval, TFI) was 21 months. Overall, median survival after recurrence was 24 months. Patients with longer (>24 months) TFI had a higher median survival after subsequent treatment at 35 months compared to only 10 months in those who recurred <or=24 months (p=0.003). CONCLUSIONS Although patients with primary early-stage high-risk ovarian cancer have an overall favorable prognosis, survival after recurrence is poor and comparable to those with recurrent advanced-stage disease. Novel therapeutic modalities are warranted in these high-risk patients.

Adherence to the 2012 national cervical cancer screening guidelines: a pilot study

OBJECTIVE The goal of this pilot study was to evaluate adherence to the 2012 cervical cancer screening guidelines among health care providers in a large health maintenance organization. STUDY DESIGN A cross-sectional survey evaluating knowledge, reported practices, and views of the 2012 cervical cancer screening guidelines was distributed to 325 health care providers within HealthPartners. The survey was divided into 3 sections: (1) provider demographics; (2) knowledge of the 2012 age-specific cancer screening guidelines; and (3) provider practice. Comparisons based on appropriate knowledge and practice of the guidelines were made using Fisher exact tests. RESULTS The response rate was 42%. Of 124 respondents, 15 (12.1%) reported they were not aware of the 2012 guideline changes. Only 7 (5.7%) respondents answered all the knowledge questions correctly. A majority of respondents reported correct screening practices in the 21-29 year patient age group (65.8%) and in the >65 year patient age group (74.3%). Correct screening intervals in the 30-65 year patient age group varied by modality, with 89.3% correctly screening every 3 years with Pap smear alone, but only 57.4% correctly screening every 5 years with Pap smear + human papillomavirus cotesting. The most frequently cited reasons for not adhering were lack of knowledge of the guidelines and patient demand for a different screening interval. CONCLUSION Adherence to the 2012 cervical cancer screening guidelines is poor due, in part, to a lack of knowledge of the guidelines. Efforts should focus on improved provider and patient education, and methods that facilitate adherence to the guidelines such as electronic health record order sets.

Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells

In this study, we demonstrated that hypoxic conditions stimulated an increase in tunneling nanotube (TNT) formation in chemoresistant ovarian cancer cells (SKOV3, C200). We found that suppressing the mTOR pathway using either everolimus or metformin led to suppression of TNT formation in vitro, verifying TNTs as a potential target for cancer-directed therapy. Additionally, TNT formation was detected in co-cultures including between platinum-resistant SKOV3 cells, between SKOV3 cells and platinum-chemosensitive A2780 cells, and between SKOV3 cells cultured with benign ovarian epithelial (IOSE) cells; these findings indicate that TNTs are novel conduits for malignant cell interactions and tumor cell interactions with other cells in the microenvironment. When chemoresistant C200 and parent chemosensitive A2780 cells were co-cultured, chemoresistant cells displayed a higher likelihood of TNT formation to each other than to chemosensitive malignant or benign epithelial cells. Hypoxia-induced TNT formation represents a potential mechanism for intercellular communication in ovarian cancer and other forms of invasive refractory cancers.

Evaluation of the performance of the ACS NSQIP surgical risk calculator in gynecologic oncology patients undergoing laparotomy

OBJECTIVE The objective of this study was to evaluate the ability of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) surgical risk calculator to predict complications in gynecologic oncology patients undergoing laparotomy. METHODS A chart review of patients who underwent laparotomy on the gynecologic oncology service at a single academic hospital from January 2009 to December 2013 was performed. Preoperative variables were abstracted and NSQIP surgical risk scores were calculated. The risk of any complication, serious complication, death, urinary tract infection, venous thromboembolism, cardiac event, renal complication, pneumonia and surgical site infection were correlated with actual patient outcomes using logistic regression. The c-statistic and Brier score were used to calculate the prediction capability of the risk calculator. RESULTS Of the 1094 patients reviewed, the majority were <65years old (70.9%), independent (95.2%), ASA class 1-2 (67.3%), and overweight or obese (76.1%). Higher calculated risk scores were associated with an increased risk of the actual complication occurring for all events (p<0.05). The calculator performed best for predicting death (c-statistic=0.851, Brier=0.008), renal failure (c-statistic=0.752, Brier=0.015) and cardiac complications (c-statistic=0.708, Brier=0.011). The calculator did not accurately predict most complications. CONCLUSIONS The NSQIP surgical risk calculator adequately predicts specific serious complications, such as postoperative death and cardiac complications. However, the overall performance of the calculator was worse for gynecologic oncology patients than reported in general surgery patients. A tailored prediction model may be needed for this patient population.

Dasatinib (BMS-35482) has synergistic activity with paclitaxel and carboplatin in ovarian cancer cells

PURPOSE To explore the activity of dasatinib alone and in combination with paclitaxel and carboplatin in ovarian cancer cells and to determine if dasatinib activity can be predicted based on evaluation of the SRC pathway. EXPERIMENTAL DESIGN Microarray analysis was performed for IGROV1, OVCAR3, A2780 and SKOV3 ovarian cancer cells and the status of the genomic SRC signature pathway was determined. Cells were treated with carboplatin, paclitaxel and dasatinib individually and in combination. Pre- and post-treatment phospho-SRC (pSRC) and SRC protein expression was determined. Dose-response curves were constructed, and drug interaction was assessed by the Combination Index (CI) method. RESULTS SRC protein expression levels reflected the SRC pathway genomic signature in the cell lines with the lowest (SKOV3) and highest (IGROV1) pathway expression, but not in those with intermediate expression (OVCAR3, A2780). Dasatinib treatment caused loss of pSRC in all cell lines, with 50% growth inhibition for IGROV1 at 70 nM, OVCAR3 at 34 nM, A2780 at 4.1 μM and SKOV3 at 530 nM. Dasatinib combined with cytotoxics yielded a synergistic effect (CI=0.46 to 0.79) in all cell lines except SKOV3. CONCLUSION Dasatinib in combination with standard chemotherapeutic agents appears to interact in a synergistic manner in some ovarian cancer cell lines. Further research is needed to evaluate tumor cell characteristics which predict response to dasatinib.

The effect of anesthesia choice on post-operative outcomes in women undergoing exploratory laparotomy for a suspected gynecologic malignancy

OBJECTIVE To determine how anesthesia choice in women undergoing laparotomy for gynecologic malignancy affects pain control and narcotic use. METHODS This is a retrospective study of women who underwent laparotomy for suspected gynecologic malignancy from May 2012 to January 2013. Patients were categorized into one of three groups: 1) patient controlled analgesia (PCA); 2) PCA+transversus abdominis plane block (TAP); and 3) patient-controlled epidural analgesia (PCEA). Mean narcotic use and patient reported pain scores were compared. RESULTS The analysis includes 112 women (44 PCA, 30 TAP, 38 PCEA). Intraoperative factors were not different between groups with the exception of a significant difference in the rate of intra-operative complications (p=0.020), with lower rates in the PCEA group. The groups differed in intravenous narcotic use in each of the first three postoperative days (day 0: p=0.014; day 1: p<0.0001; day 2: p=0.048), with patients in the TAP group using the least on day 0 and those in the PCEA group using less on postoperative days 1 and 2. In addition, the PCEA group reported lower pain scores on postoperative days 1 and 2 (day 1: p=0.046; day 2: p=0.008). CONCLUSIONS The use of patient controlled epidural anesthesia after laparotomy for gynecologic malignancy is associated with decreased IV and PO narcotic use and improved pain control without increasing complications or length of hospital stay. Further investigation with prospective randomized trials is warranted to elucidate the optimal post-operative pain management technique.

Cost comparison of strategies for the management of venous thromboembolic event risk following laparotomy for ovarian cancer

OBJECTIVE To evaluate the costs and effectiveness of thromboprophylaxis strategies following laparotomy for ovarian cancer. METHODS We constructed a decision model to evaluate six strategies for management of postoperative venous thromboembolism (VTE) risk: (1) no thromboprophylaxis; (2) inpatient sequential compression device (SCD); (3) inpatient unfractionated heparin (UFH) 5000 units TID; (4) inpatient low molecular weight heparin (LMWH) 40 mg daily; (5) UFH 5000 units TID×1 month; (6) LMWH 40 mg daily×1 month. Rates of VTE, heparin-induced thrombocytopenia, and significant bleeding for each strategy were obtained from published literature. Costs were based on institutional charges or obtained from the Agency for Healthcare Research and Quality Nationwide Inpatient Sample database for 2008 and average wholesale pricing. Sensitivity analyses were performed to account for uncertainty in estimates. RESULTS In the base case, UFH×1 month was the least expensive (mean cost