Leslie M. Randall

Bevacizumab toxicities and their management in ovarian cancer

OBJECTIVES The purpose of this review is to discuss the side effect profile of bevacizumab, to discuss proposed mechanisms of these toxicities, and to provide suggestions for management of adverse events. METHODS A search of MEDLINE and ASCO and SGO abstract databases of articles published between January 1970 and August 2009 addressing the toxicity of bevacizumab in solid tumors was conducted. Reporting was limited to best available evidence including any available phase III studies and ovarian cancer phase II studies. Original publications addressing underlying mechanisms of bevacizumab toxicities were included. RESULTS Extensive experience with bevacizumab has proven the agent to be generally well tolerated, with an adverse event profile distinct from traditional cytotoxic chemotherapy and likely peculiar to its novel mechanism of action. The most common bevacizumab-attributable adverse event, hypertension, can be medically-managed, but more serious adverse events such as bowel perforation require drug discontinuation. CONCLUSIONS Current best evidence supports the use of bevacizumab in selected patients, and safe administration of bevacizumab requires an understanding of the management of adverse events attributable to its use.

High-volume ovarian cancer care: Survival impact and disparities in access for advanced-stage disease ☆

OBJECTIVE To characterize the impact of hospital and physician ovarian cancer case volume on survival for advanced-stage disease and investigate socio-demographic variables associated with access to high-volume providers. METHODS Consecutive patients with stage IIIC/IV epithelial ovarian cancer (1/1/96-12/31/06) were identified from the California Cancer Registry. Disease-specific survival analysis was performed using Cox-proportional hazards model. Multivariate logistic regression analyses were used to evaluate for differences in access to high-volume hospitals (HVH) (≥20 cases/year), high-volume physicians (HVP) (≥10 cases/year), and cross-tabulations of high- or low-volume hospital (LVH) and physician (LVP) according to socio-demographic variables. RESULTS A total of 11,865 patients were identified. The median ovarian cancer-specific survival for all patients was 28.2 months, and on multivariate analysis the HVH/HVP provider combination (HR = 1.00) was associated with superior ovarian cancer-specific survival compared to LVH/LVP (HR = 1.31, 95%CI = 1.16-1.49). Overall, 2119 patients (17.9%) were cared for at HVHs, and 1791 patients (15.1%) were treated by HVPs. Only 4.3% of patients received care from HVH/HVP, while 53.1% of patients were treated by LVH/LVP. Both race and socio-demographic characteristics were independently associated with an increased likelihood of being cared for by the LVH/LVP combination and included: Hispanic race (OR = 1.72, 95%CI = 1.22-2.42), Asian/Pacific Islander race (OR = 1.57, 95%CI = 1.07-2.32), Medicaid insurance (OR = 2.51, 95%CI = 1.46-4.30), and low socioeconomic status (OR = 2.84, 95%CI = 1.90-4.23). CONCLUSIONS Among patients with advanced-stage ovarian cancer, the provider combination of HVH/HVP is an independent predictor of improved disease-specific survival. Access to high-volume ovarian cancer providers is limited, and barriers are more pronounced for patients with low socioeconomic status, Medicaid insurance, and racial minorities.

PREDICTIVE AND PROGNOSTIC ANGIOGENIC MARKERS IN A GYNECOLOGIC ONCOLOGY GROUP PHASE II TRIAL OF BEVACIZUMAB IN RECURRENT AND PERSISTENT OVARIAN OR PERITONEAL CANCER

OBJECTIVE Potential predictive/prognostic angiogenic markers were prospectively examined in a phase II trial of bevacizumab in epithelial ovarian cancer (EOC)/primary peritoneal cancer (PPC). METHODS Recurrent/persistent EOC/PPC patients were treated with bevacizumab (15 mg/kg IV q21days) until disease progression. Validated-immunohistochemistry (IHC) assays were performed on pre-cycle 1/4 tumor biopsies for CD31-microvessel density (MVD), VEGF-histoscore (HS), p53-HS, and TSP1 image analysis score (IA). Pre-cycle 1/4 serum and plasma VEGF were quantified using a validated-ELISA. RESULTS CD31-MVD and serum VEGF, evaluated pre-cycle 1 in 41/61 and 51/61 eligible patients, respectively, did not appear to be correlated. High CD31-MVD, categorized at the median, appeared to be associated with tumor response, a 13-month shorter median survival, and an increased risk of death (unadjusted hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.067-4.467). In addition, each standard deviation (SD) increase in CD31-MVD appeared to be associated with worse survival in unadjusted and adjusted analyses. IHC and plasma biomarkers did not change with bevacizumab treatment except for serum VEGF, which appeared to decrease during bevacizumab treatment. This decrease was not associated with response. High pre-cycle 1 serum VEGF, categorized at the median, was associated with 22-month shorter median survival and an increased risk of death (unadjusted HR = 2.7, 95% CI = 1.369-5.191). Categorized p53 appeared to be associated with unadjusted survival and each SD increase in TSP1-IA appeared to be associated with a decreased risk of progression in unadjusted and adjusted analyses. CONCLUSIONS Despite the limitations in sample size and exploratory nature of the study, angiogenic markers in tumor and serum may provide prognostic value in recurrent/persistent EOC/PPC, and are being prospectively evaluated in the GOG phase III trial of carboplatin, paclitaxel and bevacizumab/placebo in previously untreated EOC/PPC.

Prognostic relevance of carbonic anhydrase-IX in high-risk, early-stage cervical cancer: a Gynecologic Oncology Group study.

OBJECTIVES This study aimed to determine whether carbonic anhydrase-IX (CA-IX) was associated with progression-free survival (PFS) and overall survival (OS) in women with high-risk, early-stage cervical cancer treated with adjuvant pelvic radiotherapy with or without radiosensitizing chemotherapy. METHODS CA-IX expression was detected using an immunohistochemistry assay and categorized as low when <or=80% of tumor cells exhibited CA-IX staining and high when >80% tumor cells display CA-IX staining. Associations between CA-IX expression and clinical characteristics, angiogenesis marker expression, and clinical outcome were evaluated. RESULTS High CA-IX expression was observed in 35/166 (21.1%) of cases. CA-IX expression was not associated with age, race, stage, cell type, grade, positive margins, parametrial extensions, positive lymph nodes, or lymphovascular space invasion but was associated with tumor size categorized as <2 , 2-2.9 , or >or=3 cm (high expression: 4.7% vs. 23.2% vs. 32.5%, P=0.003) and cervical invasion confined to the inner two-thirds compared with the outer third of the cervix (high expression: 6.1% vs. 23.7%, P=0.028). CA-IX expression was not associated with immunohistochemical expression of p53, CD31, CD105, thrombospondin-1, or vascular endothelial growth factor-A. Women with high versus low CA-IX expression had similar PFS (P=0.053) and significantly worse OS (P=0.044). After adjusting for prognostic clinical covariates, high CA-IX expression was an independent prognostic factor for PFS (hazard ratio [HR]=2.12; 95% confidence interval [CI]=1.13-3.95; P=0.019) and OS (HR=2.41; 95% CI=1.24-4.68; P=0.009). CONCLUSIONS Tumor hypoxia measured by immunohistochemical expression of CA-IX is an independent prognostic factor for both PFS and OS in high-risk, early-stage cervical cancer.

Inhibition of enhancer of zeste homolog 2 (EZH2) expression is associated with decreased tumor cell proliferation, migration, and invasion in endometrial cancer cell lines.

Objective To investigate the impact of enhancer of zeste homolog 2 (EZH2) expression on endometrial cancer cell line behavior. Materials and Methods Enhancer of zeste homolog 2 expression levels were compared between the nonmalignant endometrial cell line T-HESC and 3 endometrial cancer cell lines, ECC-1, RL95-2, and HEC1-A. Stable EZH2 knockdown cell lines were created, and the impact on cellular proliferation, migration, and invasion were determined. Fluorescent activated cell sorting was used to examine effects of EZH2 silencing on cell cycle progression. Enhancer of zeste homolog 2 expression in endometrial cancer tissue specimens was examined using immunohistochemistry. Comparison of differences between control and short-hairpin EZH2 cell lines was performed using the Student t test and the Fischer exact test. Results Enhancer of zeste homolog 2 protein expression was increased in all 3 cancer cell lines and human endometrial cancer tissue specimens relative to control. RNA interference of EZH2 expression in ECC-1, RL95-2, and HEC1-A significantly decreased cell proliferation, migration, and invasion. Down-regulation of EZH2 expression resulted in a significant increase in the proportion of cells arrested in the G2/M phase. RNA interference of EZH2 expression was associated with an increase in the expression of Wnt pathway inhibitors sFRP1 and DKK3 and a concomitant decrease in &bgr;-catenin. Enhancer of zeste homolog 2 expression in human tissue samples was significantly associated with increased stage, grade, depth of invasion, and nodal metastasis. Conclusions Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation, migration, and invasion in 3 endometrial cancer cell lines as well as with increased stage, grade, depth of invasion, and nodal metastasis in human cancer tissue specimens. Further investigation into this potential therapeutic target is warranted.

Bevacizumab in the treatment of ovarian cancer.

Despite advances in surgical cytoreduction and cytotoxic chemotherapy, ovarian cancer continues to be the leading cause of death in women with gynecologic malignancy. Our understanding of the treatment of ovarian cancer was revolutionized with the discovery of platinum- and taxane-based adjuvant chemotherapy regimens. Since that time however, overall survival has been stable. Given the above, an emphasis has been placed on exploring alternative therapeutics. Recent research efforts have improved our understanding of the molecular biology of ovarian cancer and novel targeted treatment strategies have emerged. The most studied of these agents has been the monoclonal anti-vascular endothelial growth factor antibody bevacizumab. The purpose of this review is to discuss management issues related to the treatment of ovarian cancer, with a focus on the utilization of bevacizumab, summarizing applicable clinical trials, its potential benefits, and reported adverse events.

Flavokawain B, a novel, naturally occurring chalcone, exhibits robust apoptotic effects and induces G2/M arrest of a uterine leiomyosarcoma cell line

Aim:  To examine the effects of flavokawain B (FKB), a novel kava chalcone, on the growth of uterine leiomyosarcoma (LMS) cells and investigated its utility in the treatment of uterine LMS.

Differentiating squamous cell carcinoma of the cervix and epithelioid trophoblastic tumor.

Background: Epithelioid trophoblastic tumor (ETT) is a recently described subtype of gestational trophoblastic neoplasia (GTN). Its diagnosis requires a high level of suspicion because it is often mistaken for more common cervical or uterine corpus epithelial neoplasms. Case: This is a 39-year-old woman who presented with a cervical mass and positive human chorionic gonadotropin and was diagnosed with both locally advanced squamous cell cervical carcinoma and nonmetastatic GTN. She was treated unsuccessfully with concurrent intravenous cisplatin plus pelvic radiation and single-agent intravenous methotrexate. A retrospective review of the cervical biopsy using immunohistochemistry as well as genotyping of the tumor changed the original diagnosis to ETT. It is known that ETT is relatively unresponsive to chemotherapy compared with most other types of GTN; therefore, surgery would have been the optimal treatment. She died despite multiple salvage chemotherapies. Conclusions: Malignant GTN is one of the most curable gynecologic malignancies; however, its correct diagnosis is critical for the appropriate treatment. It can be easily misdiagnosed as a carcinoma because of their morphologic similarity. Genetic fingerprinting and immunohistochemistry are potentially valuable tools to confirm the diagnosis of ETT.

Uterine leiomyomatosis with intracaval and intracardiac extension.

► Intravenous leiomyomatosis is histologically benign, but biologically aggressive. ► No diagnostic tools reliably distinguish it from leiomyosarcoma prior to surgery. ► Complete resection is curative, but antiestrogens can stabilize disease.

Racial disparities and patterns of ovarian cancer surgical care in California

OBJECTIVE To investigate disparities in the frequency of ovarian cancer-related surgical procedures and access to high-volume surgical providers among women undergoing initial surgery for ovarian cancer according to race. METHODS The California Office of Statewide Health Planning and Development database was accessed for women undergoing a surgical procedure that included oophorectomy for a malignant ovarian neoplasm between 1/1/06 and 12/31/10. Multivariate logistic regression analyses were used to evaluate differences in the odds of selected surgical procedures and access to high-volume centers (hospitals ≥ 20 cases/year) according to racial classification. RESULTS A total of 7933 patients were identified: White = 5095 (64.2%), Black = 290 (3.7%), Hispanic/Latino = 1400 (17.7%), Asian/Pacific Islander = 836 (10.5%) and other = 312 (3.9%). White patients served as reference for all comparisons. All minority groups were significantly younger (Black mean age 57.7 years, Hispanic 53.2 years, Asian 54.5 years vs. 61.1 years, p < 0.01). Hispanic patients had lower odds of obtaining care at a high-volume center (adjusted OR (adj. OR) = 0.72, 95% CI = 0.64-0.82, p < 0.01) and a lower likelihood of lymphadenectomy (adj. OR = 0.80, 95% CI=0.70-0.91, p<0.01), bowel resection (adj. OR = 0.80, 95% CI = 0.71-0.91, p < 0.01), and peritoneal biopsy/omentectomy (adj. OR = 0.69, 95% CI = 0.58-0.82, p<0.01). Black racial classification was associated with a lower likelihood of lymphadenectomy (adj. OR = 0.76, 95% CI = 0.59-0.97, p = 0.03). CONCLUSIONS Among women undergoing initial surgery for ovarian cancer, Hispanic patients are significantly less likely to be operated on at a high-volume center, and both Black and Hispanic patients are significantly less likely to undergo important ovarian cancer-specific surgical procedures compared to White patients.