Standardized Surgical Video Curriculum for Teaching Residents Principles of Abdominal Hysterectomy.

OBJECTIVES: To evaluate whether an institutionally created video-based educational module will improve obstetrics and gynecology residents' understanding of surgical anatomy and principles for performing abdominal hysterectomy. Secondary aims included evaluating the trainees' confidence levels and perceptions before and after the educational experience and ultimately implementing the module into the program curriculum, if successful. METHODS: In this prospective study, postgraduate obstetrics and gynecology resident physicians (n = 27) at the McGaw Medical Center of Northwestern University were assigned to watch an institutionally created video-based educational module on abdominal hysterectomy before the start of their gynecologic oncology rotation. A knowledge assessment and a postmodule survey were given to participants immediately following the module and repeated at the end of the 4-week rotation. RESULTS: Participants reported a median rating of 4 (n = 21, interquartile range 4-4) on a 5-point Likert scale when asked to rate the quality of the module. The module also was rated as equally effective both immediately after watching the module and after completing their gynecologic oncology rotation (median 4, interquartile range 3-4 at both times; p = 0.299, Wilcoxon signed rank test). Overall trends revealed that the video module had a greater impact on knowledge of surgical anatomy than on self-reported surgical skills and that postgraduate year 2 and postgraduate year 3 residents benefited more from the intervention. CONCLUSIONS: A video module can be a high-quality and effective educational tool for teaching the surgical principles, anatomy, and steps to perform abdominal hysterectomy to obstetrics and gynecology residents.

Phase I trial of selenium plus chemotherapy in gynecologic cancers.

PURPOSE: Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium. METHODS: Chemo-naïve patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. RESULTS: Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 µg to 5000 µg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors. CONCLUSION: Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 µg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.

Targeting the Microenvironment in High Grade Serous Ovarian Cancer.

Cancer⁻stroma interactions play a key role in cancer progression and response to standard chemotherapy. Here, we provide a summary of the mechanisms by which the major cellular components of the ovarian cancer (OC) tumor microenvironment (TME) including cancer-associated fibroblasts (CAFs), myeloid, immune, endothelial, and mesothelial cells potentiate cancer progression. High-grade serous ovarian cancer (HGSOC) is characterized by a pro-inflammatory and angiogenic signature. This profile is correlated with clinical outcomes and can be a target for therapy. Accumulation of malignant ascites in the peritoneal cavity allows for secreted factors to fuel paracrine and autocrine circuits that augment cancer cell proliferation and invasiveness. Adhesion of cancer cells to the mesothelial matrix promotes peritoneal tumor dissemination and represents another attractive target to prevent metastasis. The immunosuppressed tumor milieu of HGSOC is permissive for tumor growth and can be modulated therapeutically. Results of emerging preclinical and clinical trials testing TME-modulating therapeutics for the treatment of OC are highlighted.

The Hispanic Paradox in endometrial cancer: A National Cancer Database study.

OBJECTIVE: To compare the overall survival of non-Hispanic white and Hispanic women with endometrial cancer. METHODS: We performed an observational retrospective cohort study of Hispanic and non-Hispanic women with endometrial cancer from the 2004-2014 National Cancer Database. Baseline characteristics were compared with the Chi-squared test for categorical variables or the Mann-Whitney U test for ordinal or continuous variables. The Kaplan-Meier method was used to estimate unadjusted survival times, which were compared with the log-rank test. Missing data was imputed using multiple imputation with chained equations. A multivariable parametric accelerated failure time model for survival was used. Sensitivity analyses were performed using matched cohort analyses of the overall cohort, and of subgroups based on stage or type. RESULTS: 112,574 non-Hispanic and 6313 Hispanic women met inclusion criteria. Five-year survival was slightly higher for Hispanic women (83.1% (82.1-84.3%) versus 81.4% (81.2-81.7%), P=0.002). Hispanic women were younger, treated at lower volume hospitals, and more often diagnosed with a type II histology and stage II-IV disease compared to non-Hispanic women (all P<0.001). With multivariable adjustment for measured confounders, Hispanic women lived 8% longer than non-Hispanic women (time-ratio (95% CI) 1.08 (1.02-1.14), P=0.01). When bias-reducing matched cohort analyses were used for sensitivity analyses, Hispanic women did not have significantly different survival than non-Hispanic women. CONCLUSION: Hispanic ethnicity was not associated with a clinically meaningful difference in survival among women with endometrial cancer.

Cancer-testis antigen expression is shared between epithelial ovarian cancer tumors.

OBJECTIVES: Cancer-testis (CT) antigens have been proposed as potential targets for cancer immunotherapy. Our objective was to evaluate the expression of a panel of CT antigens in epithelial ovarian cancer (EOC) tumor specimens, and to determine if antigen sharing occurs between tumors. METHODS: RNA was isolated from EOC tumor specimens, EOC cell lines and benign ovarian tissue specimens. Real time-PCR analysis was performed to determine the expression level of 20 CT antigens. RESULTS: A total of 62 EOC specimens, 8 ovarian cancer cell lines and 3 benign ovarian tissues were evaluated for CT antigen expression. The majority of the specimens were: high grade (62%), serous (68%) and advanced stage (74%). 58 (95%) of the EOC tumors analyzed expressed at least one of the CT antigens evaluated. The mean number of CT antigen expressed was 4.5 (0-17). The most frequently expressed CT antigen was MAGE A4 (65%). Antigen sharing analysis showed the following: 9 tumors shared only one antigen with 62% of the evaluated specimens, while 37 tumors shared 4 or more antigens with 82%. 5 tumors expressed over 10 CT antigens, which were shared with 90% of the tumor panel. CONCLUSION: CT antigens are expressed in 95% of EOC tumor specimens. However, not a single antigen was universally expressed across all samples. The degree of antigen sharing between tumors increased with the total number of antigens expressed. These data suggest a multi-epitope approach for development of immunotherapy for ovarian cancer treatment.

Association of Lymph Node Count and Overall Survival in Node-Negative Endometrial Cancers.

Purpose: To estimate whether the number of lymph nodes removed during surgery is associated with overall survival among women with endometrial cancer. Methods: We performed a retrospective cohort study of women with node-negative, stage I to IIIB endometrial cancer (n = 152,702) identified from the 1998-2011 National Cancer Database. Multivariable Cox proportional hazards regression tested for an association of lymph node count with survival. Restricted mean survival and relative hazard curves were plotted for survival as a function of number of removed lymph nodes. Results: Among women with node-negative endometrioid endometrial cancer, for each additional five lymph nodes removed, the hazard for death decreased: stage I, the hazard ratio (HR) was 0.95 (95% CI, 0.93 to 0.97; P < .001), stage II, HR was 0.90 (95% CI, 0.87 to 0.94; P < .001); and stage IIIA-B, HR was 0.92 (95% CI, 0.88 to 0.96; P < .001). When grouped by grade, each additional five lymph nodes removed was also associated with decreased hazard for death: grade 1, HR was 0.96 (95% CI, 0.93 to 0.99; P = .009); grade 2,HR was0.91 (95%CI, 0.89 to0.94; P <.001);and grade 3,HR was 0.95 (95%CI, 0.92 to 0.97; P <.001). Increased lymph node dissection was also associated with increased survival among women with node-negative stage II (HR, 0.92; 95% CI, 0.86 to 0.98; P = .01) or stage IIIA-B (HR, 0.94; 95% CI, 0.89 to 0.99; P = .025) uterine serous carcinoma, but not among women with carcinosarcoma or clear cell adeno-carcinoma. Five-year survival for women with one to four nodes removed and endometrioid or serous histology was 85% (95% CI, 84% to 85%) and 54% (95% CI, 50% to 59%), respectively. Five-year survival was significantly higher for women with ≥ 20 removed nodes and endometrioid (91%; 95% CI, 90% to 91%) or serous (72%; 95% CI, 68% to 76%) histology (P < .001). Conclusion: Increased lymph node count is associated with a 1% to 14% decreased hazard of death per each additional five lymph nodes removed and a 5% to 20% increased 5-year survival among women with pathologically node-negative endometrioid and serous endometrial cancers.

Survival Disparities by Hospital Volume Among American Women With Gynecologic Cancers.

PURPOSE: We describe survival disparities among women with uterine, ovarian, or cervical cancer by cancer-specific mean annual hospital volume. METHODS: National Cancer Database 1998-2011 uterine (n = 441,863), ovarian (n = 223,017), and cervical (n = 146,698) cancer data sets were used. Cancer-specific mean annual hospital volumes were calculated. Overall survival (OS) was plotted by hospital volume using restricted mean OS times from Cox regression. RESULTS: Uterine, ovarian, and cervical cancers were reported from 1,651, 1,633, and 1,600 hospitals, respectively. Median values of mean annual hospital volumes among hospitals were 8.6 (interquartile range [IQR], 2.6 to 20.8), 4.4 (IQR, 1.4 to 10.3), and 2.4 (IQR, 0.6 to 6.6) for uterine, ovarian, and cervical cancers, respectively. Increased hospital volume was associated with increased OS among women with stage III to IV high-grade serous ovarian cancer, stage II to IV squamous or adenocarcinoma cervical cancer, and stage I to IV endometrioid, clear cell, serous, or carcinosarcoma uterine cancers (all P < .03). Differential OS between women treated at higher- versus lower-volume cancer centers exceeded 5, 5, and 13 months among women with advanced endometrial, ovarian, or cervical cancer, respectively (all P < .001). Hospital volume was not associated with OS among patients with stage II to IV cervical cancer treated with brachytherapy ( P = .17). Use of adjuvant therapies decreased OS disparities by hospital volume among women with advanced ovarian or endometrial cancer. CONCLUSION: Increased delivery of brachytherapy for treatment of cervical cancer may decrease survival disparities by hospital volume. Standardization of adjuvant therapies may diminish survival disparities by hospital volume among women with advanced ovarian or endometrial cancer. In addition, survival of American women with gynecologic cancer may be increased by centralization of care.

Survival After Pelvic Exenteration for Cervical Cancer: A National Cancer Database Study.

OBJECTIVE: To determine overall survival (OS) and factors associated with OS after pelvic exenteration for cervical cancer. METHODS: Women with cervical cancer who underwent exenteration (n = 517) were identified from the 1998 to 2011 National Cancer Database. Kaplan-Meier and multivariate Cox proportional-hazards survival analyses were performed to test for associations of potential explanatory variables with OS. Analyzed confounders included age, insurance status, income, distance from home to treatment center, stage, exenteration type, surgical margin status, and treatment with adjuvant radiation and/or chemotherapy. RESULTS: Among the entire cohort with clinical follow-up (n = 313), median OS was 24 months. Stage (P = 2.5 × 10), lymph node status (P = 1.3 × 10), insurance status (P = 1.5 × 10), and histologic type (P = 0.04) were significantly associated with OS by the log-rank test. Unadjusted median OS was 24.2 and 61.8 months for women with squamous and adenocarcinoma histologies, respectively. By multivariate Cox regression, age, insurance status, stage, margin status, and adjuvant radiation were associated with OS. Histology was not independently associated with OS on multivariate regression. Among women with node-negative disease, median OS was 73.2 months. CONCLUSIONS: Exenteration may be curative for more than half of women with node-negative cervical cancer. Stage, insurance status, lymph node status, and surgical margin are independently associated with differential OS after exenteration.

Chemotherapy delay after primary debulking surgery for ovarian cancer.

OBJECTIVE: To determine the association of chemotherapy delay with overall survival (OS) and investigate predictors of delay among a population-representative American ovarian cancer cohort. METHODS: An observational retrospective cohort analysis of women with ovarian cancer who received National Comprehensive Cancer Network guideline-consistent care was performed with the 1998-2011 National Cancer Data Base. Chemotherapy delay was defined as initiation of multiagent chemotherapy >28days from primary debulking surgery. Associations of patient and disease characteristics with chemotherapy delay were tested with multivariate logistic regression. Survival analyses for women diagnosed from 2003 to 2006 approximated a 21-daycycle intravenous platinum-taxane chemotherapy cohort. Overall survival was estimated by Kaplan-Meier analyses and Cox proportional-hazards regressions, with sensitivity analyses using matched cohorts. RESULTS: 58.1% (26,149/45,001) of women experienced chemotherapy delay. Race, insurance status, cancer center type, and community median income were significantly associated with chemotherapy delay (P<0.001). Odds for chemotherapy delay were higher for older or sicker women, women with endometrioid or mucinous histology, lower stage or grade disease, and uninsured or low-income women (P<0.05). Chemotherapy delay >35days from surgery was associated with a 7% (95% confidence interval, 2-13%) increased hazard of death (P=0.01). Relative hazard of death was lowest between 25 and 29days after surgery but was not significantly different within the longer two-week interval from 21 to 35days. CONCLUSION: A survival benefit may be achieved by consistently starting chemotherapy between 21 and 35days from primary debulking surgery. Women at higher risk for chemotherapy delay may be targeted for close follow-up.

Survival after pelvic exenteration for uterine malignancy: A National Cancer Data Base study.

OBJECTIVE: To determine overall survival (OS) and factors associated with OS after pelvic exenteration for uterine cancer. METHODS: Women with uterine cancer who underwent exenteration (n=1160) were identified from the 1998-2011 National Cancer Data Base. Kaplan-Meier and multivariate Cox proportional-hazards survival analyses were performed to test for associations of potential explanatory variables with OS. Analyzed confounders included age, comorbidity score, insurance status, income, distance from home to treatment center, stage, distant and nodal metastasis, tumor size, surgical margin status, exenteration type, and treatment with radiation and/or chemotherapy. RESULTS: Among women with follow-up data (n=652), median (IQR) OS was 63.1 (42.2-107.2) and 17.6 (14.7-23.9) months for women with node-negative versus node-positive disease, respectively. Histology (p=1.5×10-4), grade (p=7.9×10-14), race (p=0.0002), lymph node status (p=1.0×10-14), surgical node evaluation (p=2.8×10-8), surgery for distant metastasis (p=0.004), distant metastasis at diagnosis (p=1.3×10-10), positive surgical margins (p=1.6×10-9), radiotherapy (p=0.004), and insurance status (p=6.5×10-6) were significantly associated with differential, unadjusted Kaplan-Meier OS estimates. Exenteration type was not associated with OS (p=0.357). By multivariate regression, increased age, positive surgical margins, nodal metastasis or unknown nodal status, higher histologic grade, and black race were associated with increased hazards for death. CONCLUSION: Exenteration may be curative for well-selected women with uterine cancer, particularly among women with pathologically negative lymph nodes.

Does time interval between surgery and intraperitoneal chemotherapy administration in advanced ovarian cancer carry a prognostic impact? An NRG Oncology/Gynecologic Oncology Group study ancillary study.

OBJECTIVES: To determine the relationship of the time from surgery to intraperitoneal (IP) chemotherapy (TSIC) initiation with survival of patients with stage III epithelial ovarian cancer (EOC) patients using ancillary data from cooperative group clinical trials. METHODS: Data from 420 patients with stage III EOC treated with IP chemotherapy under GOG-0114 and 172 were reviewed. The Cox proportional hazards model was used to evaluate independent prognostic factors and estimate their covariate-adjusted effects on PFS and OS. RESULTS: The median TSIC was 62.5days (interquartile range 28-83). The median TSIC was longer for patients in GOG-0114 vs those in GOG-172 (83 vs 26days, p<0.001). TSIC was significantly associated (p=0.049) with PFS: each 10% increase in TSIC (days) decreases the risk of progression by 3%. TSIC was not significantly associated with OS in this model. In a linear regression model, gross residual disease was significantly associated with shorter TSIC (R2 -0.141, 95%CI -0.217, -0.064, p<0.001). When only data from GOG-172 were considered, no statistical significant association was found between TSIC and PFS or OS. CONCLUSIONS: In this ancillary data study, TSIC was not associated with improved OS in patients with stage III epithelial ovarian cancer. TSIC was significantly associated with PFS for the entire cohort, suggesting increase in PFS with longer TSIC. However, this was not found when only data from GOG 172 or GOG 114 were analyzed separately. Hence, the relationship between IP chemotherapy initiation and time from surgery needs to be studied further.

Receipt of vaginal brachytherapy is associated with improved survival in women with stage I endometrioid adenocarcinoma of the uterus: A National Cancer Data Base study.

BACKGROUND: Randomized controlled trials have consistently shown that the use of postoperative radiotherapy (RT) for stage I endometrial cancer leads to a reduction in the incidence of pelvic recurrences without a corresponding reduction in overall mortality. It was hypothesized that a reduction in mortality associated with the receipt of RT could be identified in a large data set with greater statistical power. METHODS: Women with surgically staged IA or IB endometrial adenocarcinoma who were treated with total hysterectomy between 2003 and 2011 were identified in the National Cancer Data Base. Chi-square tests and multivariate logistic regression were performed to analyze factors associated with the treatment type. A survival analysis was performed with log-rank testing, Cox proportional hazards regression, and Kaplan-Meier estimates. RESULTS: A total of 44,309 eligible women were identified (33,380 at stage IA and 10,929 at stage IB): 88.4% of the women with stage IA tumors and 51.6% of the women with stage IB tumors received no RT. Older age, comorbid disease, a higher histologic grade, and a larger tumor size were independently associated with an increase in mortality. The receipt of vaginal brachytherapy (VB) was independently associated with a reduction in mortality for both stage IA disease (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.67-0.97) and stage IB disease (HR, 0.62; 95% CI, 0.51-0.74). CONCLUSIONS: Analyses of this large database support the utility of postoperative VB for many women with stage I endometrial cancer. Unfortunately, RT appears to be underused in this population. Greater adherence to consensus guidelines may lead to improved outcomes. Cancer 2016;122:3724-31. © 2016 American Cancer Society.

Phase 2 trial of paclitaxel, 13-cis retinoic acid, and interferon alfa-2b in the treatment of advanced stage or recurrent cervical cancer.

OBJECTIVE: Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer. MATERIALS AND METHODS: Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m, days 1 to 4, and intravenous paclitaxel, 175 mg/m, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate. RESULTS: Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 [48%]), febrile neutropenia (n = 1 [3%]), and anemia (n = 1 [3%]). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0-7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5-26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years. CONCLUSIONS: Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer.

Taxanes in combination with biologic agents for ovarian and breast cancers.

Taxane-based cytotoxic therapy is commonly prescribed for breast and ovarian cancers. Although these cancers are often sensitive to such therapy, clinical benefit and overall survival are limited owing to the development of chemoresistance and recurrence. Biologic agents that specifically target proteins of growth factor signaling pathways, which are hyperactivated in cancers, offer attractive targets for cancer therapeutics and may work synergistically with standard taxane-based chemotherapy to improve patient outcomes. We review clinical trials of biologic agents--angiogenic, tyrosine kinase, and antibody inhibitors--in combination with taxane-based therapy for ovarian and breast cancers. Many clinical trials have shown promising results. However, some biologic agents still need larger trials to assess safety and efficacy. As research into the heterogeneity and complexity of ovarian and breast cancers improves our understanding of the molecular pathways involved, there is no question that targeted therapies with biologic agents will expand the future array of available cancer therapeutics.

Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy.

Defective apoptosis not only promotes tumorigenesis, but also can confound chemotherapeutic response. Here we demonstrate that the proapoptotic BH3-only protein BIM is a tumor suppressor in epithelial solid tumors and also is a determinant in paclitaxel sensitivity in vivo. Furthermore, the H-ras/mitogen-activated protein kinase (MAPK) pathway conferred resistance to paclitaxel that was dependent on functional inactivation of BIM. Whereas paclitaxel induced BIM accumulation and BIM-dependent apoptosis in vitro and in tumors in vivo, the H-ras/MAPK pathway suppressed this BIM induction by phosphorylating BIM and targeting BIM for degradation in proteasomes. The proteasome inhibitor Velcade (P-341, Bortezomib) restored BIM induction, abrogated H-ras-dependent paclitaxel resistance, and promoted BIM-dependent tumor regression, suggesting the potential benefits of combinatorial chemotherapy of Velcade and paclitaxel.