Patient reported outcomes after risk-reducing surgery in patients at increased risk of ovarian cancer.

OBJECTIVE: To describe the quality of life of women at an increased risk of ovarian cancer undergoing risk-reducing bilateral salpingo-oophorectomy (RRBSO). METHODS: Patients evaluated in our gynecologic oncology ambulatory practice between January 2018-December 2019 for an increased risk of ovarian cancer were included. Patients received the EORTC QLQ-C30 and PROMIS emotional and instrumental support questionnaires along with a disease-specific measure (PROM). First and last and pre- and post-surgical PROM responses in each group were compared as were PROMs between at-risk patients and patients with other ovarian diseases. RESULTS: 195 patients with an increased risk of ovarian cancer were identified, 155 completed PROMs (79.5%). BRCA1 or BRCA2 mutations were noted in 52.8%. Also included were 469 patients with benign ovarian disease and 455 with ovarian neoplasms. Seventy-two at-risk patients (46.5%) had surgery and 36 had both pre- and post-operative PROMs. Post-operatively, these patients reported significantly less tension (p = 0.011) and health-related worry (p = 0.021) but also decreased levels of health (p = 0.018) and quality of life <7d (0.001), less interest in sex (p = 0.014) and feeling less physically attractive (p = 0.046). No differences in body image or physical/sexual health were noted in at-risk patients who did not have surgery. When compared to patients with ovarian neoplasms, at-risk patients reported lower levels of disease-related life interference and treatment burden, less worry, and better overall health. CONCLUSIONS: In patients with an increased risk of ovarian cancer, RRBSO is associated with decreased health-related worry and tension, increased sexual dysfunction and poorer short-term quality of life. Patients with ovarian neoplasms suffer to a greater extent than at-risk patients and report higher levels of treatment burden and disease-related anxiety.

Multivariable analysis of association of beta-blocker use and survival in advanced ovarian cancer.

OBJECTIVE: In this study, we sought to evaluate the relationship between survival and beta blocker use in both the primary and interval debulking setting while adjusting for frequently co-administered medications. METHODS: We performed a retrospective cohort study reviewing charts of women who underwent primary or interval cytoreduction for stage IIIC and IV epithelial ovarian cancer. The exposure of interest was beta-blocker use identified at the time of cytoreduction. The outcomes of interest were PFS and OS. We collected demographic/prognostic variables and information about use of aspirin, metformin, and statins. We used the Kaplan-Meier method and Cox proportional hazards models in survival analyses. RESULTS: 534 women who underwent surgery for stage IIIC or IV ovarian cancer were included in the study. The median age at diagnosis was 64 and 84.8% of women had serous carcinoma. We identified 105 women (19.7%) on a beta-blocker of whom 94 (90%) were on a cardioselective beta-blocker. Additionally, 24 women (4.5%) were on metformin, 91 (17%) on aspirin, and 128 (24%) on a statin. In univariable analysis, beta-blocker users had a median overall survival of 29 months vs 35 months among non-users (hazard ratio HR = 1.52, p = 0.007). After adjustment for important demographic, clinical, and histopathologic factors, as well as use of other common medications, beta-blocker use remain associated with an increased hazard of death (adjusted HR 1.57, p = 0.006). CONCLUSION: In this retrospective study, we found that patients identified as being on a beta-blocker at the time of surgery had worse overall survival and greater risk of death when compared to those patients not on betablockers. Importantly, 90% of patients on beta-blockers were identified as being on a cardioselective beta-blocker.

Gynecologic oncology care in the world of accountable care organizations.

Accountable Care Organizations (ACOs) are an example of alternative payment models that are becoming increasingly common in our healthcare system. ACOs focus on increasing value through cost reduction and improved outcomes, and historically focus on Medicare patients within primary care practices. As ACOs grow, attention will likely turn to costly subspecialty care as an area for improvement and standardization. This brief communication addresses the potential benefits and consequences of ACOs on Gynecologic Oncologists and for patients with gynecologic malignancies.

Patient, treatment and discharge factors associated with hospital readmission within 30days after surgery for vulvar cancer.

OBJECTIVES: The majority of hospital readmissions are unexpected and considered adverse events. The goal of this study was to examine the factors associated with unplanned readmission after surgery for vulvar cancer. METHODS: Patient demographic, treatment, and discharge factors were collected on 363 patients with squamous cell carcinoma in situ or invasive cancer who underwent vulvectomy at our institution between January 2001 and June 2014. Clinical variables were correlated using χ2 test and Student's t-test as appropriate for univariate analysis. Multivariate analysis was then performed. RESULTS: Of 363 eligible patients, 35.6% had in situ disease and 64.5% had invasive disease. Radical vulvectomy was performed in 39.1% and 23.4% underwent lymph node assessment. Seventeen patients (4.7%) were readmitted within 30days, with length of stay ranging 2 to 37days and 35% of these patients required a re-operation. On univariate analyses comorbidities, radical vulvectomy, nodal assessment, initial length of stay, and discharge to a post acute care facility (PACF) were associated with hospital readmission. On multivariate analysis, only discharge to a PACF was significantly associated with readmission (OR 6.30, CI 1.12-35.53, P=0.04). Of those who were readmitted within 30days, 29.4% had been at a PACF whereas only 6.6% of the no readmission group had been discharged to PACF (P=0.003). CONCLUSIONS: Readmission affected 4.7% of our population, and was associated with lengthy hospitalization and reoperation. After controlling for patient comorbidities and surgical radicality, multivariate analysis suggested that discharge to a PACF was significantly associated with risk of readmission.

A SNaPshot of potentially personalized care: Molecular diagnostics in gynecologic cancer.

BACKGROUND: Genetic abnormalities underlie the development and progression of cancer, and represent potential opportunities for personalized cancer therapy in Gyn malignancies. METHODS: We identified Gyn oncology patients at the MGH Cancer Center with tumors genotyped for a panel of mutations by SNaPshot, a CLIA approved assay, validated in lung cancer, that uses SNP genotyping in degraded DNA from FFPE tissue to identify 160 described mutations across 15 cancer genes (AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, IDH1, KIT, KRAS, MAP2KI, NOTCH1, NRAS, PIK3CA, PTEN, TP53). RESULTS: Between 5/17/10 and 8/8/13, 249 pts consented to SNaPshot analysis. Median age 60 (29-84) yrs. Tumors were ovarian 123 (49%), uterine 74(30%), cervical 14(6%), fallopian 9(4%), primary peritoneal 13(5%), or rare 16(6%) with the incidence of testing high grade serous ovarian cancer (HGSOC) halving over time. SNaPshot was positive in 75 (30%), with 18 of these (24%) having 2 or 3 (n=5) mutations identified. TP53 mutations are most common in high-grade serous cancers yet a low detection rate (17%) was likely related to the assay. However, 4 of the 7 purely endometrioid ovarian tumors (57%) harbored a p53 mutation. Of the 38 endometrioid uterine tumors, 18 mutations (47%) in the PI3Kinase pathway were identified. Only 9 of 122 purely serous (7%) tumors across all tumor types harbored a 'drugable' mutation, compared with 20 of 45 (44%) of endometrioid tumors (p<0.0001). 17 pts subsequently enrolled on a clinical trial; all but 4 of whom had PIK3CA pathway mutations. Eight of 14 (47%) cervical tumors harbored a 'drugable' mutation. CONCLUSION: Although SNaPshot can identify potentially important therapeutic targets, the incidence of 'drugable' targets in ovarian cancer is low. In this cohort, only 7% of subjects eventually were treated on a relevant clinical trial. Geneotyping should be used judiciously and reflect histologic subtype and available platform.

Management and outcomes for elderly women with vulvar cancer over time.

OBJECTIVE: To examine changes over time in survival and treatment for women diagnosed with vulvar squamous cell carcinoma included in the Surveillance, Epidemiology, and End Results (SEER) Program. DESIGN: Retrospective analysis. SETTING: USA, data obtained from the SEER Program for 1988-2009. POPULATION: Women with vulvar squamous cell carcinoma. METHODS: Women were stratified by age: <50, 50-64, 65-79, and ≥80 years. Differences in survival and treatment patterns were analysed between age groups. Multivariate logistic regression models were constructed to examine treatment patterns. Kaplan-Meier and Cox proportional hazards survival methods were used to assess survival. MAIN OUTCOME MEASURES: Vital status from the date of diagnosis until death, censoring or last follow-up. RESULTS: The final study group consisted of 8553 women, 1806 (21.12%) <50 years, 2141 (25.03%) 50-64 years, 2585 (30.22%) 65-79 years, and 2021 (23.63%) >80 years old. After adjusting for patient and tumour characteristics, older women were less likely to have surgery and more likely to receive radiotherapy. Compared with women under 50 years, women 50-64 had a two-fold higher risk of death (HR 1.91, 95% CI 1.55-2.34); those 65-79 years had a four-fold higher risk of death (HR 4.01, 95% CI 3.32-4.82), and those ≥80 years had a seven-fold higher risk of death (HR 6.98, 95% CI 5.77-8.46). These trends stayed relatively constant over the time periods studied. CONCLUSIONS: Women over 50 years are at a higher risk of vulvar cancer-specific mortality, which increases with age. These trends stayed relatively constant over the time periods studied.

A comparison of outcome in patients with stage 1 clear cell and grade 3 endometrioid adenocarcinoma of the endometrium with and without adjuvant therapy.

OBJECTIVE: To determine the outcomes in patients with Stage I uterine clear cell carcinoma (UCCC) treated with and without adjuvant therapy, and to compare the outcomes in these patients to that of matched controls, patients with Stage I, grade 3, endometrioid adenocarcinoma of the endometrium (EC). METHODS: Patients with FIGO Stage I UCCC who underwent comprehensive surgical staging between January 1996 and January 2007 were identified. Cases (UCCC) were matched by age, stage, adjuvant therapy, and year of diagnosis to controls consisting of patients with grade 3 EC. Recurrence and survival were analyzed using the Kaplan-Meier method. RESULTS: 25 patients with Stage I UCCC were identified of whom 13 (52%) received no adjuvant therapy and 12 (48%) received adjuvant radiation therapy (XRT). The 5-year disease-free survival and overall survival rates for the observation and the XRT groups were 78% and 75%, (p = 0.7) and 85% and 82% (p = 0.1), respectively. When compared to controls, the 5-year disease-free survival rates and overall survival rates of patients with Stage I UCCC were not significantly different, 77% vs 75% (p = 0.8) and 84% vs 88% (p = 0.5), respectively. CONCLUSIONS: In patients with Stage I UCCC tumors there was no clear benefit to adjuvant radiation given the absence of improvement in recurrence risk or any survival benefit. These data question the benefit of radiation therapy in UCCC patients with disease confined to the uterus.

Prognostic implication of endometriosis in clear cell carcinoma of the ovary.

OBJECTIVE: The aim of this study is to investigate whether the presence of endometriosis is a prognostic factor in patients diagnosed with clear cell carcinoma (CCC) of the ovary. METHODS: Retrospective chart review was performed to all patients diagnosed with CCC and endometriosis between 1975 and 2002. All pathology reports were reviewed and slides were reviewed when available. Cox regression analysis and Kaplan-Meier test were used to calculate survival prognostic factors. The level of significance was set at 0.05. RESULTS: Eighty-four patients with CCC were identified with a 49% rate of coexisting endometriosis. Patients with tumors arising in endometriosis (n=15), with endometriosis found elsewhere in the specimen (n=26), and those without endometriosis (n=43) were analyzed comparatively. Patients with CCCs arising in endometriosis were 10 years younger (95% C.I. 0.6-18 years) than those with CCC not arising in endometriosis (P<0.05). Patients with endometriosis anywhere in the surgical specimen presented at early stage 66% of the times versus 42% for patients without endometriosis (P<0.05). Median overall survival (OS) for patients with endometriosis was 196 months (95% C.I. 28-363) versus 34 months (95% C.I. 13-55) for patients without endometriosis (P=0.01). Advanced tumor stage at diagnosis (HR 13, 95% C.I. 5-29, P=0.001) and absence of endometriosis (HR 2, 95% C.I. 1-3.9, P=0.03) were the only significant prognostic factors associated with poor survival. Disease recurrence or death among optimally and completely cytoreduced patients was 31% and 59% for those with and without endometriosis respectively (P>0.05). CONCLUSIONS: Our study suggests that the presence of endometriosis in patients with CCC of the ovary is associated with progression free and OS advantages with no difference in initial resectability.

Intraoperative radiation therapy in the treatment of pelvic gynecologic malignancies: a review of fifteen cases.

OBJECTIVE: The aim of this study was to review the experience with intraoperative radiation therapy (IORT) in the treatment of gynecologic pelvic malignancies at the Massachusetts General Hospital. METHODS: From July 3, 1996, through July 28, 1999, 15 patients were treated with IORT for gynecologic malignancies in a dedicated IORT operating room suite at the Massachusetts General Hospital. Hospital medical records, radiation oncology records, and office charts were reviewed on all patients treated with IORT. IORT was given in the presence of positive surgical margins and where the doses needed for adjuvant postoperative external beam radiotherapy (EBRT) would exceed those tolerated by normal structures. One patient presented with primary disease and 14 with local or regional recurrence. Follow-up time ranged from 3 to 36 months. RESULTS: Treatment in conjunction with IORT included surgery only (7 patients); preoperative EBRT, preoperative brachytherapy, and surgery (1 patient); preoperative chemotherapy and surgery (2 patients); and surgery and postoperative chemotherapy (5 patients). IORT doses ranged from 10 to 22.5 Gy. At the completion of this review, 4 patients (26.6%) have died, 6 (40%) are alive and free of disease, and 5 (33%) are alive with disease persistence or relapse. Of the 10 patients with gross total resection, 5 are alive and free of disease. Of the 5 women with gross residual disease at the time of IORT, only 1 is alive and free of disease. CONCLUSIONS: The volume of residual disease prior to IORT may be an important prognostic indicator for disease relapse. Both local recurrence and distant metastasis were more common among patients with gross residual disease at the time of IORT. Our institutional experience with IORT further supports the importance of optimal surgical resection.

The role of intraoperative radiation therapy (IORT) in the treatment of locally advanced gynecologic malignancies.

The prognosis in women with locally advanced primary or recurrent gynecologic malignancies is rather poor. Doses of external beam radiation necessary to treat gross or microscopic recurrence among patients surgically treated or previously irradiated exceed what is tolerated by normal structures. In this group of patients, intraoperative radiation therapy (IORT) can be utilized to maximize local tumor control, minimizing the radiation exposure of dose-limiting surrounding structures. Review of the available literature indicates that IORT may improve long-term local control and overall survival in women with pelvic sidewall and/or para-aortic nodal recurrence. The most encouraging results have been reported in the cases of microscopic residual disease, following surgical debulking.

Ethnic differences in patterns of care of stage 1A(1) and stage 1A(2) cervical cancer: a SEER database study.

OBJECTIVE: The aim of this study was to evaluate patterns of care for women with Stage 1A(1) and 1A(2) cervical cancer utilizing the SEER database. METHODS: Review of SEER data from 11 registries from 1990 to 1995 was performed. Data from 2358 women were reviewed and stratified by substage, ethnicity, type of therapy, and age. RESULTS: Three remarkable differences among subgroups were identified. (1) Among women >/=35 years of age, whites were more likely to have Stage 1A(1) cancer than blacks or Hispanics; OR (95% CI) = 1.56 (1. 05, 2.31) and 1.41 (1.04, 1.91), respectively. (2) Patients >/=35 years of age were more likely to undergo hysterectomy than younger patients both for 1A(1) and 1A(2) stages; OR (95% CI) = 2.31 (1.68, 3.19) and 2.78 (2.21, 3.50), respectively, with Mantel-Haenszel test of independence chi(2) = 102.9943, P value < 0.001. (3) Black and Hispanic women >/=35 years of age with 1A(2) disease were less likely to have a hysterectomy than whites. Only 15% of Hispanic patients and 9% of blacks over the age of 35 and with Stage 1A(2) were treated via hysterectomy, compared to 76% of white women. Differences in hysterectomies for <35 years of age, 1A(1) patients approached but did not reach statistical significance: blacks 36% versus Hispanic/whites 59%, P value = 0.07. CONCLUSIONS: Older white women were more likely to have cervical carcinoma diagnosed at an earlier stage (1A(1)) than age-matched blacks or Hispanics. Older patients, across all ethnic groups analyzed, were also more likely to be treated for both Stage 1A(1) and 1A(2) disease via hysterectomy than younger patients. Ethnic differences in the management of women with Stage 1A(2) cervical cancer do exist: older minority women are less likely to have a hysterectomy and more likely to be treated via fertility-sparing, less definitive procedures than whites.

Brain opioid receptor measurements by positron emission tomography in normal cycling women: relationship to luteinizing hormone pulsatility and gonadal steroid hormones.

The regulation of central mu-opioid receptors in women during the menstrual cycle was explored with positron emission tomography and the selective radiotracer [11C]carfentanil. Ten healthy women were studied twice, during their follicular and luteal phases. Plasma concentrations of estradiol, progesterone, testosterone, and beta-endorphin were determined immediately before scanning. LH pulsatility was measured over the 9 h preceding each of the two positron emission tomography scans. No significant differences in the binding potential of mu-opioid receptors (binding capacity/Kd) were observed between phases of the menstrual cycle. However, significant negative correlations were observed between circulating levels of estradiol during the follicular phase and mu-receptor binding measures in the amygdala and hypothalamus, two regions thought to be involved in the regulation of GnRH pulsatility. LH pulse amplitude was positively correlated with mu binding in the amygdala, whereas LH pulse number was negatively correlated with binding in this same region. No significant associations were noted between LH pulse measures and the hypothalamus for this sample. These results suggest that amygdalar mu-opioid receptors exert a modulatory effect on GnRH pulsatility, and that circulating levels of estradiol also regulate central mu-opioid function.