Intraperitoneal and Hyperthermic Intraperitoneal Chemotherapy for the Treatment of Ovarian Cancer.

OPINION STATEMENT: In our clinical practice, we have shifted away from the use of adjuvant normothermic intraperitoneal (IP) chemotherapy, particularly following the publication of GOG 252. Our decision is rooted in the accumulating evidence indicating a lack of demonstrable superiority, alongside the recognized toxicities and logistical challenges associated with its administration. This strategic departure is also influenced by the rising utilization of maintenance therapies such as bevacizumab and PARP inhibitors, which present viable alternatives for improving patient outcomes. Our utilization of hyperthermic IP chemotherapy (HIPEC) is currently reserved for a specific cohort of patients, mirroring the patient population studied in the OVHIPEC-1 trial. Specifically, our HIPEC protocol applies to patients presenting with newly diagnosed stage IIIC high-grade epithelial ovarian cancer who are deemed ineligible for primary debulking surgery. Patients must exhibit at least stable disease with neoadjuvant platinum-based chemotherapy, maintain a favorable performance status (ECOG score 0-1), possess good nutritional reserves (with no evidence of protein-calorie malnutrition and an albumin level exceeding 3.5), and not have chronic kidney disease. When HIPEC is planned, it is administered at the time of interval debulking surgery, contingent upon the attainment of optimal surgical outcomes (< 1 cm of residual disease). Our HIPEC protocol adheres to the original OVHIPEC-1 trial guidelines, employing cisplatin at a dosage of 100 mg/m2. We administer at least two antiemetics, antihistamines, and sodium thiosulfate to mitigate known side effects. Postoperatively, patients are admitted to the general surgical floor, reserving the intensive care unit for those in critical condition. We follow Enhanced Recovery After Surgery principles, incorporating early ambulation and feeding into our postoperative care strategy. We have encountered encouraging results with this approach, with most patients having largely uncomplicated postoperative courses and resuming adjuvant chemotherapy within 3 to 4 weeks of surgery.

Participation of Patients With Limited English Proficiency in Gynecologic Oncology Clinical Trials.

BACKGROUND: Significant disparities exist in recruitment of minorities to clinical trials, with much of the prior literature focused on race/ethnicity only. Limited English proficiency (LEP) is a known barrier in healthcare that may also drive disparities in trial enrollment. We sought to determine participation rates in gynecologic oncology trials among patients with LEP and to explore barriers to their participation. METHODS: In a retrospective cohort study, electronic health record data from >2,700 patients treated over 2 years at one academic gynecologic oncology practice were abstracted and the primary exposure of having LEP was identified. The primary outcome was enrollment in a clinical trial. Demographic, financial, clinical, and healthcare access-related covariates were also abstracted and considered as potential confounders in a multivariable logistic regression model. Age, race, ethnicity, and insurance status were further examined for evidence of effect modification. In addition, a survey was administered to all gynecologic oncology research staff and gynecologic oncology providers (n=25) to assess barriers to research participation among patients with LEP. RESULTS: Clinical trial enrollment was 7.5% among fluent English speakers and 2.2% among patients with LEP (risk ratio, 0.29; 95% CI, 0.11-0.78; P=.007), and remained significantly lower in patients with LEP after adjusting for the identified confounders of Hispanic ethnicity and insurance payer (odds ratio, 0.34; 95% CI, 0.12-0.97; P=.043). There was a trend toward race and LEP interaction: Asian patients were equally likely to participate in research regardless of language fluency, whereas White and Black patients with LEP were less likely to participate than non-LEP patients in both groups (P=.07). Providers reported that the most significant barriers to enrollment of patients with LEP in research were unavailability of translated consent forms and increased time needed to enroll patients. CONCLUSIONS: Patients with LEP were 3.4 times less likely to participate in gynecologic oncology trials than fluent English speakers. De-aggregation of race, ethnicity, and language proficiency yielded important information about enrollment disparities. These findings offer avenues for future interventions to correct disparities.

Characterization of the Early Years of Bevacizumab Use for First-Line Treatment of Ovarian Cancer in the United States.

PURPOSE: To quantify early dissemination patterns, factors influencing use, and costs of bevacizumab (BEV) for the treatment of newly diagnosed ovarian cancer (OC) in the United States before its regulatory approval for this indication (off-label use). METHODS: We identified women 18-65 years of age with newly diagnosed OC treated with surgery and platinum-based chemotherapy from 2008 to 2016 through the MarketScan database (N = 8,109). The proportion of women receiving BEV over time was calculated, multivariate logistic regression used to determine factors associated with BEV use, and total costs per cycle of chemotherapy with and without BEV abstracted. RESULTS: BEV utilization rose 1.8-fold during the study period, from 4.1% (2008) to 7.4 % (2016). BEV was used with non-platinum/taxane regimens over a third of the time (37.2%). Physician specialty (medical oncology v gyn oncology) and geography (southeast region) were significantly associated with higher rates of use. Clinical factors associated with BEV use were metastatic disease and presence of ascites. The median cost of one cycle of platinum/taxane chemotherapy plus BEV was $10,897 in US dollars (USD) (interquartile range $7,573-$18,133 USD), compared with $1,629 USD (interquartile range, $683.0-$4,461 USD) for platinum/taxane alone. CONCLUSION: Off-label use of BEV for newly diagnosed OC was rare (< 10%), but doubled following presentation of phase II and III data at international meetings. Both clinical (ascites, metastatic disease, and age) and nonclinical (specialty and region) factors were associated with BEV use, and its use was accompanied by a six-fold increase in the cost of one cycle of treatment.

Simultaneous germline and somatic sequencing in ovarian carcinoma: mutation rate and impact on clinical decision-making.

OBJECTIVE: Germline and somatic BRCA1 and BRCA2 (BRCA) mutations predict treatment response in patients with epithelial ovarian, peritoneal or fallopian tube cancer (OC), yet only germline testing is routinely pursued or reimbursed at diagnosis. We report our experience with clinical testing of paired tumor and germline DNA for OC mutations. METHODS: Simultaneous sequencing using the BROCA assay of DNA from paired blood and neoplastic tissue became clinically available at our institution in 2017. We retrospectively reviewed the medical records of OC cases tested from 7/2017 to 7/2018. We calculated the rates of known pathogenic germline mutations and actionable somatic mutations, defined as those for which targeted therapies exist. RESULTS: We identified 43 women (36 new diagnoses, seven recurrences) who underwent testing. Average age at diagnosis was 60. OC samples came from surgical specimens in 31 cases (72.1%), from biopsy in 11 cases (25.6%), and from cytology in one case (2.3%). We identified pathogenic germline mutations in six cases (14%), actionable somatic mutations in 15 cases (35%), and both a somatic and germline mutation in one case (2%). BRCA mutations accounted for 59% of all mutations. Of 40 cases with sufficient follow-up, providers documented reviewing results of genetic testing in 34 (85%), which influenced clinical decisions in 12 (30%). CONCLUSIONS: Simultaneous germline and tumor sequencing is an efficient way to provide enhanced information to guide the care of OC patients. This approach can identify somatic BRCA mutations at diagnosis, allowing physicians to provide PARP inhibitor maintenance and improve outcomes for those patients.

Patterns and duration of primary and recurrent treatment in ovarian cancer patients with germline BRCA mutations.

The objectives of this study were to describe the patterns and duration of primary and recurrent treatment in patients with ovarian cancer (OC) harboring germline BRCA1 and BRCA2 (BRCA) mutations. A retrospective review of BRCA mutation carriers with advanced, high-grade OC diagnosed between 2004 and 2014 with at least 3 years of follow-up (or until death) was undertaken. Descriptive statistics were calculated and a Swimmer's Plot used to depict disease course. Forty BRCA mutation carriers (26 BRCA1, 14 BRCA2) were identified. Mean age was 54 (range 32-77). All had cytoreductive surgery and received platinum chemotherapy. Median platinum-free interval was 11.9 months (IQR 3.6-21.9). Among 28 patients who recurred, median number of treatment lines was 4 (IQR 3-6), with a median of 2 (IQR 2-3) platinum lines. On average, patients who recurred spent 32% (IQR 20-43%) of their time after diagnosis receiving cytotoxic chemotherapy and 54% (IQR 42-67%) of the time on some cancer-directed therapy, including maintenance. Median overall survival was 79.1 months from diagnosis and 25.4 months after first recurrence. In conclusion, beyond first-line therapy, there was treatment and outcome heterogeneity for BRCA-mutated OC. After OC diagnosis, patients spent close to half their life on treatment.

A-Kinase Anchoring Protein 13 (AKAP13) Augments Progesterone Signaling in Uterine Fibroid Cells.

Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood. Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids. Methods and Results: Fibroid samples from patients treated with ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus. Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.

Robotically Assisted Laparoscopic Ovarian Transposition in Women with Lower Gastrointestinal Cancer Undergoing Pelvic Radiotherapy.

BACKGROUND: Pelvic radiotherapy (RT) is a standard component of the management for patients with locally advanced rectal cancer or squamous cell carcinoma of the anus. Pelvic RT leads to permanent and irreversible ovarian failure in young women. This study aimed to determine the effectiveness of robotically assisted laparoscopic ovarian transposition (OT) before RT in women with rectal or anal cancer who wanted to preserve normal ovarian function. METHODS: The study reviewed the medical records of all patients treated at our institution from August 2009 to October 2014 who received robotically assisted laparoscopic OT for rectal or anal cancer before RT. Clinical and hormonal data were abstracted to determine ovarian function. RESULTS: The study identified 22 women with rectal (n = 20) or anal (n = 2) cancer. The median age of the women was 39 years (range 26-45 years). For one patient, OT was technically not feasible. The postoperative course was uneventful in all but one case. Follow-up data on ovarian function were unavailable for 3 patients. The median times from RT initiation to the last gynecologic or hormonal evaluation were 9 months (range 5-47 months) and 10.5 months (range 5-47 months), respectively. At the last gynecologic or hormonal follow-up visit, ovarian function was preserved in 12 (67%) of 18 evaluable patients, including 9 (90%) of 10 patients 40 years of age or younger and 3 (38%) of 8 patients older than 40 years (P = 0.07). CONCLUSIONS: Robotically assisted laparoscopic bilateral OT is safe and can lead to preservation of ovarian function in two-thirds of patients with low gastrointestinal cancer undergoing pelvic RT. It should be considered in this setting, especially for women age 40 years or younger, to avoid premature menopause and its associated sequelae.

Characteristics, treatment and outcomes of women with immature ovarian teratoma, 1998-2012.

OBJECTIVE: To explore the presentation, management and outcomes of adult women diagnosed with immature ovarian teratoma. METHODS: The National Cancer Database (NCDB) was used to identify women≥18years of age diagnosed with an immature teratoma from 1998 to 2012. We analyzed demographic, clinical and tumor characteristics, and treatment trends. Multivariable models were employed to examine predictors of adjuvant chemotherapy use and survival. RESULTS: We identified a total of 1045 adult women with immature teratoma. The median age of diagnosis was 27years and most were diagnosed between ages 18 and 39 (88.9%). The majority presented with early-stage (I/II) disease (76.0%), underwent unilateral salpingo-oophorectomy (52.5%) and received adjuvant chemotherapy (56.8%). The probability of receiving chemotherapy increased with stage, grade, and treatment at academic compared to community based centers (P<0.05.). Older age, advanced stage, and grade III histology were associated with worse survival (P<0.05). Five-year survival rates were: 98.3% (95% CI 96.8-99.1), 93.2% (95% CI 82.8-97.4), 82.7% (95% CI 74.3-88.5), and 72.0% (95% CI 50.1-85.5) for stages I, II, III, and IV disease, respectively. CONCLUSIONS: The incidence of immature teratoma is highest in young adults aged 18 to 39. Most patients present with early-stage disease, are managed with fertility sparing surgery and chemotherapy and have an excellent prognosis. Later age at diagnosis, advanced stage, and high-grade histology confer a worse prognosis.

Prescription of extended-duration thromboprophylaxis after high-risk, abdominopelvic cancer surgery.

OBJECTIVE: Extended-duration thromboprophylaxis for 4weeks after discharge has been demonstrated to reduce venous thromboembolic events (VTE) in cancer patients undergoing abdominopelvic surgery and is recommended in national guidelines. We examined the utilization and effectiveness of extended-duration low molecular weight heparin prophylaxis in high-risk cancer patients. METHODS: We analyzed patients with colon, ovarian, and uterine cancer who underwent surgery from 2009 to 2013 and who were recorded in the MarketScan database. Multivariable models and propensity score analysis with inverse probability of treatment weight were developed to examine uptake and predictors of use of post-discharge low molecular weight heparin (LMWH), as well as associated adverse events (transfusion, and hemorrhage). RESULTS: A total of 63,280 patients were identified. Use of extended-duration prophylaxis increased from 2009 to 2013 from 1.4% to 1.7% (P=0.67) for colectomy, 5.9% to 18.3% for ovarian cancer surgery (P<0.001), and 6.3% to 12.2% (P<0.001) for hysterectomy for endometrial cancer. There was no association between use of extended-duration prophylaxis and reductions in VTE for any of the procedures: colectomy (2.4% with extended-duration prophylaxis vs. 2.9% without prophylaxis, OR=0.84; 95% CI, 0.54-1.31), ovarian cancer-directed surgery (3.7% vs. 3.6%, OR=1.01; 95% CI, 0.76-1.33), hysterectomy (2.1% vs. 2.1%; OR=0.96; 95% CI, 0.67-1.38). Extended-duration prophylaxis was associated with an increased risk of adverse postoperative events: 2.20 (95% CI, 1.51-3.19) after colectomy, 1.24 (95% CI, 0.92-1.68) following ovarian cancer-directed surgery and 0.99 (95% CI, 0.66-1.48) for hysterectomy for endometrial cancer. CONCLUSION: Use of extended-duration thromboprophylaxis is low among high-risk cancer patients undergoing surgery.

Magnitude of risk for nodal metastasis associated with lymphvascular space invasion for endometrial cancer.

OBJECTIVES: While lymphvascular space invasion (LVSI) is a risk factor for nodal metastasis in endometrial cancer, the magnitude of risk is poorly described. We examined the risk of nodal metastasis associated with LVSI for various combinations of tumor grade and depth of invasion and examined the effect of LVSI on survival. METHODS: We identified patients with T1A (<50% myoinvasion) and T1B (>50% myoinvasion) endometrioid adenocarcinomas of the endometrium diagnosed between 2010 and 2012 and recorded in the National Cancer Database. The risk of nodal metastasis associated with LVSI stratified by grade and stage is reported. The association of LVSI and survival was examined using Kaplan-Meier analyses and Cox proportional hazards models. RESULTS: We identified 25,907 patients, including 3928 (15.2%) with LVSI. Among patients with LVSI, 21.0% had positive lymph nodes, compared to 2.1% in patients without LVSI (P<0.0001). In analyses stratified by stage and grade, LVSI was associated with increased risks of LN metastasis by a magnitude of 3 to over 10-fold. In a multivariable model controlling for clinical and demographic characteristics, the risk ratio of nodal disease with LVSI was 9.29 (95% CI, 7.29-11.84) for T1A tumors and 4.64 (95% CI 3.99-5.39) for T1B tumors. LVSI was associated with decreased survival even after adjustment for the presence of lymph node metastases (HR=1.92, 95% CI 1.56-2.36). CONCLUSIONS: LVSI is independently associated with lymph node metastases in women with apparent early-stage endometrial cancer and an independent predictor of survival even after adjustment for the presence of lymph node metastases.

Utilization and Outcomes of Ovarian Conservation in Premenopausal Women With Endometrial Cancer.

OBJECTIVE: To examine the trends in use and safety of ovarian conservation in young women with early-stage endometrial cancer undergoing hysterectomy. METHODS: We conducted a population-based analysis. The National Cancer Database was used to identify women younger than 50 years of age with stage I endometrioid adenocarcinoma of the endometrium who underwent hysterectomy from 1998 to 2012. Patients were stratified based on whether they underwent oophorectomy or had ovarian conservation. Multivariable models were used to examine predictors of ovarian conservation and the association between ovarian conservation and survival. RESULTS: The cohort of 15,648 women included 1,121 (7.2%) who had ovarian conservation and 14,527 (92.8%) who underwent oophorectomy. The rate of ovarian conservation was relatively stable from 6.9% (95% confidence interval [CI] 4.9-9.7%) in 1998 to 7.1% (95% CI 5.8-8.7%) in 2012 (P=.91). Ovarian conservation was more commonly performed in younger women, black women, those with low-grade and earlier stage tumors, and in women treated at community hospitals. In a multivariable model, ovarian conservation was not independently associated with survival (hazard ratio 0.94, 95% CI 0.65-1.37). Similarly, in a Kaplan-Meier analysis, there was no association between ovarian conservation and survival (P=.19). CONCLUSION: Ovarian conservation does not adversely affect survival for women with early-stage endometrial cancer. Despite the oncologic safety of ovarian conservation, the majority of young women with endometrial cancer still undergo oophorectomy at the time of surgery.

Dynamic reciprocity between cells and their microenvironment in reproduction.

Dynamic reciprocity (DR) refers to the ongoing, bidirectional interaction between cells and their microenvironment, specifically the extracellular matrix (ECM). The continuous remodeling of the ECM exerts mechanical force on cells and modifies biochemical mediators near the cell membrane, thereby initiating cell-signaling cascades that produce changes in gene expression and cell behavior. Cellular changes, in turn, affect the composition and organization of ECM components. These continuous interactions are the fundamental principle behind DR, and its critical role throughout development and adult tissue homeostasis has been extensively investigated. While DR in the mammary gland has been well described, we provide direct evidence that similar dynamic interactions occur in other areas of reproductive biology as well. In order to establish the importance of DR in the adaptive functioning of the female reproductive tract, we present our most current understanding of DR in reproductive tissues, exploring the mammary gland, ovary, and uterus. In addition to explaining normal physiological function, investigating DR may shed new light into pathologic processes that occur in these tissues and provide an exciting opportunity for novel therapeutic intervention.

Mechanical signaling in reproductive tissues: mechanisms and importance.

The organs of the female reproductive system are among the most dynamic tissues in the human body, undergoing repeated cycles of growth and involution from puberty through menopause. To achieve such impressive plasticity, reproductive tissues must respond not only to soluble signals (hormones, growth factors, and cytokines) but also to physical cues (mechanical forces and osmotic stress) as well. Here, we review the mechanisms underlying the process of mechanotransduction-how signals are conveyed from the extracellular matrix that surrounds the cells of reproductive tissues to the downstream molecules and signaling pathways that coordinate the cellular adaptive response to external forces. Our objective was to examine how mechanical forces contribute significantly to physiological functions and pathogenesis in reproductive tissues. We highlight how widespread diseases of the reproductive tract, from preterm labor to tumors of the uterus and breast, result from an impairment in mechanical signaling.