Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer.

BACKGROUND: Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear. METHODS: In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort. RESULTS: In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy. CONCLUSIONS: In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.).

Doubling down on the future of gynecologic oncology: The SGO future of the profession summit report.

The original vision of the field of gynecologic oncology was to establish a multidisciplinary approach to the management of patients with gynecologic cancers. Fifty years later, scientific advances have markedly changed the overall practice of gynecologic oncology, but the profession continues to struggle to define its value-financial and otherwise. These issues were examined in full at the Society of Gynecologic Oncology (SGO) Future of the Profession Summit and the purpose of this document is to summarize the discussion, share the group's perceived strengths, weaknesses, opportunities, and threats (SWOT) for gynecologic oncologists, further educate members and others within the patient care team about the unique role of gynecologic oncologists, and plan future steps in the short- and long- term to preserve the subspecialty's critical mission of providing comprehensive, longitudinal care for people with gynecologic cancers.

Trends in treatment patterns and costs of care among patients with advanced stage cervical cancer.

BACKGROUND: Current treatments for recurrent or metastatic cervical cancer (r/mCC) do not offer satisfactory clinical benefits, with most patients progressing beyond first-line (1L) treatment. With new treatments under investigation, understanding current treatment patterns, the impact of newly approved therapies, and total costs of care for r/mCC are important. METHODS: A retrospective analysis of a US commercial insurance claims database to identify adult patients with r/mCC between 2015 and Q1-2020; defining 1L treatment as the first administration of systemic treatment without concomitant chemoradiation or surgery. Patient characteristics, treatment regimens, duration of therapy, and total costs of care were evaluated for each line of therapy. RESULTS: 1323 women initiated 1L treatment for r/mCC (mean age, 56.1 years; mean follow-up, 16.5 months). One-third (n = 438) had evidence of second-line (2L) treatment; of these, 129 (29%) had evidence of third-line (3L) treatment. No regimen represented a majority among 2L+ treatments. The 2018 approval of pembrolizumab led to increased 2L immunotherapy use (0% in 2015, 37% in 2019/Q1-2020). However, only a small proportion of patients stayed on immunotherapy for a prolonged period. Mean per-patient-per-month total costs of care during treatment were $47,387 (1L), $77,661 (2L), and $53,609 (3L), driven primarily by outpatient costs. CONCLUSIONS: No clear standard of care was observed in 2L+. Although immunotherapy is increasingly used in 2L+, only a small subset of patients stayed on immunotherapy for a prolonged period, suggesting a need for more therapeutic options. Better understanding of disease biology and the introduction of new therapies may address these unmet needs.

Phase II study of irinotecan in combination with bevacizumab in recurrent ovarian cancer.

OBJECTIVES: To evaluate the efficacy and safety of irinotecan and bevacizumab in recurrent ovarian cancer. The primary objective was to estimate the progression free survival (PFS) rate at 6months. Secondary objectives included estimation of overall survival (OS), objective response rate (ORR), duration of response, and an evaluation of toxicity. METHODS: Recurrent ovarian cancer patients with no limit on prior treatments were eligible. Irinotecan 250mg/m2 (amended to 175mg/m2 after toxicity assessment in first 6 patients) and bevacizumab 15mg/kg were administered every 3weeks until progression or toxicity. Response was assessed by RECIST or CA-125 criteria every 2cycles. RESULTS: Twenty nine patients enrolled (10 were platinum-sensitive and 19 were platinum-resistant). The median number of prior regimens was 5 (range 1-12); 13 patients had prior bevacizumab and 11 prior topotecan. The PFS rate at 6months was 55.2% (95% CI: 40%-77%). The median number of study cycles given was 7 (range 1-34). Median PFS was 6.8months (95% CI: 5.1-12.1months); median OS was 15.4months (95% CI: 11.9-20.4months). In this study, no complete response (CR) was observed. The objective response rate (ORR; PR or CR) for all patients entered was 27.6% (95% CI: 12.7%-47.2%) and the clinical benefit rate (CR+PR+SD) was 72.4% (95% CI: 52.8%-87.3%); twelve patients experienced duration of response longer than 6months. In the 24 patients with measurable disease, a partial response (PR) was documented in 8 (30%) patients; 13 patients maintained stable disease (SD) at first assessment. The most common grade 3/4 toxicity was diarrhea. No treatment-related deaths were observed. CONCLUSIONS: Irinotecan and bevacizumab has activity in heavily pre-treated patients with recurrent ovarian cancer, including those with prior bevacizumab and topoisomerase inhibitor use.

Preoperative experience for public hospital patients with gynecologic cancer: Do structural barriers widen the gap?

BACKGROUND: Widespread disparities in care have been documented in women with gynecologic cancer in the United States. This study was designed to determine whether structural barriers to optimal care were present during the preoperative period for patients with gynecologic cancer. METHODS: A retrospective review was conducted for patients undergoing surgery for a gynecologic malignancy at a public hospital or a private hospital staffed by the same team of gynecologic oncologists between July 1, 2013 and July 1, 2014. RESULTS: Two hundred fifty-seven cases were included for analysis (public hospital, 69; private hospital, 188). Patients treated at the private hospital were older (58 vs 52 years; P = .004) and had similar medical comorbidities (median Charlson comorbidity index at both hospitals, 6) but required fewer hospital visits in preparation for surgery (2 vs 4; P < .001). Public hospital patients had a longer wait time from the diagnosis of disease to surgery (63 vs 34 days; P < .001). According to a multiple linear regression model, the public hospital setting was associated with a longer interval from diagnosis to surgery with adjustments for the insurance status, age at diagnosis, cancer stage, and number of preoperative hospital visits (P < .001). CONCLUSIONS: Patients at the public hospital were subject to a greater number of preoperative visits and had to wait longer for surgery than patients at the private hospital. Attempts to reduce health care disparities should focus on improving efficiency in health care delivery systems once contact has been established.

Dual mTORC1/2 inhibition in a preclinical xenograft tumor model of endometrial cancer.

OBJECTIVES: Up to 70% of endometrioid endometrial cancers carry PTEN gene deletions that can upregulate mTOR activity. Investigational mTOR kinase inhibitors may provide a novel therapeutic approach for these tumors. Using a xenograft tumor model of endometrial cancer, we assessed the activity of mTOR and downstream effector proteins in the mTOR translational control pathway after treatment with a dual mTOR complex 1 and 2 (mTORC1/2) catalytic inhibitor (PP242) compared to that of an allosteric mTOR complex 1 (mTORC1) inhibitor (everolimus, RAD001). METHODS: Grade 3 endometrioid endometrial cancer cells (AN3CA) were xenografted into nude mice. Animals were treated with PP242, PP242 and carboplatin, carboplatin, RAD001, and RAD001 and carboplatin. Mean tumor volume was compared across groups by ANOVA. Immunoblot analysis was performed to assess mTORC1/2 activity using P-Akt, P-S6 and P-4E-BP1. RESULTS: The mean tumor volume of PP242+carboplatin was significantly lower than in all other treatment groups, P < 0.001 (89% smaller). The RAD001+carboplatin group was also smaller, but this did not reach statistical significance (P = 0.097). Immunoblot analysis of tumor lysates treated with PP242 demonstrated inhibition of activated P-Akt. CONCLUSIONS: Catalytic mTORC1/2 inhibition demonstrates clear efficacy in tumor growth control that is enhanced by the addition of a DNA damage agent, carboplatin. Targeting mTORC1/2 leads to inhibition of Akt activation and strong downregulation of effectors of mTORC1, resulting in downregulation of protein synthesis. Based on this study, mTORC1/2 kinase inhibitors warrant further investigation as a potential treatment for endometrial cancer.

The doc versus the bot: A pilot study to assess the quality and accuracy of physician and chatbot responses to clinical questions in gynecologic oncology.

Artificial intelligence (AI) applications to medical care are currently under investigation. We aimed to evaluate and compare the quality and accuracy of physician and chatbot responses to common clinical questions in gynecologic oncology. In this cross-sectional pilot study, ten questions about the knowledge and management of gynecologic cancers were selected. Each question was answered by a recruited gynecologic oncologist, ChatGPT (Generative Pretreated Transformer) AI platform, and Bard by Google AI platform. Five recruited gynecologic oncologists who were blinded to the study design were allowed 15 min to respond to each of two questions. Chatbot responses were generated by inserting the question into a fresh session in September 2023. Qualifiers and language identifying the response source were removed. Three gynecologic oncology providers who were blinded to the response source independently reviewed and rated response quality using a 5-point Likert scale, evaluated each response for accuracy, and selected the best response for each question. Overall, physician responses were judged to be best in 76.7 % of evaluations versus ChatGPT (10.0 %) and Bard (13.3 %; p < 0.001). The average quality of responses was 4.2/5.0 for physicians, 3.0/5.0 for ChatGPT and 2.8/5.0 for Bard (t-test for both and ANOVA p < 0.001). Physicians provided a higher proportion of accurate responses (86.7 %) compared to ChatGPT (60 %) and Bard (43 %; p < 0.001 for both). Physicians provided higher quality responses to gynecologic oncology clinical questions compared to chatbots. Patients should be cautioned against non-validated AI platforms for medical advice; larger studies on the use of AI for medical advice are needed.

Health disparities in cervical cancer: Estimating geographic variations of disease burden and association with key socioeconomic and demographic factors in the US.

BACKGROUND: Despite advances in cervical cancer (CC) prevention, detection, and treatment in the US, health disparities persist, disproportionately affecting underserved populations or regions. This study analyzes the geographical distribution of both CC and recurrent/metastatic CC (r/mCC) in the US and explores potential risk factors of higher disease burden to inform potential strategies to address disparities in CC and r/mCC. METHODS: We estimated CC screening rates, as well as CC burden (number of patients with CC diagnosis per 100,000 eligible enrollees) and r/mCC burden (proportion of CC patients receiving systemic therapy not in conjunction with surgery or radiation), at the geographic level between 2017-2022 using administrative claims. Data on income and race/ethnicity were obtained from US Census Bureau's American Community Survey. Brachytherapy centers were proxies for guideline-conforming care for locally advanced CC. Associations among demographic, socioeconomic, and healthcare resource variables, with CC and r/mCC disease burden were assessed. RESULTS: Between 2017-2022, approximately 48,000 CC-diagnosed patients were identified, and approximately 10,000 initiated systemic therapy treatment. Both CC and r/mCC burden varied considerably across the US. Higher screening was significantly associated with lower CC burden only in the South. Lower income level was significantly associated with lower screening rates, higher CC and r/mCC burden. Higher proportion of Hispanic population was also associated with higher CC burden. The presence of ≥1 brachytherapy center in a region was significantly associated with a reduction in r/mCC burden (2.7%). CONCLUSION: CC and r/mCC disparities are an interplay of certain social determinants of health, behavior, and race/ethnicity. Our findings may inform targeted interventions for a geographic area, and further highlight the importance of guideline-conforming care to reduce disease burden.

Mucinous histology is a risk factor for nodal metastases in endometrial cancer.

OBJECTIVES: Mucinous adenocarcinoma of the endometrium (MUC) is a rare histological variant of endometrial carcinoma accounting for 1-9% of endometrioid tumors. Few studies have characterized its clinical behavior. This is a case-control study at a single institution comparing the risk factors and clinical course of MUC relative to endometrioid adenocarcinoma. METHODS: A case-control study was performed including patients treated for endometrial cancer between 1996 and 2006. 41 cases of mucinous adenocarcinoma were identified. Each case was matched with two controls of endometrioid histology by age and histological grade. Cases and controls were compared with regard to known risk factors for endometrial cancer and the extent of disease at diagnosis. Chi-square tests were used to compare proportions and Student's t-tests for the comparison of means. Multivariate regression was used to identify the independent predictors of lymph node metastases. Overall survival was calculated using the Kaplan-Meier method and compared with the Log-rank test. p<.05 was considered significant for all tests. RESULTS: Cases and controls were matched by age and FIGO grade and were found to be similar in regard to ethnicity, body mass index and medical history. No significant difference in myometrial invasion (MI)>50% or the presence of lymph-vascular space invasion was found between cases and controls, however, 17% of patients with MUC had lymph node metastases compared to 3% of controls (p=.01). Multivariate analysis controlling for both tumor grade and depth of MI identified mucinous histology as an independent predictor of lymph node metastasis (p=.02). There was no difference in adjuvant treatment, recurrence rate or survival between the two groups. CONCLUSION: Mucinous differentiation was found to be an independent predictor of lymph node metastasis in the study population. Comprehensive surgical staging including retroperitoneal node dissection should be strongly considered in all endometrial cancer patients with predominantly mucinous histology.

An analysis of patients with bulky advanced stage ovarian, tubal, and peritoneal carcinoma treated with primary debulking surgery (PDS) during an identical time period as the randomized EORTC-NCIC trial of PDS vs neoadjuvant chemotherapy (NACT).

OBJECTIVE: The recent EORTC-NCIC randomized trial comparing primary debulking surgery (PDS) to neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian carcinoma (EOC) reported a median progression-free survival (PFS) of 12 months and overall survival (OS) of 30 months for both arms. Due to the equivalent survival and decreased morbidity with NACT, many now consider it the preferred approach. We analyzed the outcomes of patients treated with PDS at our institution during the same time period in which the EORTC-NCIC trial was conducted, using identical inclusion criteria. METHODS: We identified all patients undergoing primary treatment for advanced EOC at our institution from 9/98-12/06. Study inclusion and exclusion criteria were identical to those of the EORTC-NCIC trial. Standard statistical tests were used. RESULTS: Of 316 eligible patients, 285 (90%) underwent PDS and 31 (10%) received NACT due to extra-abdominal disease, medical comorbidities, and/or advanced age (>85 years). Of the 285 patients who underwent PDS, most had carcinoma of ovarian origin (248, 87%); stage IIIC disease (249, 87%); grade 3 tumors (237, 83%); and serous histology (249, 87%). Optimal cytoreduction (≤1 cm residual) was achieved in 203 patients (71%). Postoperative platinum-based chemotherapy was given to 281 of 285 patients (99%). The median PFS and OS were 17 and 50 months, respectively. CONCLUSION: PDS should continue to be the preferred initial management for patients with bulky stages IIIC-IV ovarian carcinoma. NACT should be reserved for those who cannot tolerate PDS and/or for whom optimal cytoreduction is not feasible.

Does the presence of adenomyosis and lymphovascular space invasion affect lymph node status in patients with endometrioid adenocarcinoma of the endometrium?

OBJECTIVE: We sought to determine the prevalence of adenomyosis and assess its effect on lymph node status in endometrioid adenocarcinoma of the endometrium (EAC). STUDY DESIGN: Hysterectomy specimens from a single institution were reviewed for the presence of adenomyosis, lymphovascular space invasion (LVSI), tumor grade, histology, and lymph node status. Standard statistical analysis was used to compare variables. RESULTS: Adenomyosis was present in 42% of total and 66% of malignant hysterectomy specimens (P = .009). Adenomyosis was most commonly associated with EAC histology (P = .023). LVSI was found to be an independent predictor of lymph node metastasis in EAC patients without adenomyosis, but not in those with coexisting adenomyosis (odds ratio, 58.7; P = .03; and odds ratio, 4.98; P = .15; respectively). CONCLUSION: Adenomyosis was associated with a lower risk of lymph node metastasis in EAC patients with LVSI. Further studies are needed to investigate the role of adenomyosis in lymphatic tumor infiltration.

Uterine Sarcomas: How to Navigate an Ever-Growing List of Subtypes.

Uterine sarcomas are rare mesenchymal tumors that are aggressive cancers. The rarity of these tumors, and consequently limited prospective data, has made surgical management of uterine sarcomas challenging. One major obstacle in the management of uterine sarcomas is establishing the diagnosis prior to surgery, which is crucial for appropriate intraoperative management. This paper serves to review aspects of surgical management of uterine sarcomas that remain unanswered. Distinguishing common benign myomas from rare uterine sarcomas is important for operative planning and subspecialty care because benign myomas are frequently managed with minimally invasive hysterectomy or myomectomy, whereas the mainstay of management of uterine sarcomas is hysterectomy without specimen fragmentation. Preoperative clinical presentation, serum studies, imaging, and histologic examination all have limitations in establishing a preoperative diagnosis. In addition, patients are often of reproductive age and desire fertility preservation. Although surgery remains the cornerstone for management, high-quality data guiding best practices are sparse. Morcellation should be avoided. Expert pathologic review, imaging to assess for metastatic disease, and consideration of hormone receptor testing are advisable. Recent data have further informed surgical approach and fertility preservation in early-stage disease, but controversy remains. Despite substantial advancement in the medical management of uterine sarcomas, surgical management of uterine sarcomas remain challenging. Larger studies with long-term follow-up are needed to guide fertility preservation surgery options, both local resection and ovarian preservation, further in young women. Development of novel methods to differentiate between benign and malignant uterine masses is needed.

Lymph nodes: is total number or station number a better predictor of lymph node metastasis in endometrial cancer?

OBJECTIVE: Gynecologic oncologists have sought to define adequate lymphadenectomy. The purpose of this study is to determine the probability of detecting lymph node metastasis by lymph node count compared to number of nodal stations sampled. METHODS: This is a clinicopathologic review of surgically staged endometrial carcinoma patients from 2000 to 2008. Information was extracted from patients' medical records. Student t-test, Wilcoxon rank sum test, Chi-square and Fisher exact tests were used. Elimination logistic regression was performed to identify independent significant predictors of lymph node metastasis. p<.05 was considered significant for all tests. RESULTS: The study population consisted of 352 patients with a mean age of 65. Forty patients (11.36%) had lymph node metastasis. Number of nodes sampled was not associated with lymph node status on univariate analyses. Patients with lymph node metastases detected was increased when 8 or more nodal stations were sampled compared to less than 8 (19.4% vs. 9.8%, p=.04). More significance was seen when 9 or more stations were sampled (32% vs. 9.8%, p=.004). Multivariate logistic regression analysis, controlling for age, grade, depth of myometrial invasion, number of nodes sampled, and number of nodal stations sampled, found only grade (p=.002), depth of myometrial invasion (p<.0003), and sampling of 9 or more nodal stations (p=.03) to be independent predictors of node status. CONCLUSIONS: Lymph node count did not accurately predict risk of lymph node metastasis. Number of nodal stations sampled was a more precise predictor of lymph node metastases.

Postoperative bowel herniation in a 5-mm nonbladed trocar site.

BACKGROUND: Incisional hernias are a rare complication of laparoscopic surgery, with a reported incidence of <1%. CASE REPORT: We describe a case of bowel herniation and strangulation involving a 5-mm trocar site. CONCLUSION: Although there is growing literature supporting fascial closure of abdominal port sizes ≥ 10 mm, there is sparse data to suggest closure of 5-mm port sites. Our case illustrates that in appropriate clinical scenarios, the possibility of a strangulated hernia involving a 5-mm port site warrants consideration.

Diagnosis and Management of Adenocarcinoma in Situ: A Society of Gynecologic Oncology Evidence-Based Review and Recommendations.

This publication represents an extensive literature review with the goal of providing guidelines for the evaluation and management of cervical adenocarcinoma in situ (AIS). The authors drafted the guidelines on behalf of the Society of Gynecologic Oncology, and the guidelines have been reviewed and endorsed by the ASCCP. These guidelines harmonize with the ASCCP Risk-Based Management Consensus Guidelines and provide more specific guidance beyond that provided by the ASCCP guidelines. Examples of updates include recommendations to optimize the diagnostic excisional specimen, AIS management in the setting of positive compared with negative margins on the excisional specimen, surveillance and definitive management after fertility-sparing treatment, and management of AIS in pregnancy. The increasing incidence of AIS, its association with human papillomavirus-18 infection, challenges in diagnosis owing to frequent origin within the endocervical canal, and the possibility of skip lesions all make AIS a unique diagnosis whose management needs to be differentiated from the management of the more prevalent squamous cell dysplasia.

Neoadjuvant chemotherapy in patients with advanced endometrial cancer.

OBJECTIVES: Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is a treatment strategy for ovarian cancer patients with unresectable disease or poor performance status (PS). This strategy has been used in the treatment of advanced endometrial cancer and a survival benefit has been shown in patients who are subsequently able to undergo interval cytoreduction. This study sought to review our single institution experience with NACT for advanced endometrial cancer. METHODS: We conducted a retrospective review of all patients who received NACT for advanced endometrial cancer at two institutions in New York City between 2002 and 2016. RESULTS: We identified 39 patients (median age 61, range 35-89). The histologic subtype distribution was: serous (44%), endometrioid (28%), carcinosarcoma (10%), clear cell (8%), mixed (8%), neuroendocrine (3%). Contraindications to primary surgery included: unresectable disease (72%), poor PS (15%), unresectable disease and poor PS (13%). Twenty-three patients (59%) did not undergo IDS due to: progression of disease (70%), medical ineligibility (4%), unresectable disease (17%), lost to follow-up (4%), death (4%). Sixteen patients (41%) underwent IDS, 81% had an optimal cytoreduction. Disease status at NACT completion was: partial response (56%), stable disease (3%) and progression of disease (41%). There were no complete responses. Patients who responded to NACT had a significantly longer overall survival than those who did not (15 vs. 5 months. P = 0.015). IDS was also associated with an improvement in overall survival versus no surgery (16 vs. 6 months, P = 0.04). CONCLUSIONS: Unlike ovarian cancer, less than half of the patients undergoing NACT for endometrial cancer underwent IDS, none had a complete response, and 41% had disease progression during NACT. However, endometrial cancer patients who underwent IDS had a high rate of optimal cytoreduction. Both response to NACT and IDS were associated with improved survival.

Carboplatin (every 21 days) and divided-dose paclitaxel (days 1, 11): rationale and tolerance in chemotherapy naïve women with high-grade epithelial cancers of Mullerian origin.

PURPOSE: We report here on the tolerance of a carboplatin-'divided dose' paclitaxel (given on days 1 and 11) regimen in chemotherapy-naïve patients with resected and staged endometrial epithelial neoplasms deemed at high-risk of recurrence or early stage epithelial high-grade serous tubo-ovarian adenocarcinomas after risk-reducing surgery. More recently, we applied this regimen as neoadjuvant chemotherapy for advanced ovarian cancer presentations. METHODS: A retrospective chart review of patients receiving this day 1, 11 paclitaxel regimens in combination with carboplatin at AUC 6 every 3 weeks since 2004 was carried out by the second author with subsequent updates by the first and third authors. Tolerance over the first three cycles was analyzed. RESULTS: A total of 27 women were treated with at least three cycles of this paclitaxel 'divided dose' schedule combined with carboplatin: 6 had endometrial adenocarcinoma, 9 had early stage ovarian cancer, and 12 received it as part of neoadjuvant therapy prior to undergoing cytoreductive surgery. Only 14 of 27 patients required dose reductions to complete the first three cycles of treatment. CONCLUSIONS: A median of three cycles of divided dose paclitaxel (D1, D11) concurrent with carboplatin dosed every 3 weeks was found to be safe and feasible as adjuvant to surgery in early endometrial and ovarian cancers or as neoadjuvant treatment in chemotherapy-naive women with ovarian cancer.

Dual mTORC1/2 Inhibition as a Novel Strategy for the Resensitization and Treatment of Platinum-Resistant Ovarian Cancer.

There is considerable interest in the clinical development of inhibitors of mTOR complexes mTORC1 and 2. Because mTORC1 and its downstream mRNA translation effectors may protect against genotoxic DNA damage, we investigated the inhibition of mTORC1 and mTORC1/2 in the ability to reverse platinum resistance in tissue culture and in animal tumor models of serous ovarian cancer. Cell survival, tumor growth, PI3K-AKT-mTOR pathway signaling, DNA damage and repair response (DDR) gene expression, and translational control were all investigated. We show that platinum-resistant OVCAR-3 ovarian cancer cells are resensitized to low levels of carboplatin in culture by mTOR inhibition, demonstrating reduced survival after treatment with either mTORC1 inhibitor everolimus or mTORC1/2 inhibitor PP242. Platinum resistance is shown to be associated with activating phosphorylation of AKT and CHK1, inactivating phosphorylation of 4E-BP1, the negative regulator of eIF4E, which promotes increased cap-dependent mRNA translation and increased levels of CHK1 and BRCA1 proteins. Animals with platinum-resistant OVCAR-3 tumors treated with carboplatin plus mTORC1/2 inhibition had significantly longer median survival and strikingly reduced metastasis compared with animals treated with carboplatin plus everolimus, which inhibits only mTORC1. Reduced tumor growth, metastasis, and increased survival by mTORC1/2 inhibition with carboplatin treatment was associated with reduced AKT-activating phosphorylation and increased 4E-BP1 hypophosphorylation (activation). We conclude that mTORC1/2 inhibition is superior to mTORC1 inhibition in reversing platinum resistance in tumors and strongly impairs AKT activation, DNA repair responses, and translation, promoting improved survival in the background of platinum resistance. Mol Cancer Ther; 15(7); 1557-67. ©2016 AACR.

Cross-Sectional Study of the Impact of a Natural Disaster on the Delivery of Gynecologic Oncology Care.

OBJECTIVE: We aimed to compare access to gynecologic oncology care at a private and a city hospital, both of which closed for a period of time because of Hurricane Sandy. METHODS: This was a cross-sectional study of gynecologic oncology chemotherapy, radiotherapy, and surgical patients from October 29, 2012 (the eve of the storm), to February 7, 2013 (the reopening of the city hospital). New referrals during this time were excluded. Delays in chemotherapy, radiotherapy, and surgery were compared. RESULTS: Analysis included 113 patients: 59 private patients (52.2%) and 54 city patients (47.8%). Of the private patients, 33/59 received chemotherapy (55.9%), 1/59 received radiotherapy (1.7%), and 28/59 had planned surgery (47.5%). Of the city patients, 40/54 received chemotherapy (74.1%), 7/54 received radiotherapy (12.3%), and 18/54 had planned surgery (33.3%). The mean delay in chemotherapy was 7.6 days at the private hospital and 21.7 days at the city hospital (P=0.0004). The mean delay in scheduled surgery was 14.2 days at the private hospital and 22.7 days at the city hospital (P=0.3979). The mean delay in radiotherapy was 0.0 days at the private hospital and 25.0 days at the city hospital (P=0.0046). Loss to follow-up rates were 3/59 of the private patients (5.1%) and 3/54 of the city patients (5.6%). CONCLUSIONS: Gynecologic oncology care was maintained during a natural disaster despite temporary closure and relocation of services. Disparity in care was in access to chemotherapy.

A pharmacokinetic evaluation of topotecan as a cervical cancer therapy.

INTRODUCTION: Topotecan was initially approved for the treatment of recurrent ovarian cancer. In cervical cancer, it has been investigated for its potential as part of systemic therapy for advanced and/or recurrent disease and in combination with cisplatin and radiation as a first-line treatment for advanced disease. As a topoisomerase I (topo I) inhibitor, its activity is predicted to be schedule-dependent and potentiated in a schedule-dependent manner by its interaction with DNA damaging agents. AREAS COVERED: The cytotoxicity of topotecan is believed to be due to double-stranded DNA damage produced when the DNA replication 'fork' on the opposing DNA strand is interrupted by the ternary complex formed by topotecan, topoisomerase I and DNA. This review focuses on: i) combination studies of cisplatin + topotecan both as neoadjuvant and with concomitant radiation; ii) adding this drug as a radiosensitizer in pilot studies for locally advanced disease and iii) topotecan as part of non-cisplatin combinations in metastatic disease. EXPERT OPINION: Cervical cancer continues to claim many victims among parts of the world where early detection and/or vaccination programs are not systemically applied. Topotecan is an attractive building block for improving therapy against advanced disease.