Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial.

PURPOSE: Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS: This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS: Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION: Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.

A rare case of follicular dendritic sarcoma of the vagina.

Follicular dendritic sarcoma of the vagina is an exceptionally rare malignancy. Here, we present a reproductive-aged female with no pertinent past medical history who initially presented with a protruding vaginal mass. Pathology from initial excision was consistent with follicular dendritic sarcoma of the vagina. This was ultimately treated with wide radical resection of the mass leading to iatrogenic vaginal stenosis.

Radiofrequency and microwave ablation for treatment of recurrent gynecologic malignancies.

OBJECTIVE: Radiofrequency ablation and microwave ablation are used to vaporize tumors not amenable to surgical resection. We sought to evaluate the safety and efficacy of radiofrequency and microwave ablation for the treatment of isolated lesions in patients with recurrent gynecologic malignancy. METHODS: Patients with gynecologic malignancies treated with radiofrequency or microwave ablation at a university-affiliated cancer center from April 2007 to January 2020 were evaluated. Clinical records were reviewed for number of prior chemotherapy regimens, response to ablation, time to progression, and location of progression. RESULTS: Thirty-two patients received ablative therapy for treatment of isolated recurrences. Seventeen (53%) patients had ovarian cancer, seven (22%) had endometrial cancer, and eight (25%) had cervical cancer. Thirteen (41%) patients received radiofrequency ablation and 19 (59%) received microwave ablation. Patients had a median of 2 (range 1-12) prior lines of chemotherapy. Sixteen (50%) patients achieved a partial or complete response with two patients experiencing no progression at time of submission. Six (19%) patients had stable disease and 10 (31%) patients had progression at time of initial follow-up imaging. Median progression-free survival for the cohort was 7.3 months (range 1.4-64.7). No significant improvement in median progression-free survival was seen with the addition of adjuvant systemic therapy to radiofrequency or microwave ablation (6.9 vs 7.7 months; HR 0.7, 95% CI 0.3 to 1.7). Clinical benefit, defined as absence of definitive progression at the site of ablation or new target lesions at 4 months, was seen in 22 (68.8%) patients. No major complications occurred, with two patients reporting pain or weakness at the site of ablation. CONCLUSION: Radiofrequency and microwave ablation demonstrated that 68.8% (n=22) of patients experienced clinical benefit at 4 months. Ablative therapy may be considered for the treatment of isolated lesions in patients with recurrent gynecologic malignancies.

FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways.

Focal adhesion kinase (FAK) is highly expressed in a variety of human cancers and is a target for cancer therapy. Since FAK kinase inhibitors only block the kinase activity of FAK, they are not highly effective in clinical trials. FAK also functions as a scaffold protein in a kinase-independent pathway. To effectively target FAK, it is required to block both FAK kinase-dependent and FAK-independent pathways. Thus, we tested a new generation drug FAK PROTAC for ovarian cancer therapy, which blocks both kinase and scaffold activity. We tested the efficacy of FAK PROTAC and its parent kinase inhibitor (VS-6063) in ovarian cancer cell lines in vitro by performing cell functional assays including cell proliferation, migration, invasion. We also tested in vivo activity in orthotopic ovarian cancer mouse models. In addition, we assessed whether FAK PROTAC disrupts kinase-dependent and kinase-independent pathways. We demonstrated that FAK PROTAC is highly effective as compared to its parent FAK kinase inhibitor VS-6063 in inhibiting cell proliferation, survival, migration, and invasion. FAK PROTAC not only inhibits the FAK kinase activity but also FAK scaffold function by disrupting the interaction between FAK and its interaction protein ASAP1. We further showed that FAK PROTAC effectively inhibits ovarian tumor growth and metastasis. Taken together, FAK PROTAC inhibits both FAK kinase activity and its scaffold protein activity by disrupting the interaction between FAK and ASAP1 and is highly effective in inhibiting ovarian tumor growth and metastasis.

Intergenerational gestational surrogacy in a patient with ovarian dysgerminocarcinoma.

A 20-year-old woman was diagnosed with an ovarian dysgerminoma on the right ovary and underwent fertility-preserving right salpingo-oophorectomy and staging. Eight months later she was found to have a left ovarian solid mass. She underwent controlled ovarian hyperstimulation and oocyte cryopreservation before total abdominal hysterectomy, left salpingo-oophorectomy, and exploratory surgery were performed. The patient was optimally debulked, with no recurrent cancer to date. Thirty-six oocytes were mature and cryopreserved using vitrification. Now, the patient's mother has undergone embryo transfer that resulted in a clinical pregnancy, acting as a gestational carrier, for her daughter. To our knowledge, this is the first case describing the uterine transfer of embryos into a gestational carrier where the embryos were generated using oocytes obtained through controlled ovarian hyperstimulation in the context of active ovarian cancer. In the appropriate clinical setting, women desiring future fertility with a diagnosis of ovarian cancer without the option of ovarian-sparing surgery may be candidates for controlled ovarian hyperstimulation for the purposes of fertility preservation, especially if altruistic gestational carriers are available and willing.

Same-day discharge after robotic surgery for endometrial cancer.

To assess the safety of same-day discharge (SDD) following robotic-assisted endometrial cancer staging and identify risk factors for postoperative admission in a diverse population. A review of patients who underwent robotic-assisted endometrial cancer staging from April 1, 2017 to April 1, 2019 was performed. Patients were evaluated for SDD if they met the following criteria: tolerating oral intake, voiding spontaneously, ambulating, negative orthostatic vitals, postoperative hemoglobin ≤ 2 g/dL from baseline, pain controlled on oral medications, and desire to be discharged. Risk factors for admission were identified. One hundred eighty-seven patients were identified. SDD criteria were met in 158, of which 132 (83.5%) were discharged same day. Median length of stay was 4.5 h. Reasons for admission despite meeting criteria were late surgery time (n = 15), abnormal vitals (n = 9), and personal concerns (n = 2), with risk factors being age ≥ 68 years (OR 2.72; 95% CI, 1.13-6.59), start time 1400 or later (OR = 11.25; 95% CI, 4.35-29.10), ASA ≥ 4 (OR 23.82; 95% CI, 2.54-223.15), history of CVA/MI (OR 5.61; 95% CI, 1.07-29.52), and operative time ≥ 120 min (OR = 3.83; 95% CI 1.36-10.77). Of the SDD cohort, 2 patients (1.3%) presented to the emergency room within 30 days (postoperative day 5 and 23). SDD following robotic-assisted endometrial cancer staging is safe and feasible. Age ≥ 68 years, surgery start time after 1400, ASA ≥ 4, history of CVA/MI, and operative time ≥ 120 min appear predictive of inpatient admission despite meeting SDD criteria.

NCCN Guidelines Insights: Cervical Cancer, Version 1.2020.

The NCCN Guidelines for Cervical Cancer provide recommendations for diagnostic workup, staging, and treatment of patients with the disease. These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to first- and second-line systemic therapy recommendations for patients with recurrent or metastatic disease, and emerging evidence on a new histopathologic classification system for HPV-related endocervical adenocarcinoma.

Gestational Trophoblastic Neoplasia, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Gestational trophoblastic neoplasia (GTN), a subset of gestational trophoblastic disease (GTD), occurs when tumors develop in the cells that would normally form the placenta during pregnancy. The NCCN Guidelines for Gestational Trophoblastic Neoplasia provides treatment recommendations for various types of GTD including hydatidiform mole, persistent post-molar GTN, low-risk GTN, high-risk GTN, and intermediate trophoblastic tumor.

Cervical Cancer, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology.

Cervical cancer is a malignant epithelial tumor that forms in the uterine cervix. Most cases of cervical cancer are preventable through human papilloma virus (HPV) vaccination, routine screening, and treatment of precancerous lesions. However, due to inadequate screening protocols in many regions of the world, cervical cancer remains the fourth-most common cancer in women globally. The complete NCCN Guidelines for Cervical Cancer provide recommendations for the diagnosis, evaluation, and treatment of cervical cancer. This manuscript discusses guiding principles for the workup, staging, and treatment of early stage and locally advanced cervical cancer, as well as evidence for these recommendations. For recommendations regarding treatment of recurrent or metastatic disease, please see the full guidelines on NCCN.org.

Celecoxib versus ketorolac following robotic hysterectomy for the management of postoperative pain: An open-label randomized control trial.

OBJECTIVE: Compare postoperative pain scores following hysterectomy in patients receiving perioperative celecoxib versus postoperative ketorolac as part of a multimodal pain regimen. METHODS: Patients undergoing hysterectomy were randomized to receive scheduled intravenous ketorolac in the immediate postoperative period or oral celecoxib prior to surgery and continued for a total seven days. All patients received a common multimodal pain protocol consisting of scheduled acetaminophen, gabapentin, and opioids as needed. Inpatient pain scores and postoperative opioid use were analyzed. A questionnaire regarding outpatient opioid use and return to normal activities of daily living (ADLs) was returned two weeks postoperatively. RESULTS: 192 patients were assessed for eligibility and 170 patients were randomized. Enrollment of patients undergoing open hysterectomy was closed prematurely for poor accruement (n = 32). 138 patients undergoing robotic hysterectomy were included were analyzed. There were no differences for inpatient pain scores (2.7 ±â€¯1.9 v. 2.4 ±â€¯1.6, p = 0.21). Average length of stay was similar between the two arms (11.6 ±â€¯8.1 h v. 11.9 ±â€¯7.6 h, p = 0.41). Patients in the celecoxib arm used less prescription opioids (6.0 ±â€¯3.6 v. 8.1 ±â€¯4.0, p = 0.001) and stopped using oral opioids earlier (3.8 ±â€¯2.6 days v. 5.7 ±â€¯2.8 days, p < 0.001). No differences were seen in inpatient opioid or anti-emetic usage, perioperative complications, or days to return to ADLs. CONCLUSIONS: There was no difference in inpatient pain scores between patients who received celecoxib or ketorolac as part of multimodal pain control following robotic hysterectomy. Patients who received scheduled celecoxib for seven days after surgery used less prescription narcotics.

Use of a web-based app to improve postoperative outcomes for patients receiving gynecological oncology care: A randomized controlled feasibility trial.

OBJECTIVE: Nearly 1 in 5 patients hospitalized for ovarian cancer surgery are readmitted for complications that may have been prevented with monitoring. We conducted a randomized controlled feasibility trial to evaluate a postoperative web-based app intervention to provide real-time symptom monitoring among patients diagnosed or with suspected gynecological cancer who had open bilateral salpingo-oophorectomy surgery. METHODS: Participants were randomized into two groups: (1) App + Reminder: had access to the app, and use was encouraged with daily and/or weekly reminders; (2) app: had access to the app but received no reminders. The app displayed discharge instructions and queried symptoms. Patients' self-reported health information was integrated into their electronic health records. Outcomes above a predetermined threshold triggered alerts that indicated a patient may need medical intervention. Participants completed a questionnaire at baseline and 30-day follow-up. They were also invited to provide qualitative, post-intervention feedback. RESULTS: We screened 35 patients, with high rates of recruitment (74%, N = 26) and completion (93%, N = 24). Participants in the App + Reminder group had more frequent app use relative to the app group (p = 0.05). Using differences-in-differences (DID) analysis for quality of life, the App + Reminder group had relative increase in the mental health score (DID = 7.51, p = 0.15) but decrease in the physical health score (DID = -7.49, p = 0.13). Participant feedback suggested the relative decrease in physical quality of life was attributable to the app activating patients' focus on physical symptoms, not the intervention. CONCLUSION: The pilot established feasibility, acceptability, and some potential benefits of a new web-based app intervention for gynecological oncology postoperative care.

Uterine Neoplasms, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

Endometrial carcinoma is a malignant epithelial tumor that forms in the inner lining, or endometrium, of the uterus. Endometrial carcinoma is the most common gynecologic malignancy. Approximately two-thirds of endometrial carcinoma cases are diagnosed with disease confined to the uterus. The complete NCCN Guidelines for Uterine Neoplasms provide recommendations for the diagnosis, evaluation, and treatment of endometrial cancer and uterine sarcoma. This manuscript discusses guiding principles for the diagnosis, staging, and treatment of early-stage endometrial carcinoma as well as evidence for these recommendations.

Vulvar Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is a rare gynecologic malignancy. Ninety percent of vulvar cancers are predominantly squamous cell carcinomas (SCCs), which can arise through human papilloma virus (HPV)-dependent and HPV-independent pathways. The NCCN Vulvar Cancer panel is an interdisciplinary group of representatives from NCCN Member Institutions consisting of specialists in gynecological oncology, medical oncology, radiation oncology, and pathology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vulvar Cancer provide an evidence- and consensus-based approach for the management of patients with vulvar SCC. This manuscript discusses the recommendations outlined in the NCCN Guidelines for diagnosis, staging, treatment, and follow-up.

Video-assisted genetic counseling in patients with ovarian, fallopian and peritoneal carcinoma.

OBJECTIVES: To compare the proportion of patients with ovarian, fallopian or peritoneal carcinoma who receive genetic testing after observing a genetic counseling video versus after traditional referral for genetic counseling and testing at physician discretion. METHODS: A retrospective chart review was performed of all patients seen at the West Cancer Center for evaluation of ovarian, fallopian or peritoneal carcinoma from 7/2014 to 8/2015. Patients seen between 7/2014 and 12/2014 were offered standard genetic counseling. We adopted a new standard of care from 3/2015 to 8/2015 involving the use of a genetic counseling video on a digital tablet. The video was shown to patients with ovarian, fallopian or peritoneal cancer, who were then given the option to undergo genetic testing at the end of the viewing. We compared the number and proportion of patients who received genetic testing in both groups. RESULTS: The initial group of 267 patients received referral and te\sting at the physician's discretion between 8/2014 and 12/2014. 77/267 (29%) of these patients underwent genetic testing. 295 patients viewed the condensed genetic counseling video with the option to receive testing the same day between 3/2015 and 8/2015. 162/295 (55%) of these patients received testing. The transition from a referral method to the video counseling method resulted in a significant increase of patients tested (p<0.001). CONCLUSION: Using a genetic counseling video and providing an immediate option for testing significantly increased the proportion of patients with ovarian, fallopian or peritoneal carcinoma who received genetic testing.

Fertility Preservation Through Oocyte Cryopreservation in a Patient with Ovarian Dysgerminocarcinoma: A Case Report.

BACKGROUND: This case evaluates a 20-year-old patient diagnosed with recurrent dysgerminoma who desired fertility preservation. CASE: A 20-year-old woman, GOPO, with a history of fertility-preserving right salpingo-oophorectomy and staging for dysgerminoma presented with interval change of a 5-cm left ovarian solid mass on ultrasound evaluation concerning for recurrent carcinoma. She underwent controlled ovarian hyperstimulation with injectable gonadotropins followed by transvaginal oocyte retrieval immediately followed by laparotomy, at which time ovarian dysgerminoma was confirmed. Completion total abdominal hysterectomy, left salpingo-oophorectomy, and exploratory surgery were performed. Forty-five oocytes were obtained, of which 37 mature oocytes were isolated and cryopreserved. The patient had an unremarkable postoperative course and was discharged home. CONCLUSION: Oncofertility preservation through oocyte cryopreservation may be considered a viable option for young women with ovarian cancer.

Uterine Sarcoma, Version 1.2016: Featured Updates to the NCCN Guidelines.

The NCCN Guidelines for Uterine Neoplasms provide interdisciplinary recommendations for treating endometrial carcinoma and uterine sarcomas. These NCCN Guidelines Insights summarize the NCCN Uterine Neoplasms Panel's 2016 discussions and major guideline updates for treating uterine sarcomas. During this most recent update, the panel updated the mesenchymal tumor classification to correspond with recent updates to the WHO tumor classification system. Additionally, the panel revised its systemic therapy recommendations to reflect new data and collective clinical experience. These NCCN Guidelines Insights elaborate on the rationale behind these recent changes.

Comparison of bevacizumab alone or with chemotherapy in recurrent ovarian cancer patients.

BACKGROUND: To compare the efficacy of chemotherapy (C) combined with bevacizumab (Bev) versus Bev alone in recurrent, heavily pretreated epithelial ovarian cancer (EOC). METHODS: A multicenter analysis of patients treated from 2004 to 2011 was performed. Demographic, treatment, response, and adverse event information were obtained. Progression-free (PFS) and overall survival (OS) were analyzed. RESULTS: Of 277 patients (median age: 58years), the majority had Stage III and IV (86%) disease, and 72% had serous histology. 244 (88%) were treated with C+Bev and 33 (12%) with Bev. Corresponding median progression-free survival (PFS) was 8.7 and 6.7months, and median overall survival (OS) was 14.3 and 10.5months, respectively. The chemotherapeutic agents combined with Bev and the median OS include: pegylated liposomal doxorubicin (n=19, OS of 20.4months), taxanes (n=55, OS of 20.2months), gemcitabine (n=106, OS of 14.1months), topotecan (n=43, OS of 13months), and cyclophosphamide (n=21, OS of 13months). There was no significant difference in toxicities between the C+Bev vs. Bev alone group. CONCLUSION: This retrospective analysis supports that combination chemotherapy and bevacizumab prolongs PFS and OS compared with bevacizumab alone.

Cervical Cancer, Version 2.2015.

The NCCN Guidelines for Cervical Cancer provide interdisciplinary recommendations for treating cervical cancer. These NCCN Guidelines Insights summarize the NCCN Cervical Cancer Panel's discussion and major guideline updates from 2014 and 2015. The recommended systemic therapy options for recurrent and metastatic cervical cancer were amended upon panel review of new survival data and the FDA's approval of bevacizumab for treating late-stage cervical cancer. This article outlines relevant data and provides insight into panel decisions regarding various combination regimens. Additionally, a new section was added to provide additional guidance on key principles of evaluation and surgical staging in cervical cancer. This article highlights 2 areas of active investigation and debate from this new section: sentinel lymph node mapping and fertility-sparing treatment approaches.