A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer.

BACKGROUND: Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer. PRIMARY OBJECTIVE: The primary objective is to evaluate the efficacy of intra-peritoneal Olvi-Vec followed by platinum-based chemotherapy and bevacizumab in patients with platinum-resistant/refractory ovarian cancer. STUDY HYPOTHESIS: This phase III study investigates Olvi-Vec oncolytic immunotherapy followed by platinum-based chemotherapy and bevacizumab as an immunochemotherapy evaluating the hypothesis that such sequential combination therapy will prolong progression-free survival (PFS) and bring other clinical benefits compared with treatment with platinum-based chemotherapy and bevacizumab. TRIAL DESIGN: This is a multicenter, prospective, randomized, and active-controlled phase III trial. Patients will be randomized 2:1 into the experimental arm treated with Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or the control arm treated with platinum-doublet chemotherapy and bevacizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have recurrent, platinum-resistant/refractory, non-resectable high-grade serous, endometrioid, or clear-cell ovarian, fallopian tube, or primary peritoneal cancer. Patients must have had ≥3 lines of prior chemotherapy. PRIMARY ENDPOINT: The primary endpoint is PFS in the intention-to-treat population. SAMPLE SIZE: Approximately 186 patients (approximately 124 patients randomized to the experimental arm and 62 to the control arm) will be enrolled to capture 127 PFS events. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2024 with presentation of primary endpoint results in 2025. TRIAL REGISTRATION: NCT05281471.

Cranial and intra-axial metastasis originating from a primary ovarian Dysgerminoma.

Dysgerminomas are aggressive germ cell tumors that typically have a favorable prognosis, especially in patients diagnosed with early stage disease. We recount the history of a 23-year-old woman who was treated for a stage IA ovarian dysgerminoma in November 2017. Postoperatively, the patient was noncompliant insofar as obtaining routine lab evaluations; ten months later, she was diagnosed with a cranial metastasis that extended into the meninges. The patient subsequently underwent a posterior fossa craniotomy and adjuvant etoposide, bleomycin and cisplatin chemotherapy to which she initially responded; however, during cycle 4, she developed pancytopenia whereupon the chemotherapy was summarily discontinued. Thereafter, the patient was surveilled and currently, she remains in clinical remission. Early stage ovarian dysgerminoma, albeit rarely, has the capacity to metastasize to the cranium or brain, further underscoring the significance of employing active follow-up with these patients.

The incidence of occult malignancy following uterine morcellation: A ten-year single institution experience retrospective cohort study.

INTRODUCTION: When the Food and Drug Administration (FDA) initially reported on the parlous incidence (0.28%) of occult malignancy identified following uterine power morcellation, investigations thereafter documented their particular experience with this surgical procedure. Nevertheless, the precise risk of identifying a sarcoma following uterine morcellation remains indeterminate, primarily due to varying study patient risk factors, diagnostic criteria and operative approach. METHOD: We retrospectively evaluated subjects who underwent an endoscopic hysterectomy and uterine power morcellation for the treatment of a presumptive, benign indication from January 2006 until December 2015. The primary outcome was the incidence of an occult malignancy. Secondarily, we were interested in characterizing the patients' specific clinical (age, menopausal status, body mass index (BMI)) risk factors within the context of a confirmed malignant or pre-malignant pathology. RESULTS: We identified 281 patients who underwent endoscopic surgery that incorporated uterine morcellation. During the study period, one subject was ultimately diagnosed with a uterine leiomyosarcoma; the overall incidence of occult malignancy was 0.36%. There were also 3 cases of uterine premalignant disease on final pathology (2 patients had complex hyperplasia with or without atypia and 1 subject was diagnosed with a smooth muscle tumor of uncertain malignant potential (an incidence of 1.1%)). We were unable to establish any relationship between patient age, uterine weight, menopausal status or BMI and the incidence of a malignant or pre-malignant pathology (P > 0.05). CONCLUSION: The rate of occult malignancy in the present investigation was similar to previously documented studies and that which has been reported by the FDA. Additional study of methods in which to enhance preoperative work-up and mitigate the surgical risk for tumor cell dissemination is warranted.

The safety and feasibility of minimally invasive sentinel lymph node staging using indocyanine green in the management of endometrial cancer.

OBJECTIVES: The purpose of this study was to report on the feasibility of laparoscopic sentinel lymph node (SLN) staging using indocyanine green (ICG) in the management of endometrial cancer. STUDY DESIGN: We retrospectively evaluated the charts of presumed, clinical stage I endometrial cancer patients who underwent robotic-assisted surgery that incorporated mapping with ICG and SLN dissection from January 2016 until February 2017. Patient demographics, operative characteristics (e.g., complications, lymph node counts) and pathology data were evaluated. RESULTS: There were 87 patients who were included in the study. A total of 370 lymph nodes were removed, of which 245 were SLNs; unilateral and bilateral mapping of the SLNs was achieved in 84 (96.5%) and 71 (81.6%) of subjects, respectively. There were 10 (11.5%) patients who had metastatic disease identified within 22 (5.9%) of the total (n = 370) lymph nodes extracted, 19 (7.7%) of which were sentinel lymph nodes. We did not observe any intraoperative complications. CONCLUSION: The results from our study suggest that minimally invasive SLN staging using ICG is a feasible procedure that is potentially effective at detecting metastases, which may ultimately attenuate the incidence of surgical morbidity.

Robotic, Laparoscopic, or Open Hysterectomy: Surgical Outcomes by Approach in Endometrial Cancer.

STUDY OBJECTIVES: To compare patient outcomes by surgical approach in the management of endometrial cancer (EC) in Washington State from 2008 to 2013. DESIGN: Population-based retrospective cohort study (Canadian Task Force classification II-2). SETTING: Washington State. PATIENTS: EC patients treated with robotic-assisted surgery (RAS), laparoscopy (LS), or laparotomy (XLAP). INTERVENTIONS: Comprehensive Hospital Abstract Reporting System to identify patients and assess the association of surgical approach with length of stay, readmissions, and perioperative complications. MEASUREMENTS AND RESULTS: We identified 3712 cases of EC managed with either RAS, LS, or XLAP. Mean length of stay was not clinically different for RAS (1.5 days) and LS (1.6 days) but was 2.31 days longer for XLAP compared with LS (p < .001). Odds of any readmission did not differ for either RAS or XLAP compared with LS; however, early readmissions were half as likely for RAS compared with LS (p = .014). Complications were more than 2.5 times as likely for XLAP versus LS (p < .001), whereas complications did not differ for RAS versus LS (p = .931). CONCLUSIONS: RAS is as an alternative to LS in the treatment of EC and is preferable to XLAP. The use of RAS resulted in fewer early readmissions compared with LS and resulted in an increased proportion of cases via minimally invasive surgery.

Surgical and oncologic outcomes after robotic radical hysterectomy as compared to open radical hysterectomy in the treatment of early cervical cancer.

OBJECTIVE: The use of robotic radical hysterectomy has greatly increased in the treatment of early stage cervical cancer. We sought to compare surgical and oncologic outcomes of women undergoing robotic radical hysterectomy compared to open radical hysterectomy. METHODS: The clinic-pathologic, treatment, and recurrence data were abstracted through an Institutional Review Board-approved protocol at 2 separate large tertiary care centers in Seattle, Swedish Medical Center and the University of Washington. Data were collected from 2001-2012. Comparisons between the robotic and open cohorts were made for complications, recurrence, progression-free survival (PFS), and overall survival (OS). RESULTS: In the study period, 109 robotic radical hysterectomies were performed. These were compared to 202 open radical hysterectomies. The groups were comparable in terms of age and body mass index (BMI). Length of stay (LOS) was considerably shorter in the robotic group (42.7 vs. 112.6 hours, p<0.001) as was estimated blood loss (EBL; 105.9 vs. 482.6 mL, p<0.001). There were more complications in the open radical hysterectomy group, 23.4% vs. 9.2% in the robotic group (p=0.002). The recurrence rate was comparable between the groups (10.1% vs. 10.4%, p=0.730). In multivariate adjusted analysis, robotic surgery was not a statistically significant predictor of PFS (p=0.230) or OS (0.85). CONCLUSION: Our study, one of the largest multi-institution cohorts of patients undergoing robotic radical hysterectomy, suggest robotic radical hysterectomy leads to comparable oncologic outcomes in the treatment of early stage cervical cancer with improved short-term surgical outcomes such as decreased LOS and EBL.

Association of endometrial hyperplasia and cancer with a history of gestational diabetes.

PURPOSE: Excess circulating insulin may contribute to endometrial cancer (EC) development; studies suggest increased risk of EC associated with type 2 diabetes. We investigated whether gestational diabetes is associated with increased risk of EC and its precursor, endometrial hyperplasia (EH). METHODS: We conducted a population-based, case-control study of women in Washington State. Cases were women with a hospital discharge record indicating the presence of EH/EC who could be linked to a prior delivery hospitalization or birth record from 1987 to 2013 (n = 593). Controls were randomly selected from remaining deliveries, frequency matched 10:1 on delivery year and maternal age at delivery (n = 5,743). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: After adjustment for race/ethnicity, maternal age at delivery, and delivery year, EH/EC was associated with a history of gestational diabetes (OR 1.73, 95% CI 1.27-2.35). This association was present for both EH and EC (OR 1.61, 95% CI 1.00-2.60 and OR 1.80, 95% CI 1.22-2.65, respectively). After adjustment for prepregnancy body mass index, the OR for EH/EC was attenuated and became statistically non-significant (OR 1.22, 95% CI 0.87-1.72), except in women <50 years old at the time of case ascertainment (OR 1.49, 95% CI 1.00-2.20). Associations were slightly stronger for EC than EH. CONCLUSIONS: We observed an association between EH/EC and a history of gestational diabetes specific to younger women. Future studies focusing on the relationships between gestational diabetes, obesity, and EC, including age at diagnosis, are warranted.

Route of hysterectomy and surgical outcomes from a statewide gynecologic oncology population: is there a role for vaginal hysterectomy?

BACKGROUND: Recent policy changes by insurance companies have been instituted to encourage vaginal hysterectomy (VH) as the preferred route for removal of the uterus. It is not known if advantages of VH for benign indications apply to women with gynecologic cancer. OBJECTIVE: The goal of this study was to assess trends in surgical approach to hysterectomy among gynecologic cancer patients and to evaluate outcomes by approach. We hypothesized that, among gynecologic oncology patients, postoperative complications and hospital stay would differ by surgical approach, and that advantages of VH for benign indications may not apply to gynecologic cancer patients. STUDY DESIGN: We performed a population-based retrospective cohort study of cervical, endometrial, or ovarian/fallopian tube cancer patients treated surgically in Washington State from 2004 through 2013 using the Comprehensive Hospital Abstract Reporting System. Surgery was categorized as abdominal hysterectomy (AH), laparoscopic hysterectomy (LH), or VH. We determined rate of surgical approach by year and the association with length of stay, 30-day readmission rate, and perioperative complications. RESULTS: We identified 10,117 patients who underwent surgery for gynecologic cancer, with 346 (3.4%) VH, 2698 (26.7%) LH, and 7073 (69.9%) AH. Patients undergoing AH had more comorbidities than patients with VH or LH (Charlson Comorbidity Index ≥2: 11.3%, 7.9%, and 8.1%, respectively; P < .001). From 2004 through 2013 AH and VH declined (94.4-47.9% and 4.4-0.8%, respectively; P < .001) while LH increased from 1.2-51.4% in 2013 (P < .001). Mean length of stay was 4.6 days for women undergoing AH and was 1.9 days shorter for VH (95% confidence interval, 1.6-2.3 days) and 2.6 days shorter for LH (95% confidence interval, 2.4-2.7 days) (P < .001). Risk of 30-day readmission for patients undergoing LH was 40% less likely compared to AH but not different for VH vs AH. CONCLUSION: AH and LH remain the preferred routes for hysterectomy in gynecologic oncology. Over the past decade, there has been a significant shift to LH with lower 30-day readmission and complication rates. There may be a limited role for VH in select patients. Current efforts to standardize the surgical approach to hysterectomy should not apply to patients with known or suspected gynecologic cancer.

The Role of High-Risk Human Papilloma Virus Testing in the Surveillance of Cervical Cancer After Treatment.

CONTEXT: Cervical cancer affects 12 000 women in the United States annually. However, despite its prevalence, there remains no good methodology to detect its recurrence. OBJECTIVE: To identify the role of cervicovaginal high-risk human papilloma virus (hr-HPV) testing in predicting cervical cancer recurrence. DESIGN: This is a retrospective study of patients who underwent hr-HPV testing as part of their routine surveillance for cervical cancer. Standard statistical analyses, including χ² test and multivariable logistic regression, were performed with IBM SPSS 19.0. RESULTS: A total of 133 patients were identified, of whom 107 (80%) had squamous cell carcinoma. Ninety patients (68%) had bulky disease and were treated primarily with chemoradiation and brachytherapy. Of patients whose disease recurred, 5 patients (42%) had tested positive for hr-HPV during their surveillance period, compared to 13 patients (11%) for whom disease did not recur (relative risk: 3.88, P = .002). On multivariate logistic regression, hr-HPV status remained significantly predictive of disease recurrence (odds ratio: 12.3, P = .02, 95% confidence interval: 1.5-99.6). Using 2 × 2 table analysis, we found that while cervicovaginal cytology has limited specificity (5.7%) in predicting recurrence, the combination of cytology with hr-HPV testing increases the specificity of testing to 89.3%. CONCLUSIONS: Persistence of hr-HPV is a risk factor for disease recurrence. High-risk-HPV testing is not routinely used during surveillance for cervical cancer, but this study suggests that large, prospective trials investigating the role of hr-HPV testing in cervical cancer surveillance are needed.

Retreatment with bevacizumab in patients with gynecologic malignancy is associated with clinical response and does not increase morbidity.

PURPOSE: Bevacizumab (Bev) is associated with improved progression-free survival in advanced epithelial ovarian cancer. The use of Bev in patients with gynecologic malignancy is increasing; however, little is known about cumulative toxicity and response in patients retreated with Bev. Our goal was to determine cumulative side effects and response in patients retreated with Bev. PATIENTS AND METHODS: Women with recurrent gynecologic malignancy treated with Bev between January 2007 and March 2012 at a single institution were identified, including a subset who received Bev in a subsequent regimen. The primary outcome was Bev-associated toxicity, and the secondary outcome was response. RESULTS: Of 83 patients that received Bev for recurrent disease, 23 were retreated with Bev and four received Bev maintenance. Three patients (13%) developed grade 3 or 4 hypertension; all had a history of chronic hypertension. One (4.3%) patient developed grade 3 proteinuria, and one (4.3%) developed an enterovaginal fistula. Four patients discontinued Bev secondary to toxicity. Toxicity was not related to the cumulative number of cycles. Twenty-six percent of patients responded to Bev retreatment. On univariate analysis, there was a significant (P=0.003) overall survival advantage when the Bev-free interval was >9 months (95% confidence interval [CI] 4.9-43.7) compared to ≤9 months (95% CI 2.1-11.5), 24.3 months, and 6.8 months. CONCLUSION: Retreatment of patients with recurrent gynecologic malignancy with Bev did not increase morbidity and was associated with treatment response. Physicians treating women with recurrent disease may consider a Bev-containing regimen even if prior regimen(s) included Bev. Future studies should prospectively evaluate the efficacy of this treatment strategy.

Oxaliplatin salvage for recurrent ovarian cancer: a single institution's experience in patient populations with platinum resistant disease or a history of platinum hypersensitivity.

OBJECTIVE: Hypersensitivity reactions can preclude platinum re-challenge for patients receiving second-line and higher carboplatin/cisplatin salvage therapy. The objective is to report our patient experience with oxaliplatin in recurrent or progressive epithelial ovarian (EOC), primary peritoneal (PPC) or fallopian tube cancer (FTC), including those with prior hypersensitivity reaction. METHODS: A single institution, retrospective review from 1995 to 2012 of patients receiving oxaliplatin for treatment of recurrent or progressive EOC, PPC, or FTC was performed. Data collected included patient demographics, diagnosis date, prior chemotherapy regimens, platinum-free interval(s), prior hypersensitivity reactions, oxaliplatin toxicity, length of therapy, disease response, and last follow-up. Those who received ≥1 cycles were included. A response to therapy was determined after ≥2 cycles. RESULTS: Forty-four patients were identified. All had prior carboplatin and 38.6% had prior cisplatin therapy. Twenty-three had a prior platinum hypersensitivity reaction. Patients received a median of 2 prior platinum containing regimens and 5 chemotherapy lines prior to oxaliplatin exposure. One patient experienced grade 3 pain. No grade 4 toxicities occurred. No treatment delays for pancytopenia noted. Nausea and dysesthesias were controlled medically and weren't dose-limiting. No nephropathy or neuropathy progressed on oxaliplatin or were dose-limiting. Disease response was observed in 43.2%. Of the responders, 36.8% had a prior platinum hypersensitivity reaction. Median number of 5 cycles of an oxaliplatin containing regimen was given. Median follow-up was 15.5 months. CONCLUSIONS: In our experience, oxaliplatin is well tolerated and should be considered for platinum challenge after hypersensitivity even in patients with platinum resistant disease with a reasonable chance of response.

Endometrial stromal sarcoma: analysis of recurrence following adjuvant treatment.

OBJECTIVE: Endometrial stromal sarcoma (ESS) is a rare and indolent form of uterine cancer with ill-defined post-operative treatment guidelines. The goal of this study was to evaluate the rate of recurrence and the effect of various adjuvant treatment modalities. METHODS: Patients with ESS at 4 institutions were identified (1986-2007). Patient demographics, pathology, treatment, and follow-up information were collected. Chi-square statistical analysis was performed. RESULTS: Forty-three patients with ESS were identified. All patients initially underwent hysterectomy. Twenty-eight (66.7%) had early stage, 12 (28.6%) had advanced stage ESS, and 2 (4.8%) had no staging information. Eight patients received pelvic and or vaginal cuff radiation treatment, with or without chemotherapy. Sixteen of 43 patients experienced a recurrence at an average of 100.5months. Thirty-three patients were treated with progestin therapy alone or followed expectantly. Complete outpatient records were available for 28 of these patients. Sixteen patients (57%) were followed expectantly while 12 (43%) received progestins. Patients receiving progestins vs. expectant management had a lower rate of recurrence in stage 1 (14.3% vs 38.5%, p=0.26) and all stages (33% vs 50%, p=0.38). Twenty-three of 28 (82.1%) patients underwent initial oophorectomy. Eight of 23 (34.8%) had a recurrence, compared to 4 of 5 (80%) in those who retained their ovaries (p=0.06). CONCLUSIONS: ESS is a rare cancer that is difficult to study. We found removal of the adnexa and post-operative treatment with progestin therapy decreased recurrence rates. These two treatment strategies should be considered in the treatment of patients with all stages of ESS.