An open-label, single-arm, prospective, multi-center, tandem two-stage designed phase II study to evaluate the efficacy of fulvestrant in women with recurrent/metastatic estrogen receptor-positive gynecological malignancies (FUCHSia study).

OBJECTIVE: This study aimed to evaluate fulvestrant efficacy in women with estrogen receptor-positive low-grade gynecological cancers. The primary objective was to determine the response rate. Secondary objectives were progression-free survival, clinical benefit, duration of response, safety, tolerability, and quality of life. METHODS: FUCHSia is an open-label, single-arm, prospective, multi-center phase II study. The study population included patients with recurrent/metastatic low-grade gynecological malignancies with estrogen receptor positivity who received a maximum of two lines of previous hormonal therapy. Patients received fulvestrant (FASLODEX, AstraZeneca) via two intramuscular injections (250 mg/5 mL each) in the gluteal muscle on day 1, day 15, day 29, and then every 28 days thereafter until disease progression, withdrawal from the trial due to any unacceptable adverse event, or withdrawal of patient consent. RESULTS: A total of 15 patients (uterine sarcoma n=4; sex cord-stromal ovarian tumors n=3; endometrial carcinoma n=4; serous ovarian cancer n=4) were enrolled. Median follow-up was 48 weeks (interquartile range (IQR) 26-122) in the uterine sarcoma cohort, 63 weeks (IQR 28-77) for sex cord-stromal tumors, 19 weeks (IQR 17-21) for endometrial carcinoma, and 60 weeks (IQR 40-119) for serous ovarian cancer. One partial response according to Response Evaluation Criteria in Solid Tumors v1.1 was observed in one uterine sarcoma patient. No responses were observed in the other cohorts. However, stable disease was observed in three uterine sarcomas (median duration 12 weeks), three sex cord-stromal tumors (median duration 32 weeks), and four low-grade serous ovarian cancer patients (median duration 20 weeks), leading to a disease control rate of 100% for these tumor types. All patients with endometrial carcinoma showed progressive disease. CONCLUSION: Fulvestrant may control tumor growth in recurrent/metastatic estrogen receptor-positive low-grade gynecological malignancies of specific histology. Further studies are needed to confirm these results.

Expanding the Use of HIPEC in Ovarian Cancer at Time of Interval Debulking Surgery to FIGO Stage IV and After 6 Cycles of Neoadjuvant Chemotherapy: A Prospective Analysis on Perioperative and Oncologic Outcomes.

BACKGROUND: Randomized data on patients with FIGO stage III ovarian cancer receiving ≤ 3 cycles of neoadjuvant chemotherapy (NACT) showed that hyperthermic intraperitoneal chemotherapy (HIPEC) after interval debulking surgery (IDS) improved patient's survival. We assessed the perioperative outcomes and PFS of FIGO stage IV and/or patients receiving up to 6 cycles of NACT undergoing IDS+HIPEC. METHODS: Prospectively collected cases from January 1, 2019 to July 31, 2022 were included. Patients underwent HIPEC if: age ≥ 18 years but < 75 years, body mass index ≤ 35 kg/m2, ASA score ≤ 2, FIGO stage III/IV epithelial disease treated with up to 6 cycles of NACT, and residual disease < 2.5 mm. RESULTS: A total of 205 patients were included. No difference was found in baseline characteristics between FIGO Stage III and IV patients, whereas rate of stable disease after NACT (p = 0.004), mean surgical complexity score at IDS (p = 0.001), and bowel resection rate (p = 0.046) were higher in patients undergoing delayed IDS. A lower rate of patients with at least one G3-G5 postoperative complications was observed in FIGO stage IV versus FIGO stage III disease (5.3% vs. 14.0%; p = 0.052). This difference was confirmed at multivariable analysis (odds ratio [OR] 0.24; 95% confidence interval [CI] 0.07-0.80; p = 0.02), whereas age, SCS, bowel resection, and number of cycles did not affect postoperative complications. No difference in PFS was identified neither between FIGO stage III and IV patients (p = 0.44), nor between 3 and 4 versus > 4 cycles of NACT (p = 0.85). CONCLUSIONS: Because of the absence of additional complications and positive survival outcomes, HIPEC administration can be considered in selected FIGO stage IV and patients receiving > 4 cycles of NACT.

Current and future trials about HIPEC in ovarian cancer.

Due to the typical peritoneal spread of the disease, together with cytoreductive surgery and adjuvant platinum-based chemotherapy, the role of hyperthermic intraperitoneal chemotherapy (HIPEC) is gainig more interest in advanced ovarian cancer (AOC) treatment. Indeed, the addition of hyperthemia seems to enhance the cytotoxic effect of chemotherapy directly delivered on peritoneal surface. So far, data on HIPEC administration during the primary debulking surgery (PDS) have been controversial. Indeed, despite flaws and biases, a survival advantage in a subgroup analysis of a prospective randomized trial of PDS+HIPEC treated patients was not demonstrated, whilst positive results are coming from a large retrospective cohort of patients treated with HIPEC after upfront surgery. In this setting, larger prospective data from an ongoing trial are expected by 2026. Contrariously, the addition of HIPEC with cisplatin 100mg/m2 at the time of interval debulking surgery (IDS) has shown to prolong both progression-free and overall survival by prospective randomized data, despite few controversies on the methodology and the results of this trial arose among the experts. So far, available high quality data on HIPEC treatment after surgery for disease recurrence failed to demonstrate a survival benefit in this group of patients, however few trials are ongoing and results are awaited. With this article, we aim to discuss the main findings of available evidence and the objectives of ongoing trials on the addition of HIPEC to various timing of cytoreductive surgery in AOC, also in view of the development of precision medicine and targeted therapies in AOC treatment.

Improving Endometrial cancer assessment by combining the new techniqUe of GENomic profiling with surgical Extra uterIne disEase assessment (EUGENIE).

BACKGROUND: The molecular classification of endometrial cancer revolutionized our knowledge of its biology but so far has not affected our surgical approach. The exact risk of extra-uterine metastasis and hence the type of surgical staging for each of the four molecular subgroups are currently unknown. PRIMARY OBJECTIVE: To determine the association between molecular classification and disease stage. STUDY HYPOTHESIS: Each endometrial cancer molecular subgroup has a specific pattern of spread and this pattern of spread could guide the extent of surgical staging. TRIAL DESIGN: Prospective, multicenter study MAJOR INCLUSION/EXCLUSION CRITERIA: Participants eligible for inclusion in this study must meet all the following criteria: women ≥18 years with primary endometrial cancer, any histology and stage. PRIMARY ENDPOINT: Number and site of metastasis in each endometrial cancer molecular subgroup. SAMPLE SIZE: 1000 patients will be enrolled. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The trial will last 6 years: 4 years of accrual, and 2 years of follow-up of all patients. Results on staging and oncological outcomes are expected in 2027 and 2029, respectively. TRIAL REGISTRATION: The study has been accepted by UZ Leuven Ethical Committee. Belg. Reg. nr: B3222022000997.

The impact of hysterectomy on oncological outcomes in postmenopausal patients with borderline ovarian tumors: A multicenter retrospective study.

Data about the oncological outcomes in women with borderline ovarian tumor (BOT) undergoing uterine-sparing surgery without ovarian preservation are poor. We aimed to assess the oncological outcomes in women with BOT undergoing uterine-sparing surgery without ovarian preservation. A multi-center observational retrospective cohort study was performed including all consecutive postmenopausal patients who underwent surgical treatment for BOT at three tertiary level referral centers for gynecologic oncology from January 2005 to December 2016. Patients were divided into two groups for comparisons: patients undergoing hysterectomy (hysterectomy group) and patients undergoing uterine-sparing surgery (no hysterectomy group). Study outcomes were disease-free survival (DFS), overall survival (OS), disease-specific survival (DSS) and surgical complications rate. Ninety-eight patients were included: 44 in the hysterectomy group and 54 in the no hysterectomy group. The 5- and 10-year DFS rates were 97.7% (95% CI: 84.9-99.7) and 92.3% (95% CI: 69.7-98.2), in the hysterectomy group, and 86.8% (95% CI: 74.3-93.5) and 86.8% (95% CI: 74.3-93.5), in the no hysterectomy group, respectively, without significant differences (p=0.16). Hazard ratio for DFS was 0.26 (95% CI: 0.06-1.68) for the hysterectomy group. The 5- and 10-year OS rates were 100.0% (95% CI: -) and 100.0% (95% CI: -), in the hysterectomy group, and 98.2% (95% CI: 87.6-99.7) and 94.4% (95% CI: 77.7-98.7), in the no hysterectomy group, respectively, without significant differences (p=0.23). No significant difference in complication rate was reported among the groups (p=0.48). As hysterectomy appears to not impact survival outcomes of women with BOT, it might be avoided in the surgical staging.

Impact of nerve-sparing posterolateral parametrial excision for deep infiltrating endometriosis on postoperative bowel, urinary, and sexual function.

OBJECTIVE: To evaluate the functional outcomes of nerve-sparing surgery for deep infiltrating endometriosis (DIE) with or without posterolateral parametrectomy. METHODS: A multicenter, observational, retrospective, cohort study was performed including all symptomatic women who underwent nerve-sparing laparoscopic excision of DIE and preoperative and postoperative assessment of functional outcomes through validated questionnaires between April 2019 and March 2020. Women with posterolateral parametrial DIE (P-group) and women with no parametrial involvement (NP-group) were compared in terms of preoperative and postoperative functional outcomes related to pelvic organs assessed through validated questionnaires (KESS and GIQLI for bowel function, BFLUTS for urinary function, and FSFI for sexual function); pain symptoms at 3-month follow up assessed through an 11-point visual analogue scale (VAS) for dyschezia, dysmenorrhea, dyspareunia and chronic pelvic pain; surgical outcomes; and rate of urinary voiding dysfunction at 3-month follow up. RESULTS: One-hundred patients were included: 69 in the P-group and 31 in the NP-group. Preoperative and postoperative values of questionnaires, pain symptoms, and postoperative complication rates were comparable between the two groups, except for postoperative dyspareunia and sexual dysfunction, which were statistically higher in the P-group. Only patients in the P-group experienced urinary voiding dysfunction, but no statistical significance was reached (P = 0.173). CONCLUSION: Posterolateral parametrectomy for DIE appears to be associated with a higher risk of postoperative dyspareunia and sexual dysfunction.

Fertility preservation in patients with BRCA mutations or Lynch syndrome.

Guidelines and expert consensus are lacking on fertility preservation in BRCA mutation carriers and in patients with Lynch syndrome. The safety of fertility preservation in this setting is still a topic of debate and multiple factors need to be carefully considered. The aim of this review was to analyze the reproductive potential of women harboring a genetic mutation affecting the DNA repair system and explore the efficacy and safety of existing fertility preservation strategies in these patients.

Minimally invasive surgical staging for early stage ovarian cancer: A long-term follow up.

INTRODUCTION: The standard treatment for epithelial early stage ovarian cancer (eEOC) includes laparotomic surgical staging, according to ESGO-ESMO guidelines. In the last decade, many investigators have assessed the safety and feasibility of minimally invasive surgery (MIS) staging in properly selected patients. However, survival data related to different surgical approaches (open versus MIS) are extremely limited. The aim of this study is to analyze the long-term oncological outcomes in eEOC patients treated with MIS. MATERIALS AND METHODS: This is a multicenter observational retrospective study conducted in two tertiary oncological centers. We selected all consecutive women who underwent a laparoscopic or robotic staging for eEOC. RESULTS: From January 2008 to December 2016, 254 eEOC patients underwent a MIS staging (188 laparoscopic staging and 66 robotic staging). Overall, 18.1% of patients were upstaged due to pathological findings. A total of 203 (79.9%) patients received platinum-based adjuvant chemotherapy. After a median follow-up of 61 months (range 13-118), 39 (15.3%) patients experienced recurrence. The 5-years progression free survival (PFS) and overall survival rates were 84.0% and 93.8%, respectively. In the univariate analysis, favorable variables influencing PFS were young age (≤45 years), non-serous histotype, tumor grade 1-2, and FIGO stage IA/IB. In the multivariate analysis, only grade 3 was shown to keep its negative independent prognostic value (HR = 3.47; p = 0.004), whereas FIGO stage ≥ IC showed a trend toward significance (HR = 1.75; p = 0.099). CONCLUSION: This retrospective study represents the longest follow-up of eEOC patients managed by MIS. The MIS is a valuable therapeutic option in appropriately selected patients, although a randomized controlled trial is needed.

Hyperthermic intraperitoneal chemotherapy in interval debulking surgery for advanced epithelial ovarian cancer: A single-center, real-life experience.

BACKGROUND: An improvement in survival without increasing perioperative morbidity in patients with advanced epithelial ovarian cancer treated with hyperthermic intraperitoneal chemotherapy (HIPEC) after interval debulking surgery (IDS) has been recently demonstrated in a randomized controlled trial. This study was aimed at assessing the feasibility and perioperative outcomes of the use of HIPEC after IDS at a referral cancer center. METHODS: Over the study period, 149 IDSs were performed. Patients who had at least International Federation of Gynecology and Obstetrics stage III disease, with <2.5 mm of residual disease (RD) at the end of surgery and were not participating in clinical trials received HIPEC. Moreover, specific exclusion criteria were considered. These patients were compared with 51 patients with similar clinical characteristics at the same institution and within the same timeframe who did not receive HIPEC. RESULTS: No differences in patient or disease characteristics with the exception of the type of neoadjuvant chemotherapy (P = .002) were found between the 2 groups. As for surgical characteristics, significant differences were found in RD after IDS (P = .007) and in the duration of surgery (P < .001), whereas the bowel resection and diversion rates (P = .583 and P = .213, respectively) and the postoperative intensive care unit and hospital stays (P = .567 and P = .727, respectively) were comparable. The times to start adjuvant chemotherapy were also similar (P = .998). Equally, the rates of any grade of both intraoperative complications (P = .189) and early postoperative complications (P = .238) were superimposable. CONCLUSIONS: In the authors' experience, the addition of HIPEC to IDS is feasible in 35% for the population. This value might increase with changes in the inclusion/exclusion criteria. HIPEC does not increase perioperative complications and does not affect a patient's recovery or time to start adjuvant chemotherapy. HIPEC should be offered to select patients listed for IDS.