Annamaria Ferrero

European training requirements for gynecological oncology: the European Society of Gynaecological Oncology Curriculum

Real-life clinical benefit of oral metronomic cyclophosphamide administration in elderly and heavily pretreated epithelial ovarian cancer patients

Abstract Purpose Oral metronomic cyclophosphamide (OMC) implicates the daily administration of low doses of chemotherapy. Its antitumor activity combined with an oral administration route and a good toxicity profile makes OMC an attractive option for heavily pretreated patients. We retrospectively evaluated OMC’s clinical benefit and objective response in recurrent ovarian cancer patients. Methods This is a retrospective observational study involving patients treated with OMC (50 mg daily) from 2017 to 2022 at the Academic Division Gynaecology, Mauriziano Hospital, Torino, Italy. Clinical benefit assessment included CA125 response, radiological response, and reported symptomatic improvement. Toxicities were reported using Common Terminology Criteria for Adverse Events version 5.0. Results Thirty-eight patients (average age 72, range 49–88) were included. 90% had FIGO stage III/IV at diagnosis and 64% underwent ≥ 3 previous lines of chemotherapy. Before OMC, 79% had ECOG 1 or 2. 8.6% of patients had a partial response (PR), and 40% a stable disease (SD). Median duration of response was 7.4 months. After 3 months on OMC, 51% experienced symptom improvement, and 53.3% experienced Ca125 reduction or stabilization. 66.7% of patients older than 75 responded to treatment; in 40% of cases, responses lasted ≥ 6 months (p = 0.08). No G3-4 hematological toxicities occurred. Nausea and fatigue G1–G2 were reported in 5 (13%) and 13 (34%) cases, respectively. Conclusion OMC is a feasible therapeutic option for recurrent ovarian cancer, providing satisfying clinical responses with a good toxicity profile, even in elderly and heavily pretreated patients with a suboptimal performance status.

PARP Inhibitors in Brain Metastases from Epithelial Ovarian Cancer through a Multimodal Patient Journey: Case Reports and Literature Review

Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Brain metastasis (BM) is quite an uncommon presentation. However, the likelihood of central nervous system (CNS) metastasization should be considered in the context of disseminated disease. The therapeutic management of BMs is an unmet clinical need, to date. We identified, across different cancer centers, six cases of both BRCA wild-type and BRCA-mutated EOCs spreading to the CNS. They presented either with a single brain lesion or with multiple lesions and most of them had intracranial-only disease. All cases received Poly-ADP ribose polymerase inhibitor (PARPi) maintenance, as per clinical practice, for a long time within a multimodal treatment approach. We also provide an insight into the available body of work regarding the management of this intriguing disease setting, with a glimpse of future therapeutic challenges. Despite the lack of unanimous guidelines, multimodal care pathways should be encouraged for the optimal disease control of this unfortunate patient subset. Albeit not being directly investigated in BM patients, PARPi maintenance is deemed to have a valuable role in this setting. Prospective research, aimed to implement worthwhile strategies in the multimodal patient journey of BMs from EOC, is eagerly awaited.

Development and clinical application of a tool to identify frailty in elderly patients with gynecological cancers

Frailty is more reliable than chronological age in predicting the effectiveness and tolerability of treatments in cancer patients. An increasing number of screening tools have been proposed, however none have received unanimous consent or been specifically designed for women with gynecological malignancies.This study's aim was to develop a clinical application of a screening tool to identify frail patients >70 years old diagnosed with either ovarian or endometrial cancers. A 20 item questionnaire was developed and administered to the cohort before surgery or neoadjuvant chemotherapy. A cut-off for frailty definition was determined by analyzing the correlation of questionnaire scores with the completion of treatments. The association between frailty and treatment related complications was assessed using a Chi-squared test for categorical variables and a t-test for continuous variables. Our study included 100 patients, 50% diagnosed with endometrial cancer and 50% with ovarian cancer. A questionnaire score of 4 was the best cut-off for frailty definition (sensitivity 77%, specificity 100%). Surgical grade III and grade IV complications were observed only in frail patients (p=0.01) and hospitalization was significantly longer in frail women affected by ovarian cancer (p=0.01). Frail patients were more exposed to chemotherapy administration delay (p=0.0005), treatment discontinuation (p=0.001) and hematological toxicities, especially anemia ≥grade 2 (p=0.009) and thrombocytopenia any grade (p=0.0001). With a cut-off score of 4, our tool can identify frail patients with significantly higher incidence of grade III-IV postoperative complications, length of stay, medical treatment discontinuation rates and hematological toxicities.

The “Sandwich” Schedule: A Well-Tolerated Adjuvant Treatment Both in Intermediate–High- and High-Risk Endometrial Cancer

(1) Background: In intermediate–high- and high-risk endometrial cancer (EC), radiotherapy (RT) and chemotherapy (CT) play a basic role. However, there is controversy regarding the optimal timing of their combination. The “sandwich” schedule involves adjuvant CT followed by RT and subsequent CT. The aim of this study is to assess the tolerability and efficacy of the “sandwich” schedule. (2) Methods: A retrospective study was conducted in two gynecological oncology units in Torino, Italy, from 1 January 2003 until 31 December 2021. Intermediate–high- and high-risk patients with available clinical data were included. Compliance with treatment, CT and RT toxicities, disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) were analyzed. (3) Results: A total of 118 patients were selected: 27.1% FIGO I-II stages and 72.9% III-IV. Most of the patients (75.4%) received a carboplatin–paclitaxel combination, and as much as 94.9% of CT cycles were completed. Chemotherapy-related G3-4 toxicities were detected in 5.3% of the patients, almost half of which were hematological. Grade 2 gastrointestinal and genitourinary toxicities were reported in 8.4% and 4.2% of cases, respectively. With a median follow-up of 46 months, DFS was 77.6%, CSS was 70% and 5-year OS was 54%. (4) Conclusions: The “sandwich” schedule for CT and RT combination is an effective adjuvant treatment with low toxicity both in intermediate–high- and high-risk EC.

Effectiveness of Intensive Versus Minimalist Follow-Up Regimen on Survival in Patients With Endometrial Cancer (TOTEM Study): A Randomized, Pragmatic, Parallel Group, Multicenter Trial

PURPOSE In the absence of clear evidence from randomized trials, the intensity of follow-up regimens after surgical treatment of endometrial cancer is highly variable in clinical practice. To reduce this uncertainty, we conducted a randomized trial to test whether an intensive (INT) versus a minimalist (MIN) follow-up regimen improves overall survival (OS) in patients undergoing operation for endometrial cancer. METHODS The TOTEM study was a large, pragmatic randomized trial, conducted in 42 hospitals (in Italy and France) including patients surgically treated for endometrial cancer, in complete clinical remission, International Federation of Gynecology and Obstetrics stage I-IV. After stratification by center and risk of relapse (low or high), patients were randomly assigned (1:1) to INT or MIN hospital-based follow-up regimens. The study was powered to demonstrate an absolute improvement of 5% of the 5-year OS with the INT regimen. RESULTS In total, 1,871 patients were randomly assigned between November 2008 and July 2018, and 1,847 patients (98.7%) were available for the final analysis (60% low risk). After a median follow-up of 69 months, the 5-year OS was 90.6% in the INT and 91.9% in the MIN arms (hazard ratio, 1.13, 95% CI, 0.86 to 1.50, P = .380). No differences in OS were found in subgroup analyses considering age, cancer treatment, risk of relapse, and degree of adherence of the center to the scheduled follow-up. The probability of detecting a relapse was slightly higher in the INT arm (hazard ratio, 1.17; 95% CI, 0.92 to 1.48; P = .194). CONCLUSION An INT follow-up in endometrial cancer–treated patients does not improve OS, even in high-risk patients. According to available evidence, there is no need to routinely add vaginal cytology, laboratory, or imaging investigations to the MIN regimens used in this trial.

Waist-to-hip ratio measured with computed tomography as a predictor of surgical outcomes in minimally invasive procedures for early-stage endometrial cancer

This study aimed to determine if the waist-to-hip ratio, an emerging indicator of abdominal obesity, predicts poor outcomes, such as sentinel node mapping failure, post-operative complications, conversion to laparotomy, and increased operative time, in endometrial cancer surgery. This retrospective study included patients with apparent early-stage endometrial carcinoma who underwent minimally invasive surgery at the Mauriziano Umberto I Hospital in Turin, Italy from January 2021 to January 2025. The waist-to-hip ratio was calculated using pre-operative computed tomography scans with previously described methods. Two cohorts based on a waist-to-hip ratio cutoff of 0.85, as defined by the World Health Organization, were identified and compared with statistical tests as appropriate. Univariate and multi-variable linear regression models were fit to evaluate predictors of poor surgical outcomes. A total of 151 patients were included in the study. Abdominal obesity, as defined by an abnormal waist-to-hip ratio, was identified in 127 patients (84%), of whom 62 also had obesity according to the body mass index. Patients with abnormal waist-to-hip ratios were significantly older (median: 69 vs 61 years; p = .03), had higher body mass index (median: 29 vs 21 kg/m An abnormal waist-to-hip ratio was significantly associated with increased operative time during minimally invasive surgery for endometrial cancer, whereas body mass index was not. Further research is needed to determine the predictive potential of the waist-to-hip ratio for personalized surgical planning.

Immunonutrition in ovarian cancer: clinical and immunological impact?

Malnutrition is frequent in ovarian cancer (OC) patients and may compromise post-operative outcomes. The aim of this study is to evaluate the impact of pre-operative immunonutrition on the surgical outcome of OC patients, and on their nutritional, inflammatory and peripheral blood immune status. A prospective study was performed between September 2016 and April 2020. Immune-enhancing enteral nutrition was administered to 42 patients before surgery according to their nutritional status assessed by the Malnutritional Universal Screening Tool. Biochemical and hematological monitoring was performed before and after immunonutrition. Post-operative outcomes were assessed and compared with those of a similar group of patients treated without nutritional support. Of the 42 immune-nourished patients, 23 (54.8%) had a low, 11 (26.2%) an intermediate and 8 (19%) a high risk of malnutrition. After the immunonutritional intake, significant variations of prealbumin, creatinine and white blood cells were detected. All T cell populations had an increasing trend, in particular CD3 Pre-operative immunonutrition improves the surgical outcome of OC patients. After immunonutrition, an increase of CD3

Predicting Response to Anthracyclines in Ovarian Cancer

(1) Background: Anthracyclines are intriguing drugs, representing one of the cornerstones of both first and subsequent-lines of chemotherapy in ovarian cancer (OC). Their efficacy and mechanisms of action are related to the hot topics of OC clinical research, such as BRCA status and immunotherapy. Prediction of response to anthracyclines is challenging and no markers can predict certain therapeutic success. The current narrative review provides a summary of the clinical and biological mechanisms involved in the response to anthracyclines. (2) Methods: A MEDLINE search of the literature was performed, focusing on papers published in the last two decades. (3) Results and Conclusions: BRCA mutated tumors seem to show a higher response to anthracyclines compared to sporadic tumors and the severity of hand–foot syndrome and mucositis may be a predictive marker of PLD efficacy. CA125 can be a misleading marker of clinical response during treatment with anthracyclines, the response of which also appears to depend on OC histology. Immunochemistry, in particular HER-2 expression, could be of some help in predicting the response to such drugs, and high levels of mutated p53 appear after exposure to anthracyclines and impair their antitumor effect. Finally, organoids from OC are promising for drug testing and prediction of response to chemotherapy.

PARPi and myeloid neoplasms; the Italian MITO-MaNGO experience based on a multicentric survey

The introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer has raised increasing concerns about PARPi-related myeloid neoplasms (PrMN). Therapy-related neoplasms, including myelodysplastic syndromes and acute myeloid leukemia, account for 10%-20% of cases. Expanding PARPi indications, longer survival, and aging populations may contribute to rising PrMN incidence. Randomized clinical trials and real-world analyses show a significant risk increase, but data on individual PARPi, treatment lines, and prior therapies are limited. We evaluated PrMN incidence across 17 Italian centers using a 71-item survey distributed to MITO (Multicenter Italian Trials on Ovarian cancer) and MaNGO (Mario Negri Gynecologic Oncology) centers, focusing on patients treated with PARPi outside clinical trials. Of 2320 patients (1254 BRCA-mutated), 56 (2.55%) developed MN: 35 myelodysplastic syndromes and 21 acute myeloid leukemia (2 patients had both, counted once). Among them, 31 had BRCA mutations (2.5%). Incidence by drug was: olaparib 2.5%, niraparib 2%, and rucaparib 3.4%. An unclear correlation emerged between treatment duration and PrMN risk, with a median onset of 18.9 months. Risk increased with additional therapy lines: 0.52% (first), 4.2% (second), 1.8% (third), 10.8% (fourth), and 12.2% (>fourth lines). Among PrMN cases, 4 achieved remission, 4 had partial responses, 8 progressed, and 37 died. While this survey is meant as hypotheses-generating, PrMN represent a rare but clinically relevant complication, particularly uncommon when PARPi are administered as first-line therapy. Their occurrence does not appear to be associated with the specific PARPi used or with BRCA mutation status. Early detection, monitoring, and identification of predictive factors are crucial as ovarian cancer outcomes improve and treatment exposure increases.

SUCCOR 10 years: a decade's perspective on radical hysterectomy outcomes in cervical cancer.

Interest in long-term outcomes of radical hysterectomy for cervical cancer has increased, especially after the LACC trial findings, which showed worse outcomes for minimally invasive surgery. However, limited information is available on 10-year oncological outcomes, particularly, recurrence and survival. The primary objective of this study was to analyze the 10-year oncological outcomes of patients with International Federation of Gynecology and Obstetrics 2009 stage IB1 cervical cancer treated with radical hysterectomy performed via minimally invasive or open approaches. This retrospective, multi-center, observational study updates the data from the SUCCOR cohort. Patients diagnosed between January 2013 and December 2014 with tumors ≤4 cm without extra-cervical metastasis and treated with radical hysterectomy as the primary treatment were included, and a 10-year follow-up after surgery was successfully conducted. A total of 556 patients were analyzed. The median age was 46 years (range; 18-82). The most common final International Federation of Gynecology and Obstetrics 2009 stage was IB1, 474 patients (85%), and the most common histology was squamous carcinoma, 376 patients (67.6%). The 5-year disease-free survival was 93%, and the 10-year disease-free survival was 90%. The overall survival was 97% at 5 years and 89% at 10 years. During follow-up, 9% (n = 49) of patients experienced recurrences, 78% (n = 38) within the first 5 years. Comparing surgical approaches, 10-year disease-free survival was 92% for minimally invasive surgery and 88% for open surgery (p = .12). Similarly, 10-year overall survival was 92% for minimally invasive surgery and 88% for open surgery (p = .12). Post-recurrence disease-specific survival was 47% at 60 months and 39% at 96 months. The 2-year survival after recurrence was 80% for late recurrences (>5 years) versus 69% for early recurrences. The overall survival after radical hysterectomy at 5-years was 97% in patients with early-stage cervical cancer. The recurrence rate at 10 years was 9%. No differences in 10-year survival were observed between the surgical approaches.