Clinical characteristics and survival outcome of early-stage, high-grade, serous tubo-ovarian carcinoma according to BRCA mutational status.

OBJECTIVE: To investigate the role of BRCA1/2 mutations in early ovarian cancer (eOC) (International Federation of Gynecology and Obstetrics FIGO 2014 stage I-II), and its impact on prognosis after relapse. METHODS: In this multicenter retrospective study, clinical and survival data from high-grade serous (HGS)-eOC patients at presentation and recurrence were compared according to BRCA status: BRCA-mutated (BRCAmut) vs. BRCA wild-type (BRCAwt). RESULTS: Among 191 HGS-eOC patients, 89 were BRCAmut and 102 BRCAwt. There was no significant difference according to the BRCA status in terms of Progression-Free Survival (PFS). A longer Overall Survival (OS) was found in BRCAmut patients. Stage I patients had significantly improved PFS vs stage II, regardless of BRCA status. At multivariate analysis, stage at diagnosis was the only variable with a significant effect on PFS. No factors were significantly relevant on OS, albeit younger age and BRCA mutation showed a slight impact. Post-Recurrence Survival (PRS) in the BRCAmut population was significantly improved compared with BRCAwt. At multivariate analysis, Secondary Cytoreductive Surgery was the strongest predictor for longer PRS, followed by PARPi maintenance at recurrence. CONCLUSIONS: BRCA-status is not a prognostic factor in early ovarian cancer regarding PFS. However, our data suggest a better prognosis after relapse in BRCAm population.

Combination of Electrochemotherapy with Radiotherapy: A Comprehensive, Systematic, PRISMA-Compliant Review of Efficacy and Potential Radiosensitizing Effects in Tumor Control.

Radiotherapy (RT) and electrochemotherapy (ECT) are established local treatments for cancer. While effective, both therapies have limitations, especially in treating bulky and poorly oxygenated tumors. ECT has emerged as a promising palliative treatment, raising interest in exploring its combination with RT to enhance tumor response. However, the potential benefits and challenges of combining these treatments remain unclear. A systematic review was conducted following PRISMA guidelines. PubMed, Scopus, and Cochrane libraries were searched. Studies were screened and selected based on predefined inclusion and exclusion criteria. Ten studies were included, comprising in vitro and in vivo experiments. Different tumor types were treated with ECT alone or in combination with RT. ECT plus RT demonstrated superior tumor response compared to that under single therapies or other combinations, regardless of the cytotoxic agent and RT dose. However, no study demonstrated a clear superadditive effect in cell survival curves, suggesting inconclusive evidence of specific ECT-induced radiosensitization. Toxicity data were limited. In conclusion, the combination of ECT and RT consistently improved tumor response compared to that with individual therapies, supporting the potential benefit of their combination. However, evidence for a specific ECT-induced radiosensitization effect is currently lacking. Additional investigations are necessary to elucidate the potential benefits of this combination therapy.

Minimally Invasive Compared With Open Surgery in High-Risk Endometrial Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To compare outcomes between minimally invasive surgery and open surgery in patients with high-risk endometrial cancer. DATA SOURCES: A cohort study of all patients who underwent surgery for high-risk endometrial cancer between 1999 and 2016 at Mayo Clinic (Rochester, Minnesota) and a literature search of MEDLINE, EMBASE, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, and Scopus of all published studies until December 2020. METHODS OF STUDY SELECTION: The systematic review identified 2,332 patients (14 studies, all retrospective except a subanalysis of a randomized comparison) and the cohort study identified 542 additional patients. Articles were included if reporting original data on overall survival and disease-free survival among patients with high-risk endometrial cancer, defined as International Federation of Gynecology and Obstetrics grade 3 endometrioid, serous, clear cell, mixed histology, or uterine carcinosarcoma. Studies that did not report at least one of the main outcomes, those in which one surgical technique (robotic or laparoscopic surgery) was missing in the comparison analysis with open surgery, and case reports were excluded. Additional data were extracted from a retrospective cohort of patients from Mayo. A random-effect model was used for meta-analysis. TABULATION, INTEGRATION, AND RESULTS: This systematic review and meta-analysis was registered in PROSPERO. Literature search and data extraction were performed independently by two reviewers, as well as quality assessment using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology, and the Newcastle-Ottawa Scale. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. Meta-analysis showed that disease-free survival and overall survival in patients with high-risk endometrial cancer who underwent minimally invasive surgery were not statistically different from those of patients who underwent open abdominal surgery (relative risk [RR] 0.93, 95% CI 0.82-1.05, I2 20%, P=.23; and RR 0.92, 95% CI 0.77-1.11, I2 31%, P=.12, respectively). Subgroup analysis by stage (early vs advanced) did not identify a difference between surgical approaches. CONCLUSION: Minimally invasive surgery and open surgery had similar disease-free survival and overall survival in patients with high-risk endometrial cancer. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021275535.

Current methodologies to detect circulating tumor cells: a focus on ovarian cancer.

Identification of circulating tumor cells (CTC) in liquid biopsies opens a window of opportunities for the optimization of clinical management of oncologic patients. In ovarian cancer (OC), which involves atypical routes of metastatic spread, CTC analyses may also offer novel insights about the mechanisms behind malignant progression of the disease. However, current methodologies struggle to precisely define CTC number in the peripheral blood of OC patients, and the isolation of viable cells for further characterization is still challenging. The biggest limitation is the lack of methodological standardization for OC CTC detection, preventing comprehensive definition of their clinical potential required for the transfer to practice. Here we describe and compare methods for CTC analysis that have been implemented for OC thus far, discussing pros, cons and improvements needed. We identify biophysical separation approaches as optimal for CTC enrichment. On the other hand, the identification of specific tumor antigens or gene transcripts, despite displaying drawbacks related to tumor heterogeneity, still remains the best approach for OC CTC detection.

Fertility-sparing treatment in advanced-stage serous borderline ovarian tumors. An analysis from the MITO14 study database.

OBJECTIVES: To evaluate oncological and reproductive outcomes of women undergoing fertility-sparing surgery (FSS) for stage II-III serous borderline ovarian tumors (BOTs). METHODS: A multi-institutional retrospective study was conducted within the MITO Group. RESULTS: A total of 91 patients were recruited. The median follow-up time from primary cytoreduction was 127 months (IQR range 91-179). Forty-nine patients (53.8%) experienced at least one recurrence (median time to first relapse 22 months, IQR range 9.5-57). At univariable analysis, significant predictors of relapse were: size of largest extra-ovarian lesion, peritoneal cancer index, completeness of cytoreduction, type of implants. After multivariable analysis, the size of extra-ovarian lesions and the presence of invasive implants resulted as the only independent predictors of recurrence. Median disease-free survival (DFS) was 96 months (95% CI, 24.6-167.3), while median disease-specific survival (DSS) was not reached. Twenty-nine patients (31.8%) attempted to conceive: 20 (68.9%) achieved at least one pregnancy and 18 (62%) gave birth to a healthy child. At the end of the observation period, 88 patients (96.7%) showed no evidence of disease, 2 (2.2%) were alive with disease, and 1 patient (1.1%) died from BOT. CONCLUSIONS: Despite the recurrence high rate, FSS provides good chances of reproductive success with no impact on DSS. The presence of invasive peritoneal implants affects the DFS but not DSS nor reproductive outcome. The risk of recurrence would not seem to be related to the ovarian preservation per se, but to the natural history of the initial peritoneal spread.

COVID-19 free oncologic surgical hub: The experience of reallocation of a gynecologic oncology unit during pandemic outbreak.

INTRODUCTION: During the SARS-CoV-2 pandemic, the majority of healthcare resources of the affected Italian regions were allocated to COVID-19 patients. Due to lack of resources and high risk of death, most cancer patients have been shifted to non-surgical treatments. The following reports our experience of a Gynaecologic Oncology Unit's reallocation of resources in a COVID-19 free surgical oncologic hub in order to guarantee standard quality of surgical activities. MATERIALS AND METHODS: This is a prospective observational study performed in the Gynaecologic Oncology Unit, on the outcomes of the reallocation of surgical activities outside the University Hospital of Bologna, Italy, during the Italian lockdown period. Here, we described our COVID-19 free surgical oncologic pathway, in terms of lifestyle restrictions, COVID-19 screening measures, and patient clinical, surgical and follow up outcomes. RESULTS: During the lockdown period (March 9th - May 4th, 2020), 83 patients were scheduled for oncological surgery, 51 patients underwent surgery. Compared to pre-COVID period, we performed the same activities: number of cases scheduled for surgery, type of surgery and surgical and oncological results. No cases of COVID-19 infection were recorded in operated patients and in medical staff. Patients were compliant and well accepted the lifestyle restrictions and reorganization of the care. CONCLUSIONSONCLUSIONS: Our experience showed that the prioritization of oncological surgical care and the allocation of resources during a pandemic in COVID-19 free surgical hubs is an appropriate choice to guarantee oncological protocols.

Hysteroscopic versus cervical injection for sentinel node detection in endometrial cancer: A multicenter prospective randomised controlled trial from the Multicenter Italian Trials in Ovarian cancer (MITO) study group.

AIM: During the last years, the role of sentinel lymph node mapping (SLNM) for endometrial cancer (EC) surgical treatment has increased in popularity. However, several controversies remain about different technical steps of SLNM. Thus, a randomised control trial was designed to compare cervical (CI) and hysteroscopic (HI) indocyanine green (ICG) injection for SLNM of newly diagnosed EC undergoing surgical staging. The primary end-point of the study was to compare these two techniques in terms of para-aortic detection rate. METHODS: Patients with apparent stage I or II histologically confirmed EC undergoing surgery were included in the study. This randomised trial distinguished patients in two study groups according to two different techniques of ICG SLNM: CI versus HI injection. Patients who met the inclusion criteria were randomly assigned to CI or HI injection in a 1:1 ratio. The central randomisation system allocated patient randomisation numbers sequentially in the order in which the patients were enrolled. This randomised trial was not blinded for either patients or the surgeons. RESULTS: From March 2017 until April 2019, a total of 165 patients were randomised in this study: 85 (51.5%) in the CI group and 80 (48.5%) in the HI group. After randomisation, 14 (8.5%) patients were excluded from the study. Finally, 151 patients were included in the analysis: 82 (54.3%) in the CI group and 69 (45.7%) in the HI group. Hysteroscopy injection shows an ability to detect Sentinel nodes (SNLs) in the para-aortic area of about 10% greater compared with CI injection, although this difference did not reach statistical significance. The HI technique was superior in detecting isolated para-aortic SLNs (5.8% Versus 0%). The CI injection was correlated with higher SLN detection rates at the pelvic level compared with HI injection. Pelvic and overall detection was higher in the CI group. CONCLUSIONS: The present study supports the adoption of CI instead of HI injection because the former allows better identification of sentinel nodes (especially in the pelvic area). Detection of SLN in the para-aortic area was slightly higher in patients receiving a HI injection, but the difference with the CI route was not statistically significant.

The generally low sensitivity of CA 125 for FIGO stage I ovarian cancer diagnosis increases for endometrioid histotype.

BACKGROUND: The serum marker CA 125 is still the most widely used biomarker for ovarian cancer (OC) diagnosis in gynecological and oncological setting, but its predictive role in early-stage OC is still debated. The aim of this study was to explore the value of CA 125 in distinguishing between early-stage OC and borderline ovarian tumor (BOT) and to evaluate the accuracy of CA 125 in the detection of early stage OC. METHODS: A retrospective cohort study was performed at the University Hospital of Bologna (Italy) on 1296 consecutive women suffering from OC or BOT (diagnosed at histology) between 1988-2017. Patients for whom CA 125 level was determined preoperatively were included. The positive cut-off level used was >35 U/mL. RESULTS: Of 910 patients, 192 (21.1%) were diagnosed with BOT and 718 (78.9%) with OC. The sensitivity of CA 125 for stage I OC was 54.4 (95% CI: 45.3-63.3) (51.5 for IA, 54.6 for IB, 58.3 for IC), but it increased to 78.0 (95% CI: 63.7-88.0) for stage II. Interestingly, in stage I OC, CA 125 presented a significantly higher sensitivity for the endometrioid histotype [72.4 (95% CI: 52.5-86.5) vs. 49.0 (95% CI: 38.6-59.4), P=0.026]. The positive likelihood ratio of CA 125 for early-stage OC compared to BOT was 1.29 (95% CI: 1.06-1.58). CONCLUSIONS: Despite its limited sensitivity for early-stage OCs, CA 125 still represents a useful serum marker to early differentiate between OCs and BOTs. Its sensitivity for stage I OC increases in endometrioid histotype.

Definitive Radiotherapy in Invasive Vaginal Carcinoma: A Systematic Review.

AIM: This study systematically reviews the recent literature on the role of definitive radiotherapy (RT) in the management of vaginal cancer (VC) and presents comprehensive data on clinical outcomes and toxicity. METHODS: The authors performed a literature search using PubMed (2007-2016) to identify all prospective and retrospective studies that have been published on RT in invasive VC. RESULTS: Of the 199 identified studies, 13 met the inclusion criteria. All studies had a retrospective design. Overall, 793 patients (median, 45; range, 26-138) were included. A high heterogeneity was found across studies in terms of RT techniques, assessment criteria, and reported outcomes. The majority of the patients were treated with a combination of external beam RT and brachytherapy (74.2%). Acute and late grade ≥3 toxicity rates ranged from 0.0% to 24.4% (median, 8.7%) and from 0.0% to 22.5% (median, 12.8%), respectively. The 5-year local control rates ranged between 39% and 79%. The 5-year overall survival ranged between 34% and 71.0% (median, 63.5%). Early stage of the disease (International Federation of Gynecology and Obstetrics stages I-II vs. III-IV), small tumor size (<4 cm), previous hysterectomy, high pretreatment/treatment hemoglobin levels (≥12/12.5 mg/dL), and patients' age <70 or <64 years were correlated with better clinical outcomes. CONCLUSION: Only retrospective studies, in a limited number, have been published on RT in VC in the past decade, with significant heterogeneity in terms of treatment characteristic and evaluation criteria. Clinical results were strongly influenced by tumor stage. Prospective randomized studies are needed to improve patients' outcomes, especially in advanced-stage disease. IMPLICATIONS FOR PRACTICE: This study systematically reviews the recent literature on the role of definitive radiotherapy in the management of vaginal cancer and presents comprehensive data on clinical outcome and toxicity. The prognosis of patients is dismal, with a 5-year overall survival of approximately 50%. Early stage of the disease, small tumor size, previous hysterectomy, high pretreatment/treatment hemoglobin levels, and patients' age were correlated with a better clinical outcome. A brachytherapy boost should be delivered, especially in patients with higher-stage disease. The addition of concurrent weekly cisplatin should be considered in most patients, and transfusion should be used to maintain high hemoglobin levels.

Electrochemotherapy - Emerging applications technical advances, new indications, combined approaches, and multi-institutional collaboration.

The treatment of tumors with electrochemotherapy (ECT) has surged over the past decade. Thanks to the transient cell membrane permeabilization induced by the short electric pulses used by ECT, cancer cells are exposed to otherwise poorly permeant chemotherapy agents, with consequent increased cytotoxicity. The codification of the procedure in 2006 led to a broad diffusion of the procedure, mainly in Europe, and since then, the progressive clinical experience, together with the emerging technologies, have extended the range of its application. Herein, we review the key advances in the ECT field since the European Standard Operating Procedures on ECT (ESOPE) 2006 guidelines and discuss the emerging clinical data on the new ECT indications. First, technical developments have improved ECT equipment, with custom electrode probes and dedicated tools supporting individual treatment planning in anatomically challenging tumors. Second, the feasibility and short-term efficacy of ECT has been established in deep-seated tumors, including bone metastases, liver malignancies, and pancreatic and prostate cancers (long-needle variable electrode geometry ECT), and gastrointestinal tumors (endoscopic ECT). Moreover, pioneering studies indicate lung and brain tumors as suitable future targets. A further advance relates to new combination strategies with immunotherapy, gene electro transfer (GET), calcium EP, and radiotherapy. Finally and fourth, cross-institutional collaborative groups have been established to refine procedural guidelines, promote clinical research, and explore new indications.

Electrochemotherapy pre-treatment in primary squamous vulvar cancer. Our preliminary experience.

BACKGROUND AND OBJECTIVES: Previous studies showed a local tumor control of 80% in patients with relapsed squamous cell vulvar cancer (V-SCC) treated with electrochemotherapy. These results encouraged electrochemotherapy use as neo-adjuvant treatment in V-SCC. The objective of this study was to evaluate the effectiveness of electrochemotherapy in reducing tumor burden in V-SCC. METHODS: Patients with histological diagnosis of primary V-SCC eligible for surgery were enrolled. Following accurate mapping of all the lesions, electrochemotherapy was performed. One month after electrochemotherapy clinical response was evaluated according to RECIST criteria and the type of surgery was confirmed or modified. Adjuvant therapies were prescribed depending on stage and pathological evaluation. RESULTS: We report the results from nine patients treated with electrochemotherapy before surgery. The median age was 64 years (range 51-81 years). Tumor response after electrochemotherapy was observed in seven patients (77.8%) with one CR and six PR, without complications. Tumor downsizing led to more conservative surgery in six patients (66.7%). At a median follow-up of 8 months (range 2-32 months) all patients were alive without disease. CONCLUSIONS: Our preliminary analysis suggests that ECT is a suitable treatment in patients with V-SCC before surgery, reducing the tumor size and the surgical resection.

Palliative electro-chemotherapy in elderly patients with vulvar cancer: A phase II trial.

OBJECTIVE: The primary endpoint of this trial was to assess clinical response (cCR) of squamocellular vulvar cancer (V-SCC) in elderly patients treated with electro-chemotherapy (ECT). Secondary endpoints were symptoms relief and local tumor control. METHODS: A phase II study was designed and elderly patients with V-SCC unfit for other treatments were treated. Response Evaluation Criteria in Solid Tumors (RECIST criteria) were applied to evaluate tumor response. Quality of life (QoL) was evaluated by visual analogue score (VAS) for pain and four items of vulvar cancer subscale (VCS), of functional assessment of vulvar cancer therapy (FACT-V) [16], before, one month after the procedure and during follow-up. RESULTS: Median age was 85 years (range 66-96 years). One month after treatment complete response was observed in 13 patients (52%), partial response in 7 (28%), stable disease in 3 (12%), and progressive disease in 2 (8%). Local tumor control at 1 and 6 months was 91% and 53%, respectively. Symptom free survival at 1 and 6 months was 78% and 40%, respectively, with significant reduction of pain (P < 0.01). One-year overall survival was 34%. CONCLUSIONS: Our study showed that ECT produces high response rate with significant reduction of pain and improvement of local symptoms.

Diagnostic accuracy of 18F-FDG PET/CT in characterizing ovarian lesions and staging ovarian cancer: correlation with transvaginal ultrasonography, computed tomography, and histology.

AIMS: To (a) assess the accuracy of 18F-FDG PET/CT in distinguishing malignant from benign pelvic lesions, compared to transvaginal ultrasonography (TVUS) and (b) to establish the role of whole-body 18F-FDG PET/CT, compared to contrast enhanced computed tomography (CT), in staging patients with ovarian cancer. PATIENTS: Fifty consecutive patients with a pelvic lesion, already scheduled for surgery on the basis of physical examination, TVUS, and serum Ca125 levels, were enrolled in the study. Patients' age ranged between 23 and 89 years (mean 64). All patients underwent TVUS including a colour Doppler study followed by a thorax and abdominal CT scan, and whole-body 18F-FDG PET/CT within 2 weeks prior to surgery. Histological findings obtained at surgery were taken as the 'gold standard' to compare 18F-FDG PET/CT and TVUS, and 18F-FDG PET/CT vs. CT. When tissue analysis showed ovarian cancer, the accuracy of 18F-FDG PET/CT and CT were compared for the purpose of obtaining a precise staging. RESULTS: At surgery, the ovarian lesions were malignant in 32/50 patients (64%) and benign in the remaining 18/50 patients (36%). The sensitivity, specificity, NPV, PPV and accuracy of 18F-FDG PET/CT were 87%, 100%, 81%, 100% and 92%, respectively, compared with 90%, 61%, 78%, 80% and 80%, respectively, for TVUS. In staging ovarian cancer, 18F-FDG PET/CT results were concordant with final pathological staging in 22/32 (69%) patients while CT results were concordant in 17/32 (53%) patients. CT incorrectly down-staged four out of six stage IV patients by missing distant metastasis in the liver, pleura, mediastinum, and in left supraclavicular lymph nodes, which were correctly detected by 18F-FDG PET/CT. CONCLUSION: PET/CT with 18F-FDG provides additional value to TVUS for the differential diagnosis of benign from malignant pelvic lesions, and to CT for the staging of ovarian cancer patients.