Distribution and prognostic role of BRCA status in elderly ovarian cancer patients.

OBJECTIVE: In the era of target therapy and personalized medicine, BRCA mutational status has a major influence on survival in ovarian cancer patients. Our aim is to verify if the poorer prognosis of elderly ovarian cancer patients can be related to the biology of the tumor beyond their own morbidities and/or suboptimal treatments. METHODS: This is a retrospective single-institution study evaluating prognosis of patients with a diagnosis of ovarian cancer and known BRCA status. We collected clinical and surgical characteristics and the distribution of BRCA mutational status according to age groups. RESULTS: 1840 patients were included in the analysis. The rate of BRCA mutated decreased over age-range from 49.7% in patients aged <50 years to 18.8% in ≥80 years old women. The prognostic role of BRCA status on survival is maintained when focusing on the elderly population, with improved Disease Free Survival (27.2 months vs 16.5 months for BRCA mutated and wild type respectively, p = 0.001) and Cancer Specific Survival (117.6 months vs 43.1 months for BRCA mutated and wild type respectively, p = 0.001) for BRCAmut compared to BRCAwt patients. In the multivariable analysis, among elderly women, upfront surgery and BRCA mutation are independent factors affecting survival. CONCLUSIONS: Elderly patients experiment a poorer prognosis due to multiple factors that include both their medical condition and comorbidities, under-treatment and most importantly disease characteristics. We found that beyond disparities, BRCA mutation is still the strongest independent prognostic factor affecting both the risk of recurrence and death due to disease.

Low-grade versus high-grade serous ovarian cancer: comparison of surgical outcomes after secondary cytoreductive surgery.

OBJECTIVE: Retrospective series have shown secondary cytoreductive surgery improves oncological outcomes in recurrent low-grade serous ovarian cancer. We aim to compare surgical procedures and complications between patients with low-grade and high-grade recurrent serous ovarian cancer. METHODS: This retrospective single-institution study includes patients with recurrent low-grade and high-grade serous ovarian cancer undergoing surgery between January 2012 to December 2021. Patients were propensity matched 1:3 for residual tumor at first surgery, presence of ascites and performance status. Complexity of surgery and postoperative complications were analyzed. RESULTS: A total of 116 patients undergoing secondary cytoreductive surgery were included with 29 patients (25%) having low-grade ovarian cancer. The median age of the patients was 54 years (range: 19-85) and 57 years (range: 29-78) in low-grade and high-grade ovarian cancer, respectively (p=0.13). Stages III/IV at diagnosis were more frequent in patients with high-grade ovarian cancers (p<0.001). Peritoneal involvement was higher in low-grade compared with high-grade ovarian cancer as shown by the higher rate of diaphragmatic (41.4% vs 21.8%, p=0.05), abdominal wall (41.4% vs 18.4%, p=0.02) and pelvic (51.7% vs 21.8%, p=0.01) peritonectomy. Multiple bowel resections were higher in low-grade ovarian cancer (24.1% vs 8.0%, p=0.04), while high-grade ovarian cancer had a higher rate of nodal recurrences (73.2%% vs 37.9%, p=0.03). Overall, surgical complexity was higher in low-grade ovarian cancer (58.6% vs 36.8%; p=0.05), with higher median estimated blood loss (400 vs 200 mL; p=0.01) compared with high-grade. Complete cytoreduction was achieved in 26 patients (89.7%) with low-grade and 84 (96.6%) with high-grade (p=0.16) ovarian cancer, with no significant differences in postoperative complications. CONCLUSIONS: Secondary cytoreductive surgery in low-grade serous ovarian cancer patients was associated with higher complexity, multiple bowel resections, and higher median estimated blood loss than in high-grade serous ovarian cancer. The comparable rate of postoperative complications suggests that secondary cytoreductive surgery in this group of patients is feasible in expert centers.

Genome tumor profiling in endometrial cancer and clinical relevance in endometrial cancer management: a retrospective single-center experience.

OBJECTIVE: Next-generation sequencing (NGS) analysis has become an essential tool for endometrial carcinoma management. Moreover, molecular-driven therapies play an increasingly remarkable role in the era of precision oncology. This study aims to determine the clinical relevance of NGS testing in endometrial carcinoma management by analyzing the clinical benefit of NGS-driven targeted therapies. METHODS: A single-center retrospective study was conducted on 25 endometrial carcinoma patients who underwent Foundation Medicine CDx assay at Fondazione Policlinico Universitario Agostino Gemelli, IRCCS (Rome, Italy). Tumor samples were analyzed by Foundation One CDx. A descriptive analysis of tumor genome profiles was performed. Assessment of clinical benefit according to RECIST 1.1 criteria was analyzed for patients who received a tailored treatment according to actionable targets identified by NGS testing. RESULTS: Out of 25 endometrial carcinoma patients, 11 received targeted therapy. One patient was excluded from the clinical benefit assessment because of COVID-19-related death 1 month after starting the treatment. Eight of the remaining 10 patients benefited from targeted therapies, with an overall clinical benefit rate of 80%. A targeted agent belonging to the PI3K pathway was given to seven patients, with evidence of three partial responses (42.9%), three stable diseases (42.9%), and one progressive disease (14.2%) according to RECIST 1.1 criteria. One complete response (33.3%), one stable disease (33.3%), and one progressive disease (33.3%) were observed in the three patients treated with poly(ADP-ribose) polymerase (PARP) inhibitors according to their homologous recombination deficiency (HRD) status. CONCLUSION: This study highlights the importance of characterizing the mutation profile of patient tumors through NGS. Our findings suggest a clinical benefit of using NGS-driven targeted therapies in endometrial carcinoma patients. However, this personalized approach could benefit the health system in terms of cost-effectiveness by reducing the costs of inappropriate, ineffective, and often expensive treatments.

Lung-protective ventilation during Trendelenburg pneumoperitoneum surgery: A randomized clinical trial.

Study objective To assess the effects of a protective ventilation strategy during Trendelenburg pneumoperitoneum surgery on postoperative oxygenation. DESIGNS: Parallel-group, randomized trial. SETTING: Operating room of a university hospital, Italy. PATIENTS: Morbidly obese patients undergoing Trendelenburg pneumoperitoneum gynaecological surgery. INTERVENTIONS: Participants were randomized to standard (SV: tidal volume = 10 ml/kg of predicted body weight, PEEP = 5 cmH2O) or protective (PV: tidal volume = 6 ml/kg of predicted body weight, PEEP = 10 cmH2O, recruitment maneuvers) ventilation during anesthesia. MEASUREMENTS: Primary outcome was PaO2/FiO2 one hour after extubation. Secondary outcomes included day-1 PaO2/FiO2, day-2 respiratory function and intraoperative respiratory/lung mechanics, assessed through esophageal manometry, end-expiratory lung volume (EELV) measurement and pressure-volume curves. MAIN RESULTS: Sixty patients were analyzed (31 in SV group, 29 in PV group). Median [IqR] tidal volume was 350 ml [300-360] in PV group and 525 [500-575] in SV group. Median PaO2/FiO2 one hour after extubation was 280 mmHg [246-364] in PV group vs. 298 [250-343] in SV group (p = 0.64). Day-1 PaO2/FiO2, day-2 forced vital capacity, FEV-1 and Tiffenau Index were not different between groups (all p > 0.10). Intraoperatively, 59% of patients showed complete airway closure during pneumoperitoneum, without difference between groups: median airway opening pressure was 17 cmH2O. In PV group, airway and transpulmonary driving pressure were lower (12 ± 5 cmH2O vs. 17 ± 7, p < 0.001; 9 ± 4 vs. 13 ± 7, p < 0.001), PaCO2 and respiratory rate were higher (48 ± 8 mmHg vs. 42 ± 12, p < 0.001; 23 ± 5 breaths/min vs. 16 ± 4, p < 0.001). Intraoperative EELV was similar between PV and SV group (1193 ± 258 ml vs. 1207 ± 368, p = 0.80); ratio of tidal volume to EELV was lower in PV group (0.45 ± 0.12 vs. 0.32 ± 0.09, p < 0.001). CONCLUSIONS: In obese patients undergoing Trendelenburg pneumoperitoneum surgery, PV did not improve postoperative oxygenation nor day-2 respiratory function. PV was associated with intraoperative respiratory mechanics indicating less injurious ventilation. The high prevalence of complete airway closure may have affected study results. TRIAL REGISTRATION: Prospectively registered on http://clinicaltrials.govNCT03157479 on May 17th, 2017.

Ovarian cancer onset across different BRCA mutation types: a view to a more tailored approach for BRCA mutated patients.

OBJECTIVE: To evaluate the role of different specific types of germline breast cancer susceptibility BRCA mutations on the age of onset of high grade serous ovarian cancer. METHODS: This was a multicenter, international, retrospective cohort of 474 patients diagnosed with recurrent or newly diagnosed high grade serous ovarian cancer, with known germline mutations in BRCA1/2 genes, treated between January 2011 and December 2020 in three academic centers in Europe. Patients were classified into four groups related to the type of BRCA1/2 genes mutation: frameshift, missense, nonsense, and splicing. Data from patients with splicing mutations were removed from the analysis because of the small numbers. The other three groups were compared. RESULTS: Excluding the 29 patients with a splicing mutation, 474 patients were enrolled: 309 (65.2%) with frameshift mutations, 102 (21.5%) with nonsense mutations, and 63 (13.3%) with missense mutations. The BRCA1 gene was affected in 324 (68.4%) cases, while BRCA2 was involved in 150 (31.6%) women (p=0.06). We found a difference of more than 5 years in the age of onset of high grade serous ovarian cancer between BRCA1 and BRCA2 patients (mean 53.3 years vs 58.4 years; p=0.001), with a mean age of 55.1 years. Patients with nonsense germline mutations had the youngest age of onset, while women with frameshift mutations had the oldest age of onset of high grade serous ovarian cancer (mean 52.2 years vs mean 55.9 years), both in the BRCA1 and BRCA2 subgroups. There was no statistically significant difference in age of onset between early and advanced groups (mean 55.8 years vs 55.0 years; p=0.55). CONCLUSION: Different types of germline BRCA mutations could determine different ages for onset of high grade serous ovarian cancer. If confirmed in larger series, this finding might have a clinical impact, potentially leading to a more tailored approach for risk reducing surgery for the prevention of high grade serous ovarian cancer.

Recurrent Endometrial Cancer: Which Is the Best Treatment? Systematic Review of the Literature.

BACKGROUND: Endometrial cancer is the most common gynaecological tumour in developed countries. The overall rate of relapse has remained unchanged in recent decades. Recurrences occur in approximately 20% of endometrioid and 50% of non-endometrioid cases. The aim of this systematic review is to compare different therapeutic strategies in the treatment of endometrial cancer recurrence to evaluate their prognostic and curative effects based on site and type of recurrence. METHODS: This systematic review of literature was conducted in accordance with the PRISMA guidelines. The study protocol was registered on PROSPERO (CRD42020154042). PubMed, Embase, Chocrane and Cinahl databases were searched from January 1995 to September 2021. Five retrospective studies were selected. RESULTS: A total of 3571 studies were included in the initial search. Applying the screening criteria, 299 articles were considered eligible for full-text reading, of which, after applying the exclusion criteria, 4 studies were selected for the final analysis and included in the systematic review. No studies were included for a quantitative analysis. We divided the results according to the location of the recurrence: locoregional recurrence, abdominal recurrence and extra abdominal recurrence. CONCLUSION: the treatment of choice should be assessed according to the relapse location and to the presence of single or multiple lesions. A crucial role in the decision-making algorithm is also the type of adjuvant treatment received at the time of the first diagnosis.

Management of oligometastatic ovarian cancer recurrence during PARP inhibitor maintenance.

OBJECTIVE: The benefit of surgery and maintenance treatment with PARP inhibitors (PARPi) has been clearly demonstrated in ovarian cancer. Also, the efficacy and safety of stereotactic body radiotherapy has been shown in patients with metastatic, persistent, and recurrent disease. The aim of this study is to evaluate the management of oligometastatic progression during PARPi maintenance treatment. METHODS: This is an observational, retrospective, single-arm study conducted from June 2017 to December 2020 in patients with recurrent ovarian cancer with oligometastatic progression under PARPi maintenance treatment and receiving surgery or stereotactic body radiotherapy for such recurrence. PARPi treatment was continued until further progression of the disease. The primary objective of the study was the median prolongation of the treatment-free interval-p (without platinum) after local treatment. RESULTS: A total of 186 patients with ovarian cancer were treated with PARPi at recurrence. Of these, 30 (16%) developed oligometastatic progression. The median age was 49.5 years (range 35-73). Olaparib, niraparib and rucaparib were administered to 33%, 60%, and 7% of patients, respectively. The median prolongation of the treatment-free interval-p of patients treated with surgery or stereotactic body radiotherapy was 6 and 10 months, respectively (p=0.53). The median treatment-free interval-p of patients treated with surgery or stereotactic body radiotherapy at the time of oligometastatic progression was 32 and 29 months, respectively (p=0.44). At the time of this publication, 50% of patients are still on treatment with PARPi following progression. CONCLUSIONS: Patients with recurrent ovarian cancer who have oligometastic progression during PARPi maintenance may continue to benefit from PARPi if combined with local treatment.

Further refining 2020 ESGO/ESTRO/ESP molecular risk classes in patients with early-stage endometrial cancer: A propensity score-matched analysis.

BACKGROUND: The integration of molecular features with clinicopathological findings in endometrial cancer classification seems to be able to significantly refine risk assessment. Nevertheless, clinical management remains challenging, and different therapeutic options are available for each class. Further prognostic characterization of the subgroups within each risk class could be helpful in the decision-making process. METHODS: This study evaluated the role of the 2020 European Society of Gynaecological Oncology (ESGO)/European Society for Radiotherapy and Oncology (ESTRO)/European Society of Pathology (ESP) risk assessment system and the three prognostic profiles adopted in the PORTEC-4a trial in predicting disease-free and overall survival in a retrospective study cohort of patients with early-stage endometrial cancer. Patients were selected according to a 1:2 propensity score matching analysis. Moreover, the sequencing of 29 genes was undertaken for tumor samples. RESULTS: The study included 137 patients. No differences in disease-free or overall survival at 5 years were observed among the 2020 ESGO/ESTRO/ESP risk classes without molecular features (p = .766 and p = .176, respectively). Once molecular features were integrated, the probability of overall survival was significantly different (p = .011). When the three prognostic profiles were applied, the probability of recurrence had a p value of .097, and significant differences were observed in overall survival (p = .004). Among patients experiencing recurrence, 17.6% showed mutations in BRCA1/2, RAD50, BRIP1, and XRCC2, whereas 22.5% had PD-L1-positive expression and an MUTYH mutation. CONCLUSIONS: Further stratification within each risk class according to the most relevant prognostic features could better define the prognosis of patients with early-stage endometrial cancer. Nearly half of the patients who experienced recurrence showed a targetable molecular alteration for which dedicated trials should be encouraged.

Ultrastaging of 'negative' pelvic lymph nodes in patients with low- and intermediate-risk endometrioid endometrial cancer who developed non-vaginal recurrences.

OBJECTIVE: Evidence on micrometastases and isolated tumor cells as factors associated with non-vaginal recurrence in low- and intermediate-risk endometrial cancer is limited. The goal of our study was to investigate risk factors for non-vaginal recurrence in low- and intermediate-risk endometrial cancer. METHODS: Records of all patients with endometrial cancer surgically managed at the Mayo Clinic before sentinel lymph node implementation (1999-2008) were reviewed. We identified all patients with endometrioid low-risk (International Federation of Gynecology and Obstetrics (FIGO) stage I, grade 1 or 2 with myometrial invasion <50% and negative peritoneal cytology) or intermediate-risk (FIGO stage I, grade 1 or 2 with myometrial invasion ≥50% or grade 3 with myometrial invasion <50% and negative peritoneal cytology) endometrial cancer at definitive pathology after pelvic and para-aortic lymph node assessment. All pelvic lymph nodes of patients with non-vaginal recurrence (any recurrence excluding isolated vaginal cuff recurrences) underwent ultrastaging. RESULTS: Among 1303 women, we identified 321 patients with low-risk (n=236) or intermediate-risk (n=85) endometrial cancer (median age 65.4 years; 266 (82.9%) stage IA; 55 (17.1%) stage IB). Of the total of 321, 13 patients developed non-vaginal recurrence (Kaplan-Meier rate 4.7% by 60 months; 95% CI 2.1% to 7.2%): 11 hematogenous/peritoneal and two para-aortic and distant lymphatic. Myometrial invasion and lymphovascular space invasion were univariately associated with non-vaginal recurrence. In these patients, the original hematoxylin/eosin slides review confirmed all 646 pelvic and para-aortic removed lymph nodes as negative. The ultrastaging of 463 pelvic lymph nodes did not identify any occult metastases (prevalence 0%; 95% CI 0% to 22.8% considering 13 patients; 95% CI 0% to 0.8% considering 463 pelvic lymph nodes). CONCLUSION: There were no occult metastases in pelvic lymph nodes of patients with low- or intermediate-risk endometrial cancer with non-vaginal recurrence. Myometrial invasion and lymphovascular space invasion appear to be associated with non-vaginal recurrence.

Personalized tumor-specific DNA junctions to detect circulating tumor in patients with endometrial cancer.

INTRODUCTION: There are no reliable blood biomarkers for monitoring endometrial cancer patients in the current clinical practice. Circulating tumor DNA (ctDNA) is emerging as a promising non-invasive method to measure tumor burden, define prognosis and monitor disease status in many solid cancers. In this pilot study, we investigated if unique tumor-specific DNA junctions can be used to detect ctDNA levels in patients with endometrial cancer. METHODS: Chromosomal rearrangements in primary tumors of eleven patients with high-grade or advanced stage endometrial cancer were determined by whole-genome Mate-Pair sequencing. Identified unique tumor-specific junctions were evaluated in pre- and six-week post-surgery patient plasma using individualized quantitative polymerase chain reaction (qPCR) assays. The relationship between clinicopathological features and detection of ctDNA was investigated. RESULTS: CtDNA was detected in 60% (6/10) of cases pre-surgery and in 27% (3/11) post-surgery. The detection of ctDNA pre-surgery was consistent with clinical indicators of aggressive disease such as advanced stage (80% - 4/5), lymphatic spread of disease (100% - 3/3), serous histology (80% - 4/5), deep myometrial invasion (100% - 3/3), lympho-vascular space invasion (75% - 3/4). All patients in which ctDNA was detected post-surgically had type II endometrial cancer. DISCUSSION: This pilot study demonstrates the feasibility of using personalized tumor-specific junction panels for detecting ctDNA in the plasma of endometrial cancer patients. Larger studies and longer follow-up are needed to validate the potential association between pre-surgical ctDNA detection and the presence of cancers with aggressive pathologic tumor characteristics or advanced stage observed in this study.

The shift from inpatient to outpatient hysterectomy for endometrial cancer in the United States: trends, enabling factors, cost, and safety.

OBJECTIVE: To evaluate trends in outpatient versus inpatient hysterectomy for endometrial cancer and assess enabling factors, cost and safety. METHODS: In this retrospective cohort study, patients aged 18 years or older who underwent hysterectomy for endometrial cancer between January 2008 and September 2015 were identified in the Premier Healthcare Database. The surgical approach for hysterectomy was classified as open/abdominal, vaginal, laparoscopic or robotic assisted. We described trends in surgical setting, perioperative costs and safety. The impact of patient, provider and hospital characteristics on outpatient migration was assessed using multivariate logistic regression. RESULTS: We identified 41 246 patients who met inclusion criteria. During the time period studied, we observed a 41.3% shift from inpatient to outpatient hysterectomy (p<0.0001), an increase in robotic hysterectomy, and a decrease in abdominal hysterectomy. The robotic hysterectomy approach, more recent procedure (year), and mid-sized hospital were factors that enabled outpatient hysterectomies; while abdominal hysterectomy, older age, Medicare insurance, black ethnicity, higher number of comorbidities, and concomitant procedures were associated with an inpatient setting. The shift towards outpatient hysterectomy led to a $2500 savings per case during the study period, in parallel to the increased robotic hysterectomy rates (p<0.001). The post-discharge 30-day readmission and complications rate after outpatient hysterectomy remained stable at around 2%. CONCLUSIONS: A significant shift from inpatient to outpatient setting was observed for hysterectomies performed for endometrial cancer over time. Minimally invasive surgery, particularly the robotic approach, facilitated this migration, preserving clinical outcomes and leading to reduction in costs.

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.

Substantial lymph-vascular space invasion (LVSI) as predictor of distant relapse and poor prognosis in low-risk early-stage endometrial cancer.

OBJECTIVE: The aim of this study is to analyze the prognostic role of lymph-vascular space invasion (LVSI), evaluated in a semi-quantitative fashion on prognosis of early stage, low risk endometrial cancer (EC). METHODS: We enrolled patients who underwent surgery for endometrial cancer between 2003 and 2018 in two referral cancer center. All patients had endometrioid EC, G1-G2, with myometrial invasion <50%, and no lymph-node involvement. LVSI was analyzed in a semi-quantitative way, according to a 3-tiered scoring system in absent, focal and substantial. RESULTS: Among 524 patients, any positive LVSI was found in 57 patients (10.9%) with focal LVSI (n=35, 6.7%) and substantial LVSI (n=22, 4.2%). Substantial LVSI was associated to higher rate of G2 (p<0.001), myometrial infiltration (p=0.002) and greater tumor dimensions (p=0.014). Patients with substantial LVSI were more likely to receive adjuvant treatment (6.6% vs. 52.6%, p<0.001). The 5-year OS was 99.5% in patients with absent LVSI and 70.6% in those with substantial LVSI (p<0.001). The 5-year disease free survival (DFS) was 93.6% in patients with absent LVSI and 56.5% in those with substantial LVSI (p<0.001). The rate of distant failures increased from 1.8% for absent LVSI to 22.7% for substantial LVSI (p=0.002). In univariate analysis substantial LVSI was the strongest predictor of poor overall survival (hazard ratio [HR]=11.9, p=0.001). Multivariate analysis showed that substantial LVSI was an independent predictive factor of both recurrence (HR=5.88, p=0.001) and distant failure (HR=10.6, p=0.006). CONCLUSIONS: Substantial LVSI represents the strongest independent risk factor for decreased survival and distant relapse, indicating a role for potential hematogenous dissemination.

A prospective multicenter international single-arm observational study on the oncological safety of the sentinel lymph node algorithm in stage I intermediate-risk endometrial cancer (SELECT, SEntinel Lymph node Endometrial Cancer Trial).

BACKGROUND: In the primary treatment of apparent uterine-confined endometrial carcinoma, pelvic ± para-aortic lymphadenectomy has been considered the standard of care. Although some retrospective data suggest that the sentinel lymph node algorithm without complete lymphadenectomy can be used without jeopardizing oncologic outcome, prospective data are lacking. PRIMARY OBJECTIVES: To assess the 36 month incidence of pelvic/non-vaginal recurrence in women with pathologically confirmed stage I intermediate-risk endometrioid endometrial carcinoma who have bilateral negative pelvic sentinel lymph nodes. STUDY HYPOTHESIS: We hypothesize that patients with stage I, intermediate-risk endometrioid endometrial carcinoma who have bilateral negative pelvic sentinel lymph nodes will demonstrate a pelvic/non-vaginal recurrence rate comparable to historical estimate of stage I, intermediate-risk endometrioid endometrial carcinoma patients (estimated 2.5%). TRIAL DESIGN: This prospective multicenter single-arm observational study will follow women with stage I, intermediate risk endometrioid endometrial adenocarcinoma who have undergone successful hysterectomy, bilateral salpingo-oophorectomy, and bilateral sentinel lymph node biopsies, for recurrence. All patients will undergo lymphatic mapping using indocynanine green and will either receive no adjuvant treatment or vaginal brachytherapy only. Patients will be followed for 36 months. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients will be enrolled in the study cohort if all the following criteria are met: (i) at time of surgery: hysterectomy with bilateral adnexectomy, and successful bilateral pelvic sentinel lymph node mapping; (ii) on final pathology: pathologic stage I, intermediate-risk endometrioid endometrial carcinoma (grade 1 or grade 2 with ≥50% myometrial invasion, or grade 3 with <50% myometrial invasion), negative pelvic peritoneal cytology, and bilateral sentinel lymph nodes negative for malignancy; (iii) recommended adjuvant treatment: vaginal brachytherapy or no adjuvant treatment. PRIMARY ENDPOINT: Incidence of pelvic/non-vaginal recurrence at 36 months. SAMPLE SIZE: 182 patients for study cohort ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual will be completed in 2023 with results reported in 2026. TRIAL REGISTRATION: NCT04291612.

Role of adjuvant therapy in stage IIIC2 endometrial cancer.

OBJECTIVE: The role of the different types of adjuvant treatments in endometrial cancer with para-aortic node metastases is unclear. The aim of this study was to report oncologic outcomes after adjuvant therapy in patients with stage IIIC2 endometrial cancer. METHODS: This retrospective single-institution study assessed patients with stage IIIC2 endometrial cancer who underwent primary surgery from January 1984 to December 2014. All patients had hysterectomy (±salpingo-oophorectomy) plus lymphadenectomy (para-aortic nodes, ±pelvic nodes). We included all patients with stage III endometrial cancer and documented para-aortic lymph node metastases (International Federation of Obstetrics and Gynecologists stage IIIC2). We excluded patients who did not provide consent, who had synchronous cancer, or who underwent neoadjuvant chemotherapy. Follow-up was restricted to the first 5 years post-operatively. Cox proportional hazards models, with age as the time scale, was used to evaluate associations of risk factors with disease-free survival and overall survival. RESULTS: Among 105 patients with documented adjuvant therapy, external beam radiotherapy was administered to 25 patients (24%), chemotherapy to 24 (23%), and a combination (chemotherapy and external beam radiotherapy) to 56 (53%) patients. Most patients receiving chemotherapy and external beam radiotherapy (80%) had chemotherapy first. The majority of relapses had a distant component (31/46, 67%) and only one patient had an isolated para-aortic recurrence. Non-endometrioid subtypes had poorer disease-free survival (HR 2.57; 95% CI 1.38 to 4.78) and poorer overall survival (HR 2.00; 95% CI 1.09 to 3.65) compared with endometrioid. Among patients with endometrioid histology (n=60), chemotherapy and external beam radiotherapy improved disease-free survival (HR 0.22; 95% CI 0.07 to 0.71) and overall survival (HR 0.28; 95% CI 0.09 to 0.89) compared with chemotherapy or external beam radiotherapy alone. Combination therapy did not improve prognosis for patients with non-endometrioid histology (n=45). CONCLUSIONS: In our cohort of patients with stage IIIC2 endometrioid endometrial cancer, those receiving chemotherapy and external beam radiotherapy had improved survival compared with patients receiving chemotherapy or external beam radiotherapy alone. However, the prognosis of patients with non-endometrioid endometrial cancer remained poor, regardless of the adjuvant therapy administered. Distant recurrences were the most common sites of failure.

Rare Case of Endoscopic Treatment for Bevacizumab-Related Gastric Perforation in a Patient with Ovarian Cancer.

Antiangiogenic chemotherapy is a common treatment option for patients with advanced ovarian cancer (OC) and has been proven to be effective and generally safe. Nevertheless, in rare cases, these drugs can give serious complications such as gastrointestinal perforations that can be even mortal or very difficult to treat and can heavily impact the clinical management. We present a rare case of bevacizumab-induced gastric perforation in a patient with advanced OC occurred during bevacizumab-including chemotherapy in an adjuvant setting. Surgical treatment was not possible due to the frailty of the clinical condition of the patient and the gastric perforation was successfully treated with endoscopic suturing.

External beam radiotherapy versus vaginal brachytherapy in patients with stage II endometrial cancer: a systematic review and meta-analysis.

OBJECTIVE: The choice of adjuvant treatment for women with stage II endometrial cancer is challenging, given the known increase in morbidity with external beam radiation compared with vaginal brachytherapy, and the lack of consensus on its benefits. We summarized the evidence on survival and recurrence for stage II endometrial cancer, defined as cervical stromal invasion, after adjuvant postoperative external beam radiotherapy and vaginal brachytherapy. METHODS: We searched the MEDLINE, EMBASE, CENTRAL, and Scopus databases from inception to January 2019 to identify studies that compared adjuvant postoperative external beam radiotherapy with or without vaginal brachytherapy and vaginal brachytherapy alone in stage II endometrial cancer. Our primary outcome was the locoregional recurrence rate, defined as recurrence in the pelvis or vagina. Secondary outcomes included the rate of recurrence at any site, distant recurrence rate, vaginal recurrence rate, pelvic recurrence rate, and 5 year overall survival. Study selection, assessment, and data abstraction were performed by an independent set of reviewers. Random effects models were used to synthesize quantitative data. RESULTS: We included 15 cohort studies reporting data on 1070 women. Most women with stage II endometrial cancer (848/1070, 79.3%) were treated with external beam radiotherapy with or without vaginal brachytherapy. Subgroup analysis was stratified by whether >90% of the women included underwent pelvic lymph node assessment (sampling or full dissection). Locoregional recurrence (pelvic and vaginal recurrence) was significantly reduced with external beam radiotherapy with or without vaginal brachytherapy compared with vaginal brachytherapy alone (14 studies (n=1057); odds ratio (OR) 0.33 (95% confidence interval (CI) 0.16 to 0.68); I2=5%) regardless of pelvic lymph node assessment. Most women (81.8%) who recurred locoregionally had a least one uterine risk factor (grade 3 tumor, myometrial invasion >50%, or lymphovascular invasion). There was no difference in overall survival with external beam radiotherapy with or without vaginal brachytherapy compared with vaginal brachytherapy alone (five studies (n=463); OR 0.78 (95% CI 0.34 to 1.80); I2=48%). CONCLUSIONS: External beam radiotherapy with or without vaginal brachytherapy decreased the locoregional recurrence threefold for stage II endometrial cancer, regardless of pelvic lymph node assessment. Most women who suffered recurrence locoregionally had a least one high risk factor. Vaginal brachytherapy alone may be sufficient therapy for node negative stage II endometrial cancer without uterine risk factors, while those with uterine risk factors should be considered for external beam radiotherapy with or without vaginal brachytherapy to improve locoregional control.

Trametinib response in heavily pretreated high-grade ovarian cancer: One step towards precision medicine.

Traditional treatment failure in recurrent ovarian cancer remains a challenge for clinicians. Tumor genetic testing is a promising tool which has been proved able to identify sensitivity profiles in patients affected by cancers. This may be helpful in choosing targeted systemic treatments, aiming to overcome histology boundaries and to avoid unnecessary toxicity. We describe the case of a patient affected by recurrent high-grade serous ovarian cancer responsive to MEK-inhibitors, who had undergone multiple lines of therapy. To our knowledge, this is the first reported case of recurrent high-grade ovarian cancer showing remarkable clinical, radiologic and biochemical response to trametinib. This report suggests that trametinib could be effective in high-grade serous ovarian cancer, although most of promising scientific data on this molecule have focused on low-grade ovarian cancer. Molecular profiling has gradually become part of care for patients affected by recurrent ovarian cancer, however further randomized studies are needed to prove its efficacy in everyday clinical practice.

Extreme complications related to bevacizumab use in the treatment of ovarian cancer: a case series from a III level referral centre and review of the literature.

In patients undergoing debulking surgery for ovarian cancer (OC), bevacizumab-combined chemotherapy has been reported to be associated with an increased incidence of adverse events (AEs). Reports in the literature have noted the overall morbidity of bevacizumab to be between 3.7% and 9%. The aim of this study is to report uncommon and unusual manifestations of morbidity in surgical cases performed at our third level referral centers for gynecologic oncology. Additionally, we review the rare and severe bevacizumab-related complications that have been described in the literature. We defined as "extreme", the particularly rare and/or severe complications up to determining a life-threatening condition or death, which are related to the use of bevacizumab. A case-series of extreme complications registered at our institutions were reported. In addition, a literature search of the PubMed, MEDLINE and EMBASE electronic databases was performed for this review. The studies collected included: 8 randomized controlled trials (RCT) and 5 prospective observational, 1 prospective phase-IV, 10 prospective phase-II, 2 prospective phase-I, and 20 retrospective studies, as well as 9 case reports. Bevacizumab was administered as primary treatment in adjuvant and neo-adjuvant setting in 16 and 5 studies respectively, as treatment for recurrence in 36 trials, and for secondary cytoreductive surgery (SCS) in 3 studies. The overall population administered with bevacizumab numbered 7,096 women. Extreme complications were observed in 591 patients, with a morbidity rate of the 8.3%. Overall, central nervous system (CNS), cardiovascular, gastrointestinal (GI) and primary infectious complications were seen in 22 patients (0.3%), 261 patients (3.7%), 159 patients (2.2%), and 8 patients (0.13%), respectively. Hemorrhagic and wound complications occurred in 18 women (0.25%), and 112 women (1.6%), respectively. Extreme complications related to the use of bevacizumab are rare, and often go unrecognized. The recognition and immediate management of such rare and life-threatening complications in patients treated at third level referral centers could significantly improve patient survival.

Sentinel lymph node biopsy for robotic-assisted endometrial cancer staging: further improvement of perioperative outcomes.

OBJECTIVES: It is unclear if sentinel lymph node biopsy is associated with improved surgical outcomes compared with lymphadenectomy in patients with endometrial cancer. In this study we aimed to compare peri-operative surgical outcomes and treatment-related morbidity in patients who underwent robotic-assisted sentinel lymph node biopsy versus systematic pelvic lymphadenectomy or hysterectomy alone for apparent early-stage endometrial cancer. METHODS: Records were reviewed of consecutive patients with International Federation of Gynecology and Obstetrics stages I-III endometrial cancer undergoing robotic-assisted staging from January 1, 2009, through June 30, 2016. For the purpose of this analysis we focused on the actual patients who had sentinel node biopsy only (ie, excluding those who had an associated lymphadenectomy either for failed mapping or during the learning curve). We also excluded patients who had para-aortic lymph node dissection from the lymphadenectomy group. Perioperative and 30-day surgical outcomes were compared between patients who underwent sentinel lymph node assessment and those who had pelvic lymphadenectomy or hysterectomy alone, respectively. Inverse probability of treatment weighting derived from propensity scores was used to minimize allocation bias in the comparison of outcomes between groups. RESULTS: A total of 621 patients were analyzed: 188 (30.3%) with sentinel lymph node biopsy, 198 (31.9%) with pelvic lymphadenectomy, and 235 (37.8%) with hysterectomy alone. Inverse probability of treatment weights analysis balanced for baseline characteristics (age, body mass index, American Society of Anesthesiologists score, Charlson co-morbidity index, parity, prior cesarean section, and previous abdominal operation) showed no significant differences in intra-operative and post-operative complications, re-admissions, and re-operations between the groups. Compared with pelvic lymphadenectomy, the sentinel lymph node biopsy group had a shorter mean operative time (138.0 vs 222.8 min, p<0.001) and less median blood loss (50 vs 100 mL, p<0.001). Sentinel lymph node biopsy also was not associated with worse morbidity compared with hysterectomy alone. CONCLUSIONS: Introduction of sentinel lymph node biopsy reduces operative times and improves peri-operative surgical outcomes of robotic-assisted staging for apparent early-stage endometrial cancer without worsening the morbidity of hysterectomy alone.