Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment by harnessing the immune system but ICI can induce life-threatening immune-related adverse events (irAE) affecting every organ. We extracted irAE from VigiBase, the international pharmacovigilance database, first reported in 2008 until 01/2023 to characterize irAE reporting trends, clinical features, risk factors and outcomes. We distinguished 25 types of irAE (n = 50,347cases, single irAE/case in 84.9%). Cases mainly involved anti-PD1 (programmed-death-1) monotherapy (62.4%) in male (61.7%) aged 64.3 ± 12.6 years. After 2020 vs. prior to 2016, proportion of anti-CTLA4 (Cytotoxic-T-Lymphocyte-Antigen-4) monotherapy prescription almost vanished (1.6% vs. 47%, respectively) contrasting with increased use of anti-PDL1 (PD1-ligand) monotherapy (18% vs. 0.9%) and anti-CTLA4+anti-PD(L)1 combination (20% vs. 8.9%). Anti-LAG3 (Lymphocyte-Activation-Gene-3) prescription was limited (<1%) in the studied timeframe. After 2020, over 14 different cancer types were treated vs. almost exclusively melanoma and lung cancers before 2016. Overall, the most reported irAE were skin reactions (22.9%), pneumonitis (18.5%), enterocolitis (14.4%) and thyroiditis (12.1%). ICI-myotoxicities (6.6%) included myositis, myocarditis and myasthenia-gravis like syndrome and were the most overlapping irAE (up to 30% overlap, vs. 5) were presence of thymic cancer for ICI-myotoxicities or hepatitis; presence of melanoma for vitiligo, uveitis or sarcoidosis; specific types of ICI regimen (anti-LAG3 for meningitis, anti-CTLA4 for hypophysitis); and specific reporting regions (eastern Asia for cholangitis). Median time-to-onset ranged from 31 to 273 days, being shortest for myotoxicities and most delayed for skin-bullous auto-immune reactions. Overall fatality was highest for myocarditis = 27.6%, myasthenia = 23.1%, severe cutaneous adverse reactions (SCAR) = 22.1%, myositis = 21.9%, pneumonitis = 21%, and encephalomyelitis = 18%; generally decreasing after 2020, except for myasthenia and SCAR. When reported, irAE recurrence rate after rechallenge was 28.9% (n = 275/951). This up-to-date comprehensive worldwide pharmacovigilance study defines the spectrum, characteristics, and evolution of irAE reporting summarizing over a decade of use. Multiple risk factors and clinical peculiarities for specific irAE have been identified as signals to guide clinical practice and future research. Paul Gougis was supported by the academic program: “Contrats ED: Programme blanc Institut Curie PSL” for the conduct of his PhD. Baptiste Abbar was supported by “the Fondation ARC Pour le Rechercher Sur le Cancer”. The RT2L research group ( 10.13039/501100010463 Institut Curie ) was supported by the academic program “SHS INCa”, Sanofi iTech award, and by Monoprix∗.

PURPOSE: Young age is associated with increased risk of recurrence in hormone receptor (HR)–positive early-stage breast cancer (eBC). Lack of adherence to endocrine therapy (ET) is a potential reason for the lower survival proportions observed in younger patients, but the survival benefits of improving adherence to ET in young patients remain unknown. MATERIALS AND METHODS: Using data from the French National Health Data System and target trial emulation methods, we considered three sustained ET persistence strategies (allowing treatment gaps of no more than 30, 90, or 180 continuous days) and estimated the 5-year disease-free survival (DFS) benefit of sustained ET persistence compared with observed ET persistence. RESULTS: A total of 121,601 patients with HR-positive eBC were included in the analyses, of whom 29.8% was younger than 50 years at diagnosis. Younger patients had lower DFS and were more likely to discontinue ET than older patients. In patients 34 years and younger, strict ET persistence (≤30-day gaps) improved 5-year DFS proportions from 74.5% to 78.8% (4.3 percentage points [95% CI, 2.6 to 7.2]) compared with observed persistence. ET persistence strategies allowing for ≤90-day and ≤180-day gaps reduced the 5-year DFS benefit in patients 34 years and younger to 1.3 (95% CI, 0.2 to 3.7) and 1.0 (95% CI, –0.2 to 3.4) percentage points, respectively. By contrast, DFS benefits of improved ET persistence in patients after 50 years old did not exceed 1.9 percentage points, compared with observed persistence, regardless of the persistence definition. CONCLUSION: The survival benefit that could be achieved with strict ET persistence in women 34 years and younger with HR-positive eBC highlights the need for tailored strategies to improve ET persistence in this population.

Objective Lymph nodal involvement is a prognostic factor in endometrial cancer. The added value of para-aortic lymphadenectomy compared with pelvic nodal evaluation alone remains a matter of debate in the management of patients with intermediate- and high-risk endometrial cancer. A systematic review and meta-analysis was conducted to assess the prognostic value of para-aortic lymphadenectomy in terms of overall survival and disease-free survival in patients with intermediate- and high-risk endometrial cancer. Methods The study adhered to the PRISMA guidelines. PubMed, Google Scholar and ClinicalTrials.gov were searched from January 2000 to April 2023. Studies on intermediate- and high-risk patients who underwent pelvic versus pelvic and para-aortic dissection were included in the analysis. The Methodological Index for Nonrandomized Studies (MINORS) and the Quality Assessment of Diagnostic Accuracy Studies 2 tool (QUADAS-2) were used for quality assessment of the selected articles. Results Fourteen studies were identified, encompassing 9415 patients with a median age of 62 years (IQR 56.5–66.5). The majority had International Federation of Gynecology and Obstetrics stage I–II disease (76%) and endometrioid histology (89%). The 72% of patients who underwent only pelvic nodal evaluation and the 87% who underwent pelvic and para-aortic lymphadenectomy received adjuvant treatment (p=0.44). Pelvic and para-aortic lymphadenectomy was associated with a significant improvement in 5-year overall survival (RR=0.71, 95% CI 0.57 to 0.88, p<0.01), translating to a 41% reduction in the risk of overall death. However, no significant differences were observed in the 5-year risk of recurrence (RR=1.12, 95% CI 0.94 to 1.34, p=0.15). Additionally, patients undergoing pelvic and para-aortic lymphadenectomy experienced a 26% increased risk of post-operative complications (RR=1.26, 95% CI 1.04 to 1.53, p=0.03) and prolonged operative times (MD=56.27, 95% CI 15.94 to 96.60, p<0.01). Conclusion Pelvic and para-aortic lymphadenectomy appears to confer a prognostic benefit in patients with intermediate- and high-risk endometrial cancer. Robust prospective studies are needed to further validate these findings and elucidate the precise role of para-aortic lymphadenectomy in the optimal management of these patients.

As regards ovarian cancer, the use of minimally invasive surgery has steadily increased over the years. Reluctance persists, however, about its oncological outcomes. The main objective of this meta-analysis was to compare the three and five-year mortality of patients operated by minimally invasive surgery (MIS) for ovarian cancer to those operated by conventional open surgery (OPS), as well as their respective perioperative outcomes. PubMed, Cochrane library and CinicalTrials.gov were systematically searched, using the terms laparoscopy, laparoscopic or minimally invasive in combination with ovarian cancer or ovarian carcinoma. We finally included 19 observational studies with a total of 7213 patients. We found no statistically significant difference for five-year (relative risk (RR) = 0.89, 95% CI 0.53–1.49, p = 0.62)) and three-year mortality (RR = 0.95, 95% CI 0.80–1.12, p = 0.52) between the patients undergoing MIS and those operated by OPS. When five and three-year recurrences were analyzed, no statistically significant differences were also observed. Analysis in early and advanced stages subgroups showed no significant difference for survival outcomes, suggesting oncological safety of MIS in all stages. Whether the surgery was primary or interval debulking surgery in advanced ovarian cancer, did not influence the comparative results on mortality or recurrence. Although the available studies are retrospective, and mostly carry a high risk for bias and confounding, an overwhelming consistency of the evidence suggests the likely effectiveness of MIS in selected cases of ovarian cancer, even in advanced stages. To validate the use of MIS, the development of future randomized interventional studies should be a priority.

The effect of primary cytoreductive surgery vs interval cytoreductive surgery on International Federation of Gynecology and Obstetrics stage IV ovarian cancer outcomes remains uncertain and may vary depending on the stage and the location of extraperitoneal metastasis. Emulating target trials through causal assessment, combined with propensity score adjustment, has become a leading method for evaluating interventions using observational data. This study aimed to assess the effect of primary vs interval cytoreductive surgery on progression-free and overall survival in patients with International Federation of Gynecology and Obstetrics stage IV ovarian cancer using target trial emulation. Using the comprehensive French national health insurance database, we emulated a target trial to explore the causal impacts of primary vs interval cytoreductive surgery on stage IV ovarian cancer prognosis (Surgery for Ovarian cancer FIGO 4: SOFI-4). The clone method with inverse probability of censoring weighting was used to adjust for informative censoring and to balance baseline characteristics between the groups. Subgroup analyses were conducted based on the stages and extraperitoneal metastasis locations. The study included patients younger than 75 years of age, in good health condition, who were diagnosed with stage IV ovarian cancer between January 1, 2014, and December 31, 2022. The primary and secondary outcomes were respectively 5-year progression-free survival and 7-year overall survival. Among the 2772 patients included in the study, 948 (34.2%) were classified as having stage IVA ovarian cancer and 1824 (65.8%) were classified as having stage IVB ovarian cancer at inclusion. Primary cytoreductive surgery was performed for 1182 patients (42.6%), whereas interval cytoreductive surgery was conducted for 1590 patients (57.4%). The median progression-free survival for primary cytoreductive surgery was 19.7 months (interquartile range, 19.3-20.1) as opposed to 15.7 months (interquartile range, 15.7-16.1) for those who underwent interval cytoreductive surgery. The median overall survival was 63.1 months (interquartile range, 61.7-65.4) for primary cytoreductive surgery in comparison with 55.6 months (interquartile range, 53.8-56.3) for interval cytoreductive surgery. The findings of our study indicate that primary cytoreductive surgery is associated with a 5.0-month increase in the 5-year progression-free survival (95% confidence interval, 3.8-6.2) and a 3.9-month increase in 7-year overall survival (95% confidence interval, 1.9-6.2). These survival benefits of primary over interval cytoreductive surgery were observed in both the International Federation of Gynecology and Obstetrics stage IVA and IVB subgroups. Primary cytoreductive surgery demonstrated improved progression-free survival and overall survival in patients with pleural, supradiaphragmatic, or extra-abdominal lymph node metastasis. This study advocates for the benefits of primary cytoreductive surgery over interval cytoreductive surgery for patients with stage IV ovarian cancer and suggests that extraperitoneal metastases like supradiaphragmatic or extra-abdominal lymph nodes should not automatically preclude primary cytoreductive surgery consideration in suitable patients.

Objective The primary objective of the study was to validate the European Society for Medical Oncology (ESMO)–European Society of Gynecologic Oncology (ESGO) ovarian cancer guideline as a method of assessing quality of care, and to identify patient characteristics predictive of non-adherence to European guideline care. The secondary objectives were to analyze the evolution of practices over the years and to evaluate heterogeneity between centers. Methods This retrospective multicenter cohort study of invasive epithelial ovarian cancer reported to the FRANCOGYN database included data from 12 French centers between January 2000 and February 2017. The main outcome was adherence to ESMO–ESGO guidelines, defined by recommended surgical procedures according to the International Federation of Gynecology and Obstetrics (FIGO) stage and appropriate chemotherapy. Mixed multivariable logistic regression analysis with a random center effect was performed to estimate the probability of adherence to the guidelines. Survival analysis was carried out using the Kaplan–Meier method and a mixed Cox proportional hazards model. Results 1463 patients were included in the study. Overall, 317 (30%) patients received complete guideline adherent care. Patients received appropriate surgical treatment in 69% of cases, while adequate chemotherapy was administered to 44% of patients. Both patient demographics and disease characteristics were significantly associated with the likelihood of receiving guideline adherent care, such as age, performance status, FIGO stage, and initial burden of disease. In univariate and multivariate survival analysis, adherence to the guidelines was a statistically significant and independent predictor of decreased overall survival. Patients receiving suboptimal care experienced an increased risk of death of more than 100% compared with those treated according to the guidelines (hazard ratio 2.14, 95% confidence interval 1.32 to 3.47, p<0.01). In both models, a significant random center effect was observed, confirming the heterogeneity between centers (p<0.001). Conclusions Adherence to ESMO–ESGO guidelines in ovarian cancer was associated with a higher overall survival and may be a useful method of assessing quality of care.