Sex-related differences in oncological surgery and postoperative outcomes: comprehensive, nationwide study in France.

BACKGROUND: The main objective of this study was to undertake an exhaustive investigation of sex-related differences in cancer surgery. METHODS: This observational study used data from the French national health insurance system database covering 98.8% of the population. Patients diagnosed with non-sex-specific solid invasive cancers between January 2018 and December 2019 were included. The main outcomes were likelihood of undergoing cancer surgery, type of oncological surgery performed, and associated 30-, 60-, and 90-day postoperative reoperation and mortality rates, by sex. RESULTS: For the 367 887 patients included, women were 44% more likely than men to undergo cancer surgery (OR 1.44, 95% c.i. 1.31 to 1.59; P < 0.001). However, the likelihood of surgery decreased with advancing age (OR 0.98, 0.98 to 0.98; P < 0.001), and with increasing number of co-morbid conditions (OR 0.95, 0.95 to 0.96; P < 0.001), especially in women. Men had higher 90-day reoperation (21.2 versus 18.8%; P < 0.001) and mortality (1.2 versus 0.9%; P < 0.001) rates than women, overall, and for most cancer types, with the exception of bladder cancer, for which the 90-day mortality rate was higher among women (1.8 versus 1.4%; P < 0.001). After adjustment for age, number of co-morbid conditions, and surgical procedure, 90-day mortality remained higher in men (OR 1.16, 1.07 to 1.26; P < 0.001), and men were 21% more likely than women to undergo reoperation within 90 days (OR 1.21, 1.18 to 1.23; P < 0.001). CONCLUSION: Women were much more likely than men to undergo cancer surgery than men, but the likelihood of surgery decreased with advancing age and with increasing number of co-morbid conditions, especially in women. These findings highlight a need for both increased awareness and strategies to ensure gender equality in access to oncological surgical treatment and improved outcomes.

Survival Outcomes of Primary versus Interval Cytoreductive Surgery for FIGO IV Ovarian Cancer (SOFI-4): a Nationwide Population-based Target Trial Emulation.

BACKGROUND: The effect of primary cytoreductive surgery versus interval cytoreductive surgery on FIGO IV ovarian cancer outcomes remains uncertain, and may vary depending on the stage and the extraperitoneal metastasis location. Emulating target trials through causal assessment combined with propensity score adjustment has become a leading method for evaluating interventions using observational data. OBJECTIVE: To assess the effect of primary versus interval cytoreductive surgery on progression-free and overall survival in patients with FIGO IV ovarian cancer using target trial emulation. STUDY DESIGN: Utilizing the comprehensive French national health insurance database, we emulated a target trial to explore primary versus interval cytoreductive surgery causal impacts on FIGO 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 balance baseline characteristics between the groups. Subgroup analyses were conducted based on FIGO stages and extraperitoneal metastasis locations. The study included patients under 75 years of age, in good health condition, diagnosed with FIGO IV ovarian cancer between January 1, 2014, and December 31, 2022. The primary and secondary outcomes were respectively five-year progression-free survival and seven-year overall survival. RESULTS: Among the 2,772 patients included in the study, 948 (34.2%) were classified as FIGO IVA and 1,824 (65.8%) as FIGO IVB at inclusion. Primary cytoreductive surgery was performed on 1,182 patients (42.6%), while interval cytoreductive surgery was conducted on 1,590 patients (57.4%). The median progression survival for primary cytoreductive surgery was 19.7 months (interquartile range [IQR]: 19.3-20.1), compared to 15.7 months (IQR: 15.7-16.1) for those who underwent interval cytoreductive surgery. The median overall survival was 63.1 months [IQR: 61.7-65.4] for primary cytoreductive surgery, in comparison to 55.6 months [IQR: 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 five-year progression-free survival (95% Confidence Intervals [CI]: 3.8-6.2) and a 3.9-month increase in seven-year overall survival (95% CI: 1.9-6.2). These survival benefits of primary over interval cytoreductive surgery were observed in both the FIGO IVA and IVB subgroups. Primary cytoreductive surgery demonstrated improved progression-free survival and overall survival in patients with pleural, supra-diaphragmatic, or extra-abdominal lymph node metastasis. CONCLUSIONS: SOFI-4 advocates for the benefits of primary cytoreductive surgery over interval cytoreductive surgery for patients with FIGO IV ovarian cancer, suggesting extraperitoneal metastases like supra-diaphragmatic or extra-abdominal lymph nodes should not automatically preclude primary cytoreductive surgery consideration in suitable patients.

Clinical spectrum and evolution of immune-checkpoint inhibitors toxicities over a decade-a worldwide perspective.

Background: 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. Methods: 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. Findings: 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. <3% in general for other inter-irAE overlap). The top factors associated with specific irAE (odds-ratio>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). Interpretation: 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. Funding: 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 (Institut Curie) was supported by the academic program "SHS INCa", Sanofi iTech award, and by Monoprix∗.

Early morning immune checkpoint blockade and overall survival of patients with metastatic cancer: An In-depth chronotherapeutic study.

INTRODUCTION: Recent retrospective studies suggest potential large patient's benefit through proper timing of immune checkpoint blockers (ICB). The association between ICB treatment timing and patient survival, neoplastic response and toxicities was investigated, together with interactions with performance status (PS) and sex. METHODS: A cohort of patients with metastatic or locally advanced solid tumors, who received pembrolizumab, nivolumab, atezolizumab, durvalumab, or avelumab, alone or with concomitant chemotherapy, between November 2015 and March 2021, at the Centre Leon Bérard (France), was retrospectively studied. RESULTS: 361 patients were investigated (80% non-small cell lung cancer patients, mean [SD] age: 63 [11] years, 39% of women, 83% PS0-1 at first infusion, 19% received concomitant chemotherapy). ICB were administered from 07:25 to 17:21 and optimal morning/afternoon cut-off was 11:37. Morning infusions were associated with increased OS as compared to afternoon (median 30.3 vs 15.9 months, p = 0.0024; HR 1.56 [1.17-2.1], p = 0.003). A strong PS-timing interaction was found (PS0-1 patients, HR=1.53 [1.10-2.12], p = 0.011; PS2-3 patients, HR=0.50 [0.25-0.97], p = 0.042). Morning PS0-1 patients displayed increased OS (median 36.7 vs 21.3 months, p = 0.023), partial/complete response rate (58% vs 41%, p = 0.027), and grade1-3 toxicities (49% vs 34%, p = 0.028). Mortality risk ratio between infusions at worst time-of-day, estimated at 13:36 [12:48-14:23], and in early morning was equal to 4.8 ([2.3-10.1], p = 0.008). Timing differences in toxicities resulted significant only in female patients (women vs men: p < 0.001 vs 0.4). CONCLUSIONS: Early morning ICB infusion was associated with increased OS, response, and toxicities in patients with PS0-1 as compared to later infusions within the day. Prospective randomized trials are needed to confirm this retrospective study.

Immune Checkpoint Inhibitor Use During Pregnancy and Outcomes in Pregnant Individuals and Newborns.

Importance: With the widespread use of immune checkpoint inhibitors (ICIs), concerns about their pregnancy outcomes through maternal exposure have emerged, and clinical comparative data are lacking. Objective: To assess the risk of pregnancy-, fetal-, and/or newborn-related adverse outcomes associated with exposure to ICIs compared with exposure to other anticancer agents. Design, Setting, and Participants: In this cohort study, all reports mentioning a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) used for a cancer indication registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. Exposure: Anticancer agents, including ICIs, used during pregnancy for a cancer indication. Immune checkpoint inhibitors included blockers of programmed cell death 1 (PD1) or its ligand (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Main Outcomes and Measures: The main outcome was the reporting odds ratio (ROR) for maternal, fetal, or newborn complications in patients treated with ICIs vs any other anticancer drug. Adverse events, categorized into 45 individual maternofetal adverse outcomes, were directly mapped to Medical Dictionary for Regulatory Activities preferred terms in VigiBase. Results: A total of 3558 reports (ICI: 91 [2.6%]; other anticancer drugs: 3467 [97.4%]) were included in the analysis. In the ICI group, most reports were from the US (60 [65.9%]), and the mean (SD) patient age was 28.9 (10.2) years; in 24 of 55 reports with data on cancer type (43.6%), patients were treated for melanoma. The molecules involved in the ICI group were anti-PD1 (58 reports [63.7%]), anti-PD1 plus anti-CTLA4 (15 [16.5%]), anti-CTLA4 (13 [14.3%]), anti-PD-L1 (4 [4.4%]), and anti-PD1 plus anti-lymphocyte activation gene 3 (1 [1.1%]). An ICI was used in combination with a non-ICI anticancer agent in 10 participants (11.0%). Compared with other anticancer drugs, none of the 45 adverse outcomes identified were overreported in the group exposed to ICIs. However, preterm birth was significantly overreported for the anti-PD1 plus anti-CTLA4 combination compared with other anticancer drugs (12 of 15 [80.0%] vs 793 of 3452 [23.0%]; ROR, 13.87; 95% CI, 3.90-49.28; P < .001) but not for anti-PD-L1 or anti-CTLA4 monotherapy. Three reports of possibly immune-related maternofetal events were identified: 1 case of maternal antiphospholipid syndrome leading to spontaneous abortion, 1 case of pneumonitis leading to neonatal respiratory distress syndrome and death, and 1 case of transient congenital hypothyroidism. Conclusions and Relevance: In this cohort study of 91 individuals exposed to ICIs during pregnancy, ICI exposure was not associated with overreporting of specific adverse pregnancy, fetal, and/or newborn outcomes compared with other anticancer treatments. However, due to possible rare immune-related neonatal adverse events, ICI use in pregnant women should be avoided when possible, especially the anti-PD1 plus anti-CTLA4 combination.

Concomitant medication, comorbidity and survival in patients with breast cancer.

Between 30% and 70% of patients with breast cancer have pre-existing chronic conditions, and more than half are on long-term non-cancer medication at the time of diagnosis. Preliminary epidemiological evidence suggests that some non-cancer medications may affect breast cancer risk, recurrence, and survival. In this nationwide cohort study, we assessed the association between medication use at breast cancer diagnosis and survival. We included 235,368 French women with newly diagnosed non-metastatic breast cancer. In analyzes of 288 medications, we identified eight medications positively associated with either overall survival or disease-free survival: rabeprazole, alverine, atenolol, simvastatin, rosuvastatin, estriol (vaginal or transmucosal), nomegestrol, and hypromellose; and eight medications negatively associated with overall survival or disease-free survival: ferrous fumarate, prednisolone, carbimazole, pristinamycin, oxazepam, alprazolam, hydroxyzine, and mianserin. Full results are available online from an interactive platform ( https://adrenaline.curie.fr ). This resource provides hypotheses for drugs that may naturally influence breast cancer evolution.

Association between endocrine adjuvant therapy intake timing and disease-free survival in patients with high-risk early breast cancer: results of a sub-study of the UCBG- UNIRAD trial.

BACKGROUND: Circadian rhythms regulate cellular physiology and could influence the efficacy of endocrine therapy (ET) in breast cancer (BC). We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271). METHODS: 1278 patients with high-risk hormonal receptor positive (HR+)/HER2 negative (HER2-) primary BC were randomly assigned to adjuvant ET with placebo or everolimus. Patients prospectively reported in a diary the daily timing of ET intake among four 6-h slots (06:00-11:59 (morning), 12:00-17:59 (afternoon), 18:00-23:59 (evening), or 24:00-05:59 (nighttime). The association between ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial and the results of this observational study are reported here. FINDINGS: ET timing was recorded by 855 patients (67.2%). Patients declaring morning (n = 465, 54.4%) or afternoon (n = 45, 5.4%) ET intake were older than those declaring evening (n = 339, 39.6%) or nighttime (n = 5, 0.6%) intake. With a median follow-up of 46.7 months, 118 patients had a local (n = 30) or metastasis relapse (n = 84), and 41 patients died. ET intake timing was not associated with DFS in the whole population (HR = 0.77, 95% CI [0.53-1.12]). The association between ET intake timing and DFS according to the stratification factors revealed interactions with ET agent (tamoxifen versus Aromatase inhibitors (AI) with an increased DFS in the group of evening/nighttime versus morning/afternoon tamoxifen intake (HR = 0.43, 95% CI [0.22-0.85]), while no association was found for AI intake (HR = 1.07, 95% CI [0.68-1.69]). The interaction between ET intake timing and ET agent remained in multivariable analysis (HR = 0.38 [0.16-0.91]). INTERPRETATION: Tamoxifen intake in the evening/nighttime could be recommended in patients with high-risk HR+/HER2- BC while awaiting for results from further ET timing studies. FUNDING: UNIRAD was Supported by a grant from the French Ministry of Health PHRC 2012 and received funding from La Ligue contre le Cancer, Cancer Research-UK, Myriad Genetics, and Novartis.