Neige Journy

Introduction: Fatigue is a prevalent and late effect among childhood cancer survivors (CCSs). Few large studies have comprehensively evaluated its prevalence and determinants. Identifying risk factors for fatigue and severe fatigue (SF) is crucial to improving survivorship care. This study assessed the prevalence of fatigue and SF, as well as demographic, clinical, and treatment-related predictors in the French Childhood Cancer Survivor Study (FCCSS). Methods: This cross-sectional analysis included adult 5-year CCSs diagnosed before age 21 (1946–2000) in the FCCSS cohort. Fatigue was measured using the French Multidimensional Fatigue Inventory (MFI-20); SF was defined as a total score > 60. Associations with sex, age, cancer type, treatment, and social deprivation were estimated using multivariable regressions. Analyses were stratified by central nervous system (CNS) vs. non-CNS tumors and compared to general population norms. Results: Among 3170 CCSs, fatigue scores exceeded population norms from age 30, with women affected earlier and more severely. General (10.0 ± 4.2) and physical fatigue (9.6 ± 4.2) were the most pronounced dimensions, increasing with age and peaking at ≥ 50 years. Higher fatigue scores were independently associated with female sex, obesity, older age, and CNS tumor history. SF affected 16% of CCSs, more frequently in women ( OR = 1.30), obese survivors ( OR = 2.40), CNS tumor survivors ( OR = 3.27), hematologic tumor survivors ( OR = 1.46), and radiotherapy exposure ( OR = 1.46). Conclusion: Fatigue remains a common, persistent late effect in CCSs. Female sex, older age, CNS tumors, and radiotherapy were strong predictors, underscoring the needs for targeted screening and long-term management.

(Multi-)Morbidity shares common biological mechanisms or risk factors with breast cancer. This study aimed to investigate the association between the number of morbidities and patterns of morbidity and the risk of female breast cancer. Among 239,436 women (40–69 years) enrolled in the UK Biobank cohort who had no cancer history at baseline, we identified 35 self-reported chronic diseases at baseline. We assigned individuals into morbidity patterns using agglomerative hierarchical clustering analysis. We fitted Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer risk. In total, 58.4% of women had at least one morbidity, and the prevalence of multi-morbidity was 25.8%. During a median 7-year follow-up, there was no association between breast cancer risk (5326 cases) and either the number of morbidities or the identified clinically relevant morbidity patterns: no-predominant morbidity (reference), psychiatric morbidities (HR = 1.04, 95%CI 0.94–1.16), respiratory/immunological morbidities (HR = 0.98, 95%CI 0.90–1.07), cardiovascular/metabolic morbidities (HR = 0.93, 95%CI 0.81–1.06), and unspecific morbidities (HR = 0.98, 95%CI 0.89–1.07), overall. Among women younger than 50 years of age only, however, there was a significant association with psychiatric morbidity patterns compared to the no-predominant morbidity pattern (HR = 1.25, 95%CI 1.02–1.52). The other associations did not vary when stratifying by age at baseline and adherence to mammography recommendations. In conclusion, multi-morbidity was not a key factor to help identify patients at an increased risk of breast cancer.

Importance: Meningioma is the most common subsequent neoplasm following cranial irradiation among survivors of childhood cancer, but there are still uncertainties regarding the magnitude of the radiation dose-response association, potential modifiers of radiation risks, and the role of chemotherapy.Objective: To evaluate meningioma risk in survivors of childhood cancer following radiotherapy and chemotherapy and identify possible modifying factors of radiation-associated risk.Design, Setting, and Participants: This international case-control study pooled data from 4 nested case-control studies of survivors of childhood cancer diagnosed between 1942 and 2000, followed through 2016. Cases were defined as participants diagnosed with a subsequent meningioma. Controls were matched to cases based on sex, age at first cancer diagnosis, and duration of follow-up. Data were analyzed from July 2019 to June 2022.Exposures: Radiation dose (Gy) to the meningioma site and cumulative chemotherapy doses, including intrathecal and systemic methotrexate doses.Main Outcomes and Measures: The main outcome was subsequent meningioma, assessed using odds ratios (ORs) and excess odds ratios per gray (EOR/Gy).Results: The analysis included 273 survivors of childhood cancer who developed meningioma (cases) and 738 survivors who did not (controls), with a total of 1011 individuals (median [IQR] age at first cancer diagnosis 5.0 [3.0-9.2] years; 599 [59.2%] female). Median (IQR) time since first cancer was 21.5 (15.0-27.0) years. Increasing radiation dose was associated with increased risk of meningioma (EOR/Gy, 1.44; 95% CI, 0.62-3.61), and there was no evidence of departure from linearity (P = .90). Compared with survivors who were not exposed to radiation therapy, those who received doses of 24 Gy or more had more than 30-fold higher odds of meningioma (OR, 33.66; 95% CI, 14.10-80.31). The radiation dose-response association was significantly lower among patients treated at age 10 years or older compared with those treated before age 10 years (EOR/Gy, 0.57; 95% CI, 0.18-1.91 vs 2.20; 95% CI, 0.87-6.31; P for heterogeneity = .03). Risk associated with radiation remained significantly elevated 30 years after exposure (EOR/Gy, 3.76; 95% CI, 0.77-29.15). We found an increased risk of meningioma among children who had received methotrexate (OR, 3.43; 95% CI, 1.56-7.57), but no evidence of a dose-response association or interaction with radiation dose.Conclusions and Relevance: These findings suggest that the meninges are highly radiosensitive, especially for children treated before age 10 years. These results support the reduction in whole-brain irradiation over recent decades and the prioritization of approaches that limit radiation exposure in healthy tissue for children. The persistence of elevated risks of meningiomas for 30 years after cranial radiotherapy could help inform surveillance guidelines.

Background: Childhood or adolescent cancer survivors are at increased risks of subsequent primary neoplasms (SPN) of the central nervous system (CNS) after cranial irradiation. In a large multicentric cohort, we investigated clinical and therapeutic factors associated with the long-term risk of CNS SPN, and quantified the dose–response relationships. Methods: We selected all CNS SPN cases diagnosed up to 2016 among members of the French Childhood Cancer Survivor Study at least 5 years after first cancer diagnosis in 1946–2000. Four controls per case were randomly selected within the cohort and matched by sex, year of/age at first cancer diagnosis, and follow-up time. On the basis of medical and radiological reports, cumulative radiation doses received to the SPN or matched location were retrospectively estimated using mathematical phantoms. We computed conditional logistic regression models. Results: Meningioma risk significantly increased with higher radiation doses [excess OR per Gy (EOR/Gy) = 1.377; P < 0.001; 86 cases; median latency time = 30 years], after adjustment for reported genetic syndromes and first CNS tumor. It was higher among youngest individuals at first cancer diagnosis, but did not vary with follow-up time. On the opposite, radiation-related glioma risk (EOR/Gy = 0.049; P = 0.11; 47 cases; median latency time = 17 years) decreased over time (P for time effect = 0.05). There was a significant association between meningioma risk and cumulative doses of alkylating agents, but no association with growth hormone therapy. Conclusions: The surveillance of patients with cranial irradiation should continue beyond 30 years after treatment. Impact: The identified risk factors may inform long-term surveillance strategies.

10061 Background: Platinum chemotherapy (CT) and cranial radiotherapy (RT) are risk factors of ototoxicity. Effects of RT dose at inner ear and of other CT were investigated. Methods: Of 7670 5-year childhood cancer survivors from the FCCSS treated before 20 years of age in 1942-2000 for solid cancer or lymphoma, 5243 with ototoxicity long-term follow-up data were included. Severe ototoxicity, defined as the need of hearing aids or Brock grade 3-4 hearing loss, was identified from self-administrated questionnaires, clinical visits and cohort linkage with the French Hospital Database and health insurance information system (SNIIRAM). The mean RT dose at inner ear was estimated using home-made software. Multivariable Cox models adjusted for gender, age at diagnosis, time period and social deprivation index was used to identify risk factors for severe ototoxicity. Results: After a mean follow-up of 30 years, 199 cases of severe ototoxicity were identified. Cumulative incidences at 30 and 50 years of age (30,50y-CumInc) were, 2.8% (95%CI = 2.4-3.3) and 5.5% (4.6-6.5), respectively. Mean RT dose at inner ear (Hazard Ratio HR = 1.6 (95%CI = 1.0-2.5), 4.5 (2.7-7.2), 5.7 (3.0-10.8) and 14.0 (9.2-21.2) for 0- < 5, 5- < 30, 30- < 40 and ≥40 Gy), as well as cisplatin (HR = 2.8, 95%CI = 1.9-4.0), melphalan (HR = 3.3, 95%CI = 1.9-5.7) and busulfan exposure (HR = 2.6, 95%CI = 1.6-4.4) were significantly associated with severe ototoxicity. Concerning melphalan (n = 199/5243 exposed), almost all cases were identified in neuroblostma patients (NBL), who also received cisplatin 200mg/m²/cycle (26/92 NBL, 30y-CumInc = 36.4% (95%CI = 25.9-48.4), vs. 3/107 non-NBL, 30y-CumInc = 1.6% (0.4-5.6)). Concerning busulfan (n = 131/5243 exposed), all cases were identified in NBL (n = 16/63, all treated with melphalan and cisplatin) and brain tumors (n = 13/28, all with RT at inner ear ≥5Gy). The 30y-CumInc in patients with RT at inner ear ≥5Gy was 7.4% (95%CI = 5.7-9.6) and 39.8% (22.5-60.0) respectively with and without busulfan. Conclusions: RT at inner ear has significant deleterious impact on audition, with cumulative incidence still worsening > 30years after RT, and with likely potentiation by busulfan. The deleterious effect of melphalan was related to previous treatment with cisplatin, either by interaction between these drugs, or by the high cisplatin dose by cycle used in NBL.