Risk of benign meningioma after childhood cancer in the DCOG-LATER cohort: contributions of radiation dose, exposed cranial volume, and age

Pediatric cranial radiotherapy (CrRT) markedly increases risk of meningiomas. We studied meningiomarisk factors with emphasis on independent and joint effects of CrRT dose, exposed cranial volume, exposure age, and chemotherapy. The Dutch Cancer Oncology GroupLong-Term Effects after Childhood Cancer (DCOG-LATER) cohort includes 5-year childhood cancer survivors (CCSs) whose cancers were diagnosed in 19632001. Histologically confirmed benign meningiomaswere identified from the population-based Dutch Pathology Registry (PALGA; 19902015). We calculated cumulative meningiomaincidence and used multivariable Cox regression and linear excess relative risk (ERR) modeling. Among 5843 CCSs (median follow-up: 23.3 y, range: 5.052.2 y), 97 developed a benign meningioma, including 80 after full- and 14 after partial-volumeCrRT. Compared with CrRT doses of 119 Gy, no CrRT was associated with a low meningiomarisk (hazard ratio [HR] = 0.04, 95% CI: 0.010.15), while increased risks were observed for CrRT doses of 2039 Gy (HR = 1.66, 95% CI: 0.833.33) and 40+ Gy (HR = 2.81, 95% CI: 1.306.08). CCSs whose cancers were diagnosed before age 5 versus 1017 years showed significantly increased risks (HR = 2.38, 95% CI: 1.394.07). In this dose-adjusted model, volume was not significantly associated with increased risk (HR full vs partial = 1.66, 95% CI: 0.863.22). Overall, the ERR/Gy was 0.30 (95% CI: 0.03unknown). Dose effects did not vary significantly according to exposure age or CrRT volume. Cumulative incidence after any CrRT was 12.4% (95% CI: 9.8%15.2%) 40 years after primary cancer diagnosis. Among chemotherapy agents (including methotrexate and cisplatin), only carboplatin(HR = 3.55, 95% CI: 1.627.78) appeared associated with meningiomarisk. However, we saw no carboplatindose-response and all 9 exposed cases had high-dose CrRT. After CrRT 1 in 8 survivors developed late meningiomaby age 40 years, associated with radiation dose and exposure age, relevant for future treatment protocols and awareness among survivors and physicians.