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

Abstract

Background

Pediatric cranial radiotherapy (CrRT) markedly increases risk of meningiomas. We studied meningioma risk factors with emphasis on independent and joint effects of CrRT dose, exposed cranial volume, exposure age, and chemotherapy.

Methods

The DCOG-LATER cohort includes five-year childhood cancer survivors (CCSs) diagnosed 1963-2001. Histologically confirmed benign meningiomas were identified from the population-based Dutch Pathology Registry (PALGA; 1990-2015). We calculated cumulative meningioma incidence and used multivariable Cox regression and linear excess relative risk (ERR) modelling.

Results

Among 5,843 CCSs (median follow-up: 23.3 years, range: 5.0-52.2 years), 97 developed a benign meningioma, including 80 after full- and 14 after partial-volume CrRT. Compared to CrRT doses of 1-19 Gy, no CrRT was associated with a low meningioma risk (HR=0.04,95%CI:0.01-0.15), while increased risks were observed for CrRT doses 20-39 Gy (HR=1.66,95%CI:0.83-3.33) and 40+ Gy (HR=2.81,95%CI: 1.30-6.08). CCSs diagnosed before age 5 vs 10-17 years showed significantly increased risks (HR=2.38,95% CI:1.39-4.07). In this dose-adjusted model, volume was not significantly associated with increased risk (HR full vs. partial=1.66,95%CI:0.86-3.22). Overall, the ERR/Gy was 0.30 (95%CI:0.03-unknown). Dose effects did not vary significantly according to exposure age nor 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:1.62-7.78) appeared associated with meningioma risk. However, we saw no carboplatin dose-response and all nine exposed cases had high-dose CrRT.

Conclusion

After cranial radiotherapy one in eight survivors developed late meningioma by age 40 years, associated with radiation dose- and exposure age, relevant for future treatment protocols and awareness among survivors and physicians.