Judith L Kok1,2, Jop C Teepen1,2, Flora E van Leeuwen3, Wim J E Tissing2,4, Sebastian J C M M Neggers2,5, Helena J van der Pal2, Jacqueline J Loonen6, Dorine Bresters2, Birgitta Versluys7, Marry M van den Heuvel-Eibrink2,8, Eline van Dulmen-den Broeder9, Margriet van der Heiden-van der Loo10, Berthe M P Aleman11, Laurien A Daniels12, Cornelis J A Haasbeek13, Bianca Hoeben14, Geert O Janssens2,15, John H Maduro16, Foppe Oldenburger17, Caroline van Rij18, Robbert J H A Tersteeg15, Michael Hauptmann3, Leontien C M Kremer1,2, Cécile M Ronckers1,2. 1. Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. 2. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. 3. Department of Epidemiology and Biostatistics, the Netherlands Cancer Institute, Amsterdam, the Netherlands. 4. Department of Pediatric Oncology/Hematology, University of Groningen, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands. 5. Department of Pediatric Oncology/Hematology and Medicine section Endocrinology, Sophia Children's Hospital/Erasmus Medical Center, Rotterdam, the Netherlands. 6. Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands. 7. Department of Pediatric Oncology and Hematology, Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht, the Netherlands. 8. Department of Pediatric Oncology/Hematology, Sophia Children's Hospital/Erasmus Medical Center, Rotterdam, the Netherlands. 9. Department of Pediatric Oncology/Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. 10. Dutch Childhood Oncology Group, Utrecht, the Netherlands. 11. Department of Radiation Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands. 12. Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands. 13. Department of Radiation Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. 14. Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, the Netherlands. 15. Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, the Netherlands. 16. Department of Radiation Oncology, University of Groningen/University Medical Center Groningen, Groningen, the Netherlands. 17. Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. 18. Department of Radiation Oncology, Erasmus Medical Center, Rotterdam, the Netherlands.
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 Dutch Cancer Oncology Group-Long-Term Effects after Childhood Cancer (DCOG-LATER) cohort includes 5-year childhood cancer survivors (CCSs) whose cancers were diagnosed in 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) modeling. RESULTS: Among 5843 CCSs (median follow-up: 23.3 y, range: 5.0-52.2 y), 97 developed a benign meningioma, including 80 after full- and 14 after partial-volume CrRT. Compared with CrRT doses of 1-19 Gy, no CrRT was associated with a low meningioma risk (hazard ratio [HR] = 0.04, 95% CI: 0.01-0.15), while increased risks were observed for CrRT doses of 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 whose cancers were diagnosed before age 5 versus 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 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: 1.62-7.78) appeared associated with meningioma risk. However, we saw no carboplatin dose-response and all 9 exposed cases had high-dose CrRT. CONCLUSION: After CrRT 1 in 8 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.
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 Dutch Cancer Oncology Group-Long-Term Effects after Childhood Cancer (DCOG-LATER) cohort includes 5-year childhood cancer survivors (CCSs) whose cancers were diagnosed in 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) modeling. RESULTS: Among 5843 CCSs (median follow-up: 23.3 y, range: 5.0-52.2 y), 97 developed a benign meningioma, including 80 after full- and 14 after partial-volume CrRT. Compared with CrRT doses of 1-19 Gy, no CrRT was associated with a low meningioma risk (hazard ratio [HR] = 0.04, 95% CI: 0.01-0.15), while increased risks were observed for CrRT doses of 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 whose cancers were diagnosed before age 5 versus 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 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: 1.62-7.78) appeared associated with meningioma risk. However, we saw no carboplatin dose-response and all 9 exposed cases had high-dose CrRT. CONCLUSION: After CrRT 1 in 8 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.
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