Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study
: Reulen Raoul C, Winter David L, Diallo Ibrahim, Veres Cristina, Llanas Damien, Allodji Rodrigue S, Bagnasco Francesca, Bárdi Edit, Feijen Elizabeth A M, Alessi Daniela, Fidler-Benaoudia Miranda M, Høgsholt Stine, Teepen Jop C, Linge Helena, Haddy Nadia, Byrne Julianne, Debiche Ghazi, Grabow Desiree, Gudmundsdottir Thorgerdur, Fauchery Romain, Zrafi Wael, Michel Gisela, Øfstaas Hilde, Kaatsch Peter, Vu-Bezin Giao, Jenkinson Helen, Kaiser Melanie, Skinner Roderick, Cole Trevor, Waespe Nicolas, Sommer Grit, Nordenfelt Susanne, Jankovic Momcilo, Lähteenmäki Taalas Tuomas, Maule Milena M, van der Pal Helena J H, Ronckers Cécile M, van Leeuwen Flora E, Kok Judith L, Terenziani Monica, Winther Gunnes Maria, Wiebe Thomas, Sacerdote Carlotta, Jakab Zsuzsanna, Haupt Riccardo, Lähteenmäki Päivi M, Zadravec Zaletel Lorna, Kuehni Claudia E, Falck Winther Jeanette, Kremer Leontien C M, Hjorth Lars, de Vathaire Florent, Hawkins Michael M
Publisher: Lippincott Williams & Wilkins
: 2023
: Journal of Clinical Oncology
: J Clin Oncol
: 41
: 21
: 3735
: 3746
DOI: https://doi.org/10.1200/JCO.22.02045
: https://ascopubs.org/doi/10.1200/JCO.22.02045?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
Purpose: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy.
Methods: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship.
Results: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation (Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer.
Conclusion: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.
