Risk Factors for Primary Bone Cancer in Childhood Cancer Survivors: Bone Tissue Radiation Exposure and Alkylating Agent Dose

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In a case-control study reported in the Journal of Clinical Oncology, Reulen et al found that an increased risk of primary bone cancer was associated with increasing radiation dose to bone tissue and increasing alkylating agent dose among survivors of childhood cancer.

As noted by the investigators, it is uncertain what risk is posed by bone exposure to radiation doses < 10 Gy.

Study Details

As part of the PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies initiative, the current study included 228 survivors who developed primary bone cancer and 228 matched controls from 12 European countries from within a cohort of 69,460 5-year survivors of childhood cancer. Controls were matched for sex, age at childhood cancer diagnosis, calendar year of childhood cancer, retinoblastoma status (heritable/nonheritable), and interval since first primary cancer diagnosis.

Key Findings

In analysis adjusting for alkylating agent exposure, risk of primary bone cancer was significantly elevated with bone tissue exposure of 1 to 4 Gy (odds ratio [OR] = 4.8, 95% confidence interval [CI] = 1.2–19.6) and 5 to 9 Gy (OR = 9.6, 95% CI = 2.4­–37.4) compared with unexposed bone tissue. The risk of bone cancer increased linearly with increasing bone tissue radiation exposure (P for trend < .001), with odds ratios of 11.4 (95% CI = 2.9–44.4) for 10 to 19 Gy, 16.7 (95% CI = 4.7–60.0) for 20 to 39 Gy, and 78.5 (95% CI = 9.2–669.9) for ≥ 40 Gy.

In analysis adjusting for bone radiation exposure, cumulative alkylating agent doses of 10,000 to 19,999 mg/m2 (OR = 7.1, 95% CI = 2.2–22.8) and ≥ 20,000 mg/m2 (OR = 8.3, 95% CI = 2.8–24.4) were associated with an increased risk of bone cancer. Contributions to risk were found for procarbazine (excess OR per mg/m2 = 9.67, 95% CI = 0.47–124.00), ifosfamide (excess OR per mg/m2 = 0.85, 95% CI = 0.06–8.20), and cyclophosphamide (excess OR per mg/m2 = 0.29, 95% CI = 0.07–0.96).

The investigators concluded, “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 [to] 9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk [seven] to [eight]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.”

Raoul C. Reulen, PhD, of the Centre for Childhood Cancer Survivor Studies, University of Birmingham, United Kingdom, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the European Union’s Seventh Framework Programme for research, technological development, and demonstration; the Italian Association for Cancer Research; Swedish Childhood Cancer Fund; and others. For full disclosures of the study authors, visit

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