Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects

Abstract

Objectives The majority of childhood cancer patients now achieve long-term survival, but the treatments that cured their malignancy often put them at risk of adverse health outcomes years later. New cancers are among the most serious of these late effects. The aims of this review are to compare and contrast radiation dose-response relationships for new solid cancers in a large cohort of childhood cancer survivors and to discuss interactions among treatment and host factors. Methods This review is based on previously published site-specific analyses for subsequent primary cancers of the brain, breast, thyroid gland, bone and soft tissue, salivary glands and skin among 12,268 five-year childhood cancer survivors in the Childhood Cancer Survivor Study. Analyses included tumor site-specific, individual radiation dose reconstruction based on radiotherapy records. Radiation-related second cancer risks were estimated using conditional logistic or Poisson regression models for excess relative risk (ERR). Results Linear dose-response relationships over a wide range of radiation dose (0–50 Gy) were seen for all cancer sites except the thyroid gland. The steepest slopes occurred for sarcoma, meningioma and non-melanoma skin cancer (ERR/Gy > 1.00), with glioma and cancers of the breast and salivary glands forming a second group (ERR/Gy=0.27–0.36). The relative risk for thyroid cancer increased up to 15–20 Gy and then decreased with increasing dose. Risk of thyroid cancer also was positively associated with chemotherapy, but the chemotherapy effect was not seen among those who also received very high doses of radiation to the thyroid. Excess risk of radiation-related breast cancer was sharply reduced among women who received 5 Gy or more to the ovaries. Conclusions Results suggest that the effect of high-dose irradiation is consistent with a linear dose-response for most organs but also reveal important organ- and host-specific differences in susceptibility and interactions between different aspects of treatment.

Morbidity and mortality after treatment of Ewing sarcoma: A single‐institution experience

“…In addition to the nine patients who developed t‐MDS/AML, six patients developed subsequent solid malignancies. It is well‐established that radiation exposure is associated with an increased risk of second malignant neoplasms in childhood cancer survivors . In our cohort, two patients developed second solid cancers in the radiation field, while two were out of the field and two were indeterminate.…”

Radiation‐associated neoplasia: clinical, pathological and genomic correlates

“…In paediatric oncology patients, radiation is the strongest contributor to treatment‐related risk of the subsequent development of solid tumours. The Childhood Cancer Survivor Study followed >12 000 paediatric patients treated for a primary haematological or solid malignancy between 1970 and 1986 . This study documented a linear dose–response relationship between radiation therapy (RT) and the development of glioma, meningioma, breast cancer, bone and soft tissue tumours, cutaneous basal cell carcinoma, and salivary gland tumours.…”

Pediatric Exposures to Ionizing Radiation: Carcinogenic Considerations

“…Excess relative risk per Gy of radiation has been calculated for SPMs in the brain, breast, thyroid gland, bone, skin, and salivary gland [48,49,50,51,52,53,54]. The results have been reviewed by Inskip and colleagues [55]. In line with what is known from A-bomb survivors and children treated for benign conditions, the thyroid gland showed the highest excess relative risk at 1.38 per Gy.…”