The carcinogenic property of radiation is well known. Previous studies of exposed pediatric populations for treatment of Tinea capitis (34
) or hemangiomas of the skin (35
) or through atomic bomb explosions (36
) have documented a linear dose response with exposure and risk and increased risk with younger age at exposure. Subsequent malignant neoplasms have long been recognized as late sequelae of both radiation therapy and chemotherapy for cancer treatment (17
CCSS reported the experience of 13,581 childhood cancer survivors, of whom 298 developed 314 pathologically confirmed subsequent malignant neoplasms. The estimated cumulative incidence of all subsequent malignant neoplasms in the cohort was 3.2% at 20 years after the primary diagnosis of childhood cancer (38
). The standardized incidence ratio (SIR) of observed to expected subsequent malignant neoplasms was 6.38 (95% CI 5.69–7.13). The highest rates were observed for new breast cancers (SIR = 16.18; 95% CI 12.35–20.83), bone cancers (SIR = 19.14; 95% CI 12.72–27.67) and thyroid cancers (SIR = 11.34; 95% CI 8.20–15.27) (38
). Development of malignancy has long been recognized as a late effect of radiation exposure as part of treatment for childhood cancer (26
). However, while increased risk has been documented, there are rare instances where tissue-specific dose–response relationships have been determined. One of the major contributions of CCSS has been investigation of dose–response relationships between radiation therapy and risk of a second malignant neoplasm.
Using a nested case-control design, CCSS investigators individually matched (by age, sex and time since original cancer diagnosis) 116 survivors with a subsequent central nervous system (CNS) neoplasm with control subjects (1:4 ratio) consisting of survivors without a subsequent CNS neoplasm (42
). Radiation therapy was associated with an increased risk for any subsequent CNS malignant neoplasm, and specifically for subsequent gliomas [n
= 40, odds ratio (OR) = 6.78, 95% CI 1.54–29.7] and meningiomas (n
= 76, OR = 9.94, 95% CI 2.17–45.6). Importantly, linear dose–response relationships between radiation dose and the development of both gliomas and meningiomas were identified and were statistically significant. The excess relative risk per Gy, equal to the dose of the linear response function, was 0.33 (95% CI 0.07–1.71) per Gy for gliomas and 1.06 (95% CI 0.21–8.15) per Gy for meningiomas (). After adjustment for radiation dose, there were no statistically significant associations between chemotherapy exposure and the development of a second malignant neoplasm. With increasing length of follow-up, the number of new glioma cases in this population markedly declined (beyond 15–20 years after exposure), which is in contrast to the experience with Tinea capitis and atomic bomb survivors. However, the incidence of meningioma continued to increase with longer length of follow-up.
FIG. 1 Relative risk with 95% confidence intervals of subsequent glioma, meningioma (open boxes, mean observed relative risk for meningioma; closed boxes, mean observed relative risk for glioma; solid line, fitted line for meningioma risk; hatched line, fitted (more ...)
Previous investigations of survivors of atomic bombs and other analyses of pooled populations have suggested a linear dose response for the development of thyroid cancer after radiation exposure, with a loss of the linear relationship at higher doses of radiation therapy (43
). In addition, two previous studies among survivors of childhood cancer have suggested a linear dose response with a deviation from the linear model at higher doses (45
), but no study to date has had a sufficient number of thyroid cancer diagnoses, with a sufficiently wide range of radiation exposures, to comprehensively evaluate the shape of the dose–response curve. Again, using a nested case-control design, CCSS investigators evaluated 69 cases of pathologically confirmed thyroid cancer (47
). Cases were matched to controls (ratio 1:4) on sex, age at diagnosis of primary cancer, and follow-up interval. Risk of thyroid cancer increased with radiation dose to the thyroid gland for doses up to 29 Gy and decreased for doses greater than 30 Gy (). This linear exponential dose–response model for relative risk was accentuated among patients younger than 10 at the time of exposure who demonstrated a more pronounced increased and decreased risk below and above 30 Gy, respectively. Chemotherapy was not associated with thyroid cancer risk and did not modify the effect of radiation therapy. This finding of increased risk at lower doses and declining risk at higher doses adds supportive evidence consistent with the cell killing hypothesis first proposed in 1965 (49
Female survivors of childhood cancer are also at risk for secondary breast cancer. In the original CCSS report among 6,068 eligible women, 95 women had 111 confirmed cases of breast cancer. The SIR of developing breast cancer after chest radiation therapy was 24.7 (95% CI 19.3–31.0) compared to an SIR of 4.8 (95% CI 2.9–7.4) for women who received no chest radiation therapy (50
). Notably, patients who received ovarian radiation had reduced rates of breast cancer (RR 0.6, 95% CI 0.4–1.0). Patients with a family history of breast cancer (RR 2.7, 95% CI 1.3–2.5) or with a personal history of thyroid disease (RR 1.8, 95% CI 1.1–2.9) had higher risk for developing breast cancer. In Hodgkin lymphoma survivors who received chest radiation, the cumulative incidence of breast cancer at 40 years of age was 12.9% (95% CI 9.9–16.5), and it continued to increase dramatically over the subsequent decade. For survivors without previous chest irradiation, cumulative incidence of breast cancer is highest in sarcoma survivors, reaching 3.3% (95% CI 1.2–5.4) at 40 years of age.
To evaluate the dose–response relationship between chest radiation therapy and the development of breast cancer, 120 confirmed breast cancer cases were identified and matched to controls based on age at initial cancer and time since primary cancer diagnosis (51
). A linear relationship was identified between risk of developing breast cancer and radiation dose. At a dose of 40 Gy to the breast, there was an elevenfold increased risk for the development of breast cancer (). The slope of the dose–response curve changed dramatically when the radiation dose to the ovaries was considered because ovarian radiation exposure of 5 Gy or more was associated with a decreased risk of developing breast cancer. These studies represent the largest evaluation to date of breast cancer incidence after treatment for childhood cancer and are similar to those reported by Travis et al.
in survivors of adult Hodgkin lymphoma (52
Fitted breast cancer risk by radiation dose to the breast and ovary. Reprinted with permission from J. Clin. Oncol. 27, 3901–3901 (2009).