This study is unique because the large sample size allowed the first detailed evaluation of the effect of chemotherapy classes of drugs on thyroid cancer risk among childhood cancer survivors. In contrast to previous childhood cancer survivor studies, we assessed the chemotherapy risks in subgroups defined by thyroid radiation dose. Our results support the hypothesis that chemotherapy risks decreased as radiation dose increased, suggesting that the cell-killing effect of high radiation doses may indeed obscure the effects of chemotherapy.
New findings include evidence of an increased risk of thyroid cancer associated with alkylating agents among patients receiving radiation doses up to 20 Gy. Risk appeared to increase with alkylator score, with a highly significant risk in patients exposed in the highest category. Risk associated with alkylating agents decreased significantly with increasing thyroid radiation dose (p-value for trend=0.03). Drug combinations (alkylating agents, anthracyclines and/or bleomycin) did not increase risk beyond that associated with alkylating agents alone. Some evidence of an increased risk related to treatment with anthracyclines was also observed among patients receiving radiation doses up to 20 Gy and also among patients not treated with radiation. Nevertheless, risk did not appear to increase with cumulative dose of anthracyclines.
Previous studies of childhood cancer survivors were unable to identify a statistically significant association of thyroid cancer risk and exposure to chemotherapy agents (4
), possibly due to low statistical power to detect risks or the analytic strategies employed. A borderline increased risk for anthracyclines was suggested in the previous nested case-control study conducted within the CCSS (6
), D’Angio and colleagues (8
) suggested that dactinomycin (an alkylating agent) might decrease thyroid cancer risk but Tucker and colleagues (4
) reported that dactinomycin may increase thyroid cancer risk at doses over 10 Gy. These analyses were conducted using the full radiation dose range, and thus an independent chemotherapy effect evident only in the lower thyroid radiation dose range (<20 Gy) would not have been detected. Under 20 Gy is a dose range where cell sparing in the thyroid gland would be expected to predominate over cell killing or blocked cellular replication.
Alkylating agent chemotherapy has been reported to increase overall risk of second malignant neoplasms (14
) and also of specific radiation-related cancers including leukemia (18
), bone sarcomas (20
), lung cancer (24
), bladder cancer (25
), and stomach cancer (26
). A reduced risk for radiation-related breast cancer was observed, likely due to suppression of ovarian hormone production by alkylating agents (27
). Our study provides new evidence that, at lower radiation doses, there is an association between exposure to alkylating agents and subsequent thyroid cancer risk, plus an indication of increasing risk with higher doses of alkylating agents.
Strengths of this study include the large cohort size and long-term follow-up, substantial numbers of thyroid cancer cases, pathologic confirmation of reported cancers, chemotherapy and radiotherapy information on all members of the cohort, and individual radiation dosimetry. However, when interpreting the results of this study, especially for chemotherapy risk, certain limitations should be considered. Due to the strong correlation between type of treatment and type of first cancer, it can be difficult to distinguish an effect of a particular aspect of treatment from an effect of the first cancer. The inclusion of an adjustment variable does not always mitigate this effect. This is perhaps most relevant for procarbazine, an agent predominantly used to treat HL and CNS cancers in children (see supplementary table 1
). When HL patients were removed from the analysis, the procarbazine effect remained of borderline significance, but the effect was not apparent when the CNS cancer patients were excluded. The small number of cases requires cautious interpretation, but it appeared that the procarbazine association was most influenced by patients treated for CNS cancers. Interestingly, procarbazine has recently been implicated in the etiology of second primary cancers of the lung (24
) and stomach (26
). As described in our previous report (9
), other limitations are: a) the reliance on self-reported occurrence of subsequent neoplasm; b) some uncertainty in radiation doses to the thyroid gland because only typical blocking procedures of the gland were incorporated in the dosimetry and, c) the possibility of targeted clinical surveillance for Hodgkin lymphoma patients due to the high radiation dose these patients usually received. However, we did not observe a significant difference in tumor size between Hodgkin lymphoma patients and others type of first cancer. This suggests that if these patients were under a greater clinical surveillance it was uniform across type of first cancer. The possibility of different levels of surveillance among the participating institutions was not evaluated.
In summary, results from this large cohort study suggest that alkylating agents play a role in the overall risk of secondary thyroid cancer after treatment for childhood cancer, although the effect is small relative to that associated with radiation. The effect of chemotherapy was observed exclusively among those exposed to less than 20 Gy of thyroid radiation, likely due to cell-killing at higher radiation doses. Our study adds to a small but growing evidence base for chemotherapy agent-specific increased risks of thyroid cancer, which to date, were mainly thought to be related to prior radiotherapy.