General characteristics of the cohort are shown in . Of the 14,135 5-year survivors diagnosed between 1970 and 1986, 53.7% were males, and the mean age at diagnosis of the first cancer was 8.3 years. The most common cancer diagnoses were leukemia (33.6%), HL (13.4%), and cancer of the CNS (13.1%). Of the total cohort, 13,279, 12,152 and 8,173 were followed 10+, 15+, and 20+ years after diagnosis of the initial cancer, respectively. At the time of this analysis, 87% of patients were still alive. Sixty-eight percent of the cohort received radiotherapy (excluding those with unknown treatment), and, among them, the average dose to the salivary glands was 7.5 Gy (median, 2.9 Gy; maximum, 80.4 Gy). More than half of the patients received combined RT and CT. Tobacco use was reported in 23% of patients. During the time period of follow-up (228,439 PY), 23 subsequent SGC were diagnosed, among which 10 cases occurred in patients initially treated for leukemia, 6 among HL patients and 4 among NHL patients. The mean interval between diagnosis of the initial cancer and SGC was 14.9 years (median, 12.6 years), and the mean age at diagnosis of SGC was 24.8 years. Most SGC occurred in the parotid gland (O=22), with 1 case observed in the submandibular gland. Fourteen SGC cases were mucoepidermoid carcinoma, 3 were adenocarcinoma, 3 were acinar cell carcinoma and 3 were miscellaneous other types.
Demographic, clinical and lifestyle characteristics of 14,135 five-year survivors of childhood cancer diagnosed between 1970 and 1986.
The occurrence of SGC in the cohort was 39-fold higher than that predicted for the general population (SIR=39.4, 95% CI: 25.4 to 57.8), and the SIR remained significantly elevated more than 20 years after diagnosis of the first cancer (). The EAR was 9.8 per 100,000 PY and was similar for males (EAR=10.8/100,000) and females (EAR=9.2/100,000). The SIR was highest among those whose first cancer was diagnosed before age 5 or after age 14. The cumulative incidence between 5 and 25 years after the initial cancer diagnosis was 0.24%. Elevated risks were seen for adenocarcinoma (SIR=171.1, 95% CI: 55.2 to 530.7), mucoepidermoid carcinoma (SIR=57.7, 95% CI: 34.2–97.5), and acinar cell carcinoma (SIR=16.9, 95% CI: 5.5–2.5), based on small numbers. The highest SIRs were observed for persons whose first cancer was NHL, leukemia or HL.
Whereas the SIRs in are adjusted only for gender, race, attained age and attained calendar year and are based on external comparisons, the RRs obtained from the internal Poisson regression analysis are further adjusted for radiation dose and for a trend in the SIRs with attained age. Internal analyses yielded RRs that were considerably smaller than the SIRs (). The risk of SGC was higher for persons followed for more than ten years than for those followed for less than ten years, but the trend over time was not significant. There was no significant association of risk with age at diagnosis of first cancer. Elevated risk for NHL, HL and leukemia as the initial cancer, relative to other cancers (of which there were only three), persisted after adjustment for radiation dose.
Overall, patients treated with RT had higher risk of SGC compared with patients who did not receive RT (, ); however, only two cases occurred among patients who did not receive RT. There was an indication of a radiation dose-response consistent with linearity (P=0.005) (, ). The estimated excess relative risk (ERR) was 0.36 per Gy (95% CI: 0.06 to 2.5). Patients treated with alkylating agents and those treated with anthracyclines exhibited non-significantly elevated incidence of SGC. Although risk was not significantly associated with dose, a significantly elevated RR was seen among those with an alkylating agent score of 1 (RR=4.1; 95% CI: 1.4–3.7) ().
Cumulative incidence of salivary gland cancers among childhood cancer survivors by time (years) since first cancer diagnosis, overall and separately for those who did and did not receive radiotherapy.
Figure 2 Risk of subsequent primary salivary gland cancer among five year survivors of childhood cancer with respect to radiation dose to the salivary glands. The sloped dashed line is the fitted dose-response relationship. The horizontal dotted line is a reference (more ...)
Patients classified as ever cigarette smokers did not have an increased risk relative to non-smokers (RR=0.9; 95% CI: 0.2–2.4), and SGC risk did not show a significant association with pack-years of cigarette smoking (). Similarly, SGC risks did not vary significantly for patients who reported drinking alcohol compared with those who had no history of alcohol consumption (RR=1.4; 95% CI: 0.6–4.4). Among those patients who reported alcohol consumption, there was no significant trend of increasing risk of SGC with the amount of alcohol consumed per day.