Abstract
Second primary malignancies are one of the most important late effects after radioactive iodine (RAI) exposure, which is widely used in the diagnosis and treatment for thyroid cancers. However, dose-response correlation between RAI and second hematologic malignancies (SHM) was not established. Therefore, we conducted a nationwide population-based study to investigate the risk of SHM among thyroid cancer patients and the association between RAI dosage and development of SHM, including leukemia.
We recruited patients with newly diagnosed thyroid cancer aged 20 years or older without antecedent cancer from the Taiwan National Health Insurance database between 1997 and 2010. The standardized incidence ratios (SIR) of cancers were calculated to compare the cancer incidence of thyroid cancer patients to the general population according to gender, calendar year, and age in 5-year intervals by the corresponding stratum-specific person-time accrued in the cohort. The association of cumulative RAI dosage and development of SHM, including leukemia, was estimated using time-dependent analysis with 2-year latent period.
After exclusion of first-year follow-up, 692 second primary malignancies developed among 20,235 patients with thyroid cancer, with a follow-up of 134,178 person-years. Fifty SHM developed with a SIR of 2.37 (95% confidence interval 1.76-3.13). The significant increased risk of SHM included: leukemia (SIR, 2.74; 95% CI, 1.65-4.28), non-Hodgkin lymphoma (SIR, 2.38; 95% CI, 1.55-3.48). As a time-dependent covariate with a 2-year latent period, RAI significantly increased the risk of leukemia with a clear dose-response correlation (age- and sex-adjusted hazard ratio per 100 mCi increase, 1.10; 95% CI, 1.01-1.19, P = 0.032). This effect was not seen in other second primary malignancies.
Our study reveals increased risk of SHM among patients with thyroid cancer. RAI increases the risk of leukemia with a clear dose-response relationship.
Standardized incidence ratios (SIRs) for specific cancer types among patients with thyroid cancer (follow-up more than 1 year)
| Site of cancers . | Total (n = 20,235) . | . | Male (n = 4,116) . | . | Female (n = 16,119) . | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Observed . | Expected . | SIR (95% CI) . | . | Observed . | Expected . | SIR (95% CI) . | . | Observed . | Expected . | SIR (95% CI) . | ||
| All cancers | 692 | 491.53 | 1.41(1.31-1.52) | 165 | 126.18 | 1.31(1.12-1.52) | 527 | 365.35 | 1.44(1.32-1.57) | |||
| Hematologic malignancies | 50 | 21.06 | 2.37(1.76-3.13) | 16 | 5.68 | 2.81(1.61-4.57) | 34 | 15.37 | 2.21(1.53-3.09) | |||
| Non-Hodgkin lymphoma | 26 | 10.94 | 2.38(1.55-3.48) | 7 | 2.84 | 2.47(0.99-5.08) | 19 | 8.10 | 2.34(1.41-3.66) | |||
| Hodgkin's disease | 0 | 0.47 | 0.00(0.00-7.80) | 0 | 0.14 | 0.00(0.00-26.47) | 0 | 0.33 | 0.00(0.00-11.06) | |||
| Multiple myeloma | 5 | 2.70 | 1.85(0.60-4.32) | 1 | 0.76 | 1.31(0.03-7.31) | 4 | 1.94 | 2.06(0.56-5.28) | |||
| Leukemia | 19 | 6.94 | 2.74(1.65-4.28) | 8 | 1.94 | 4.12(1.78-8.11) | 11 | 5.00 | 2.20(1.10-3.94) | |||
| Site of cancers . | Total (n = 20,235) . | . | Male (n = 4,116) . | . | Female (n = 16,119) . | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Observed . | Expected . | SIR (95% CI) . | . | Observed . | Expected . | SIR (95% CI) . | . | Observed . | Expected . | SIR (95% CI) . | ||
| All cancers | 692 | 491.53 | 1.41(1.31-1.52) | 165 | 126.18 | 1.31(1.12-1.52) | 527 | 365.35 | 1.44(1.32-1.57) | |||
| Hematologic malignancies | 50 | 21.06 | 2.37(1.76-3.13) | 16 | 5.68 | 2.81(1.61-4.57) | 34 | 15.37 | 2.21(1.53-3.09) | |||
| Non-Hodgkin lymphoma | 26 | 10.94 | 2.38(1.55-3.48) | 7 | 2.84 | 2.47(0.99-5.08) | 19 | 8.10 | 2.34(1.41-3.66) | |||
| Hodgkin's disease | 0 | 0.47 | 0.00(0.00-7.80) | 0 | 0.14 | 0.00(0.00-26.47) | 0 | 0.33 | 0.00(0.00-11.06) | |||
| Multiple myeloma | 5 | 2.70 | 1.85(0.60-4.32) | 1 | 0.76 | 1.31(0.03-7.31) | 4 | 1.94 | 2.06(0.56-5.28) | |||
| Leukemia | 19 | 6.94 | 2.74(1.65-4.28) | 8 | 1.94 | 4.12(1.78-8.11) | 11 | 5.00 | 2.20(1.10-3.94) | |||
CI confidence interval.
Risk factors for leuekmia development in patients with thyroid Cancer
| Variables . | Univariate analysis . | . | Multivariate analysis . | ||
|---|---|---|---|---|---|
| HR (95% CI) . | P Value . | . | HR (95% CI) . | P Value . | |
| Age ≥ 40 | 0.96 (0.39-2.39) | 0.933 | 0.92 (0.37-2.30) | 0.863 | |
| Gender (male) | 3.07 (1.23-7.63) | 0.016 | 3.02 (1.21-7.52) | 0.017 | |
| Cumulative Dose† | 1.10 (1.01-1.19) | 0.024 | 1.10 (1.01-1.19) | 0.032 | |
| Variables . | Univariate analysis . | . | Multivariate analysis . | ||
|---|---|---|---|---|---|
| HR (95% CI) . | P Value . | . | HR (95% CI) . | P Value . | |
| Age ≥ 40 | 0.96 (0.39-2.39) | 0.933 | 0.92 (0.37-2.30) | 0.863 | |
| Gender (male) | 3.07 (1.23-7.63) | 0.016 | 3.02 (1.21-7.52) | 0.017 | |
| Cumulative Dose† | 1.10 (1.01-1.19) | 0.024 | 1.10 (1.01-1.19) | 0.032 | |
HR Hazard ratio; CI confidence interval; † per 100 mCi increase.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
