As the good prognosis of DTC, developing a SPM is probably the greatest concern in DTC survivors16. Indeed, SPM has been reported as a major cause of mortality and serious morbidity among DTC survivors. Compared to the general population, DTC survivors have a 10%-30% higher risk to develop a SPM5–8, due to the genetic predisposition, environmental factors, lifestyle, and the cancer treatment they received. Regarding to the cancer treatment, RAI is commonly used in DTC treatment for three purposes: 1) RAI remnant ablation to facilitate detection of recurrent disease in the surveillance with serum thyroglobulin; 2) RAI adjuvant therapy to destroy suspected residual disease; 3) RAI therapy to treat persistent disease9,17. Many evidences have shown that RAI can decrease the metastasis and improve the survival of DTCs patients18–20. For low- and intermediate-risk patients, RAI treatment is gradually questioned in the recent few years, as some studies indicated these patients have relative good prognosis, but will be risked to its carcinogenic effects if they receive RAI treatment6–8, 12,21. However, extensive oppositions existed22–25. Considerable arguments about the balance between benefits and harms, as well as the quality of patient care, were generated and widely spread, especially in the nuclear medicine community22–25.
The risk of SPMs development associated with RAI in DTCs survivors have been investigated and debated for decades5–8, 12,26. Many studies presented their evaluations in a way may be easily understood by statisticians, but not the majority of clinical physicians who will read these statistics with the goal of weighting the pros and cons of RAI treatment in their patients. Therefore, in this study, we comprehensively analyzed the risk associated with RAI, and compared the clinical features of SPMs as well as the mortality of RAI + and RAI- treated patients. More specifically, we estimated the proportion of SPMs risk directly associated with RAI, which is for the first time quantitatively showing the absolute risk of RAI in inducing SPMs. These data can be more easily and intuitively interpreted by physicians and patients. Our main findings include: 1) The adjusted RR associated with RAI was only significantly increased for SPMs of hematologic systems; 2) Only 0.9% of all cancer combined SPMs are estimated to be attributed to RAI treatment; the proportion is relatively high in patients developing SPMs in hematologic systems and oral cavity and pharynx system (20.1% and 11.7% respectively);3) The RRs of all cancer combined SPMs associated with RAI generally increased with age at DTC diagnosis and decreased with the latency time; by contrast, the RRs of hematologic SPMs peaked in patients with DTC diagnosed younger than 45yrs, and then decreased with age at DTC diagnosis; 4) The clinical features and mortality are overally comparable between RAI + and RAI- patients.
There is no doubt RAI would associate with a risk of SPM development as its carcinogenesis effect, but the real concern is how much RAI will contribute to this risk. In this study, we estimated that the attributable risk of RAI treatment for all cancer combined SPMs was only 0.9%. Given the relative low incidence of SPMs in DTC survivors (4.4%) and this small attributable risk proportion of RAI treatment, the absolute risk of developing SPMs associated with RAI treatment in DTC survivors would be low. Hematologic system is the most susceptible system to develop SPMs after RAI treatment, the adjusted RR is 1.36(95%CI:1.13–1.63, P = 0.001) and the attributable risk proportion of RAI treatment is around 20%, which is the highest among all cancers. However, the incidence of hematologic SPMs in all DTC survivors is only 0.46%, indicating the low absolute number. In addition, there is no way to exclude the effect of thyrotoxicosis on the hematologic SPMs development. RAI treated patients usually are in iatrogenic subclinical thyrotoxicosis, which has been reported as an independent risk factor for leukemia23,27. Taken together with these factors, we think both clinicians and patients should be rational about the risk associated with RAI in inducing hematologic SPMs. Clinical features are comparable between RAI + and RAI- patients. The overall mortalities and SPM specific mortalities tend to be lower in RAI treated patients, although are not significant different. We think this probably because RAI treated patients tend to have more frequent surveillances or are more likely to change their lifestyle due to their more advanced tumors.
The main limitation of the SEER data is lacking the amounts of administered activities of RAI, therefore, it is not possible to determine the dose-response effect of RAI in this study. Some studies with available information observed an increased leukemia risk associated with RAI, but only with a dosage higher than 100 mCi or even 150mCi12,21. This means only a small percentage of patients, who accept RAI activity that above the most commonly used 50–100 mCi, should be concern of this increased risk. However, in the other hand, patients receiving this high amount of dosage usually have advanced tumors in which RAI has shown survival advantage9. Therefore, it is critical to weight the benefits and harms of RAI treatment as well as the dosage of RAI in each individual DTC survivors in clinical practice.
In summary, in this population based data analysis, we found only for SPMs of hematologic SPMs, RAI treatment is associated with an increased RRs and accounts for a relative high attributable risk proportion of developing SPMs. For all cancer combined SPMs, a very low proportion is associated with RAI treatment. In consideration of the low incidence of SPMs in all DTC survivors, the absolute number of SPMs in DTC patients would be small, including hematologic SPMs. Tumor features and the mortality of RAI + and RAI- patients are comparable. Taken all these together, we think it is important to provide the most careful assessment of risks and benefits of RAI to each individual patient in clinical practice, but should not be panicked by the potential risk of SPMs.