Repeated RT has been widely implemented in treating of DTC with lung metastasis if the lesion continues to take up 131-I and respond clinically. However, in patients with structural non-progressive lung metastases from DTC, especially after cumulative activities of 22.2 GBq. We may face one question: for patients who need to receive multiple RTs, what is the optimal timepoint for next RT considering of a balance of benefit and adverse effects? We performed this retrospective study to evaluate the association between the interval of RTs and short-term response and adverse effects in patients who underwent multiple RTs. We found that the interval of multiple RTs did not affect short-term biochemical response, structural response or adverse effects.
The ATA guideline [5] suggested that an interval that is too short (< 6 m) should be avoided because it frequently interrupts thyroid-stimulating hormone (TSH) inhibition therapy, which may stimulate follicular cells and increase the risk of tumor recurrence. Additionally, patients may receive more frequent RTs and more quickly achieve cumulative activity of 22 GBq if the interval is short. It is confirmed that RT efficacy is mainly associated with the expression of NIS in patients who had been treated with a cumulative activity of 22 GBq, and the impairment of iodine uptake may cause delayed curative effects or disease progression [4, 14]. One study reported that CR was more likely to be achieved when the metastatic lesion dose was > 80–100 Gy, but it was rare for dosimetry to show a dose > 20 Gy after cumulative activities of 20 GBq [15].
On the flip side, longer interval may decrease the number of stimulating follicular cells, reduce the frequency of multiple RTs, more slowly achieve a cumulative activity of 22 GBq, and minimize the risk of late effects of 131-I in patients who had been treated with a cumulative activity of 22 GBq. In this retrospective study, courses were categorized into two groups by interval (≤ 12 m, > 12 m). Although a decline in sTg was observed in the two groups, no significant differences were found between the two groups in ΔsTg% and ΔLLD%, and no difference was found in biochemical or structural response between the former and latter courses with regard to different intervals. Additionally, we further performed a subanalysis of number of treatments (3 times, > 3 times), considering that patients usually achieve a cumulative activity of 22 GBq after undergoing three RTs. No significant differences were found in the subanalysis. These results present primary evidence for the assumption above.
On the other hand, a low risk of early- and late-onset complications (salivary gland damage, dental caries, nasolacrimal duct obstruction, and secondary malignancies) is associated with the cumulative administered activity of 131-I and the total number of treatments [16–18]. We evaluated whether prolonging intervals prevent several early adverse effects, and no difference was found in salivary gland function, leukocytes, platelets, AST, ALT, and Ca between former and latter courses with regard to different intervals. With a consideration of a short-term observation window, the effect of interval on late-onset complications needs to be evaluated in the future.
Two issues urgently need to be discussed in this situation. First, how can candidates who may benefit from longer intervals be identified in clinical practice? In this cohort, if lung metastases were 131I-avid, lesions were structurally stable or permissive and adverse effects were acceptable, patients would have an indication to receive repeated 131-I administrations. We did not exclude the former course of which patients were evaluated as serologic stabilization and non-effectiveness, because waiting at least 12 months for serologic progression would better establish a trend to ensure that the rise in the Tg or TgAb levels is not spurious or due to 131I-induced tumor destruction [16]. Due to the limitation of the retrospective design, we did not identify a potential index for prolonging the interval. Second, what is the reasonable maximal length of time interval? The ATA recommended that the upper limitation value of the interval was 12 m for micrometastases, which is unclear for macronodular metastases. In this cohort, the median value of interval was 513 days (ranging from 126 to 937 days) in groups with > 12 m intervals, and number of treatments were not associated with intervals. This prolonged interval may not be enough to identify the maximal length of the time interval for multiple RTs.
Indeed, the interval of treatment for each patient should be individually managed in clinical practice, and several factors should be considered as well, such as age, the therapeutic response, cumulative dose, risk of complications, additional treatments, and patient desires [4, 5, 19], which need to be confirmed in prospective studies. As the 65-year-old male presented in Fig. 3, he had undergone three RTs with a cumulative dose of 600 mCi. Considering the good response, older age, and risk of pulmonary fibrosis, we prolonged the interval with close follow-up. After a longer interval (937 days), the patients still achieved remarkable serologic and structural responses. At the last follow-up (2 months after the fourth RT), the TSH-suppressed Tg showed a continuous decline.
Our study had some limitations. First, the small number of patients might cause an insufficient statistical power. Second, there may be a potential bias of patient selection (young patients, mostly PTC, lesion < 1 cm), because we focused on patients with non-progressive lung metastases, and older age, FTC, and lesion size of ≥ 1cm were associated with disease progression. Therefore, the generalizability of the results needs to be confirmed. Third, the effect of extending the interval time of RTs on the long-term outcomes and adverse effects of patients is unclear.