In this retrospective study, PFS and OS of patients with metastatic DTC were statistically comparable, regardless of the mode of preparation for RAI therapy, either with rhTSH or with THW.
Ideally, a prospective noninferiority study to compare patients with metastatic DTC prepared for RAI therapy with exogenous or endogenous thyrotropin would be based on the best-quality evidence. Yet in a systematic literature review that included both residual disease and metastatic DTC, no randomized controlled clinical trials were identified comparing rhTSH vs THW-mediated therapy for metastatic DTC.
The first evidence of the efficacy of rhTSH-aided RAI therapy came from several case reports.[10–13] Patients were selected for their inability to produce endogenous thyrotropin, for example, in patients with hypopituitarism, those with large tumor burden producing sufficient thyroid hormone to suppress thyrotropin, or because of a medical contraindication to hypothyroidism after THW, such as in patients with unstable angina. Despite the limitations of drawing definitive conclusions from case reports, the studies indicated that rhTSH reliably elevated thyrotropin to levels considerably higher than 30 mUI/L, that most metastatic lesions demonstrated RAI uptake on posttherapy scans, and that patients benefited from the avoidance of symptoms of hypothyroidism.
Larger studies have addressed the use of rhTSH preparation for RAI therapy in patients with DTC and distant metastases. Jarzab et al prospectively evaluated 54 patients who received rhTSH to aid RAI therapy for advanced DTC including 49 patients with distant metastases, of whom 31 were RAI avid. There was no control group with THW-aided therapy, and patients served as their own controls comparing the outcome of rhTSH-aided treatment vs the outcome of previous THW-aided therapies. The authors concluded that rhTSH-aided RAI therapy could be equally effective as THW-aided RAI therapy. Tala et al published a retrospective study that included 175 patients with metastatic DTC of whom 35 patients were prepared with THW only, 58 patients with rhTSH only, and 82 patients had THW followed by rhTSH in subsequent therapies. No difference was noted in OS among the groups independent of how patients were prepared for RAI therapy. In a retrospective study from our group, the outcomes in 15 patients prepared for RAI therapy with rhTSH were compared to that for 41 patients prepared after THW. Similar efficacy and safety profiles of either method of preparation for RAI treatment of RAI-avid metastases were observed. In another retrospective study, Campopiano et al compared 2 groups of patients with metastatic DTC treated with 131I and prepared either by THW (n = 34) or rhTSH (n = 43) at each treatment. After 4 years of follow-up, although 93% of the patients had structural disease, 91% of them obtained clinical benefit from RAI therapy in terms of SD, CR, or PR. The authors concluded that the preparation with either recombinant or endogenous thyrotropin had no effect on the efficacy of RAI therapy and on the outcome of the 2 groups. The findings of the present study extend and corroborate earlier results indicating that the method of thyrotropin stimulation was not associated with a difference in OS, and we also demonstrated that PFS is similarly not affected. Consistent with the literature,[15,16] age at diagnosis was the only independent variable that affected both the risk of progression and the risk of death in our population. In fact, age is such an important prognostic factor in thyroid cancer that it is incorporated into relevant thyroid cancer staging systems.[17,18] Another finding is that the total cumulative activity of RAI is associated with an increased risk of death. We hypothesize that this is related to metastatic lesions less responsive to RAI, leading to persistent disease, repeated therapies, and poorer outcomes, rather than to an adverse effect of higher RAI activities per se.
As observed by Campopiano et al, we also found a significant number of patients with structural disease in our cohort (Figure 3). This finding may be related to factors intrinsic to the tumor, such as molecular abnormalities associated with more aggressiveness, or to the fact that our hospital is a referral center for patients with advanced cases, who are more likely to have persistent disease. Although we have not performed a subanalysis for different metastatic sites, we also found that our patients benefited from RAI therapy, as shown by the number of patients with PR and with SD (Figure 4). For patients with PD, there was no statistical difference between the groups, suggesting that factors other than the mode of preparation for RAI therapy may play a role in disease progression.
Several studies have evaluated the negative effects of levothyroxine withdrawal on patients' quality of life.[19,20] On the other hand, the cumulative experience with rhTSH has shown that it is well tolerated, with mild adverse effects. Moreover, the use of rhTSH is associated with better quality of life during the interval of RAI therapy, with minimal economic effect on the work productivity of patients, compared to levothyroxine withdrawal. Previous studies have examined the cost-effectiveness of rhTSH in Europe and in the United States.[22,23] Renal RAI clearance in rhTSH-aided therapies is higher than when THW-aided because of preserved renal function during euthyroidism. As a result, lower levels of radiation exposure in extrathyroidal tissues, such as blood and bone marrow, are expected. Yet the accelerated clearance of RAI could be considered a disadvantage for the use of rhTSH because it could result in reduced residence time of RAI in the metastatic lesions. In fact, iodine biokinetics are affected by the use of rhTSH for remnant ablation with significantly lower residence times of the RAI in the whole body and blood. We recommend a dosimetric approach to therapy to determine the optimal safe RAI activity to be administered to each individual, especially for high-risk patients. In our study population, dosimetry was performed in 89% of patients in the rhTSH-aided RAI therapy group and in 50% of THW-aided RAI therapy group. Among the disadvantages of employing rhTSH for therapies is its high cost and lack of availability in some countries.
This study is limited by its retrospective design and possible selection bias. However, the groups were statistically comparable regarding the clinicopathological features between patients prepared with THW and rhTSH, as well as for the RAI therapies administered. Another possible limitation is the number of patients in the final analysis, with patients returning to their referring institutions and lost to long-term follow-up. However, a strength of this study lies in the inclusion of patients prepared exclusively with THW or with rhTSH throughout their management. An additional cohort of 13 patients was analyzed who had THW-aided RAI therapy for initial therapy and were subsequently prepared with rhTSH. A direct comparison of the OS and PFS of these patients to those with exclusive preparations is statistically challenging because of the confounding effect of previous therapies. The mean number of RAI therapies and the mean total cumulative activity is higher for this latter group of patients, who also had a longer follow-up time. We include a description of the outcomes in this group because patients with this history are frequently seen at other institutions.
We conclude that the mode of preparation for RAI therapy does not decisively affect the outcome of RAI therapy of patients with metastatic DTC. While PFS and the OS were similar for patients with THW-aided or rhTSH-aided RAI therapies, future controlled studies are warranted to further confirm these observations.
CR, complete response; DTC, differentiated thyroid cancer; FDA, Food and Drug Administration; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RAI, radioiodine; rhTSH, recombinant human thyrotropin; StD, stable disease; TSH, thyrotropin; THW, thyroid hormone withdrawal.
This work was supported by The Catherine Heron and Al Schneider Fellowship in Thyroid Cancer Research.
Some or all data sets generated during and/or analyzed during the present study are not publicly available but are available from the corresponding author on reasonable request.
J Endo Soc. 2022;6(5) © 2022 Endocrine Society