Response to “Radioiodine Is Molecular Radiotherapy Governed by Predictable Deterministic Radiobiology Expressed in Gray,Not Millicuries” by Kao

Dear Editor:

We appreciate the interest of Dr. Kao (1) in our article, “Outcomes of Thyrotropin Alfa Versus Levothyroxine Withdrawal-Aided Radioiodine Therapy for Distant Metastasis of Papillary Thyroid Cancer,” which was recently published in Thyroid (2). We appreciate the opportunity to reply to the comments.

The main aim of our study was to analyze whether thyrotropin alfa (rhTSH) was noninferior to levothyroxine withdrawal (LTW) in radioiodine therapy (RAIT) preparation in patients with distant metastases from papillary thyroid cancer (2). Most of the clinical characteristics of the two groups were similar, including the administered RAIT activity; the outcomes regarding RAI avidity and response were also comparable.

Dr. Kao raised an important point about RAI biokinetics, suggesting that endogenous hypothyroidism may lead to a higher tumor absorbed dose of radiation than rhTSH (1). However, in patients treated with rhTSH, because an euthyroid state is maintained, renal clearance of RAI is faster than in the LTW-aided state, leading to a decrease in the radiation dose delivered to the blood. This renders this method of preparation safer, as it reduces the extrathyroidal exposure (including bone marrow) during RAIT (3). Since RAI blood residence time may influence lesions' uptake, it may be reasonable to adjust the administered activity according to the residence time in the blood, which suggests that higher RAI activities, determined by dosimetry, may be administered safely after stimulation by rhTSH (3).

Moreover, American Thyroid Association (ATA) guidelines (4) do not make any recommendation about the superiority of one method of RAI activity calculation over another. As we use empiric fixed doses in our center, we cannot address the optimal RAI activities of each method of preparation and whether patients received a sufficient radiation dose. The literature is sparse about the superiority of dosimetry-guided RAIT over empirically fixed doses. Klubo-Gwiezdzinska et al. (5) reported similar rates of complete/partial responses, stable, and progressive disease in metastatic patients whether they received dosimetry-guided or empiric-fixed activities. These same authors reported comparable benefits of RAIT therapy in metastatic patients prepared with rhTSH and after LTW, despite rhTSH-aided patients received lower cumulative RAI doses, which were more frequently based on dosimetric calculations (6), and were similar to the cumulative activity used in our rhTSH group.

Dr. Kao also suggested that the lack of significant differences in the outcomes between LTW and rhTSH was likely due to undertreatment in both groups (1). However, RAI administered activities in our center follow ATA guidelines (4). It is important to note that, in our cohort, the median age of patients submitted to rhTSH-aided RAIT was 70 years and activities higher than 150 mCi may not be indicated in these patients (4). Furthermore, higher activities may potentially augment the treatment risks (e.g., xerostomia/lacrimal gland dysfunction, bone marrow suppression, and secondary malignancies).

It is our opinion that, rather than intensifying RAI radiation, it would be more appropriate to consider redifferentiation of tumors that have a low RAI uptake with therapies targeting BRAF mutations and other genetic alterations (7).