Endocrine Abstracts

Objective: Patients with non-medullary thyroid carcinoma (NMTC) that are refractory to radioactive iodine (RAI) have a bad prognosis. For these patients, treatment options are limited. RAI refractoriness is the result of reduced RAI uptake by NMTC cells, caused by loss of function of the Na/I symporter. Strategies for restoring the ability of NMTC cells to take up RAI, so called “redifferentiation”, are promising treatment modalities. Preclinical studies have shown that the cardiac glycoside digoxin restored RAI uptake, both in human cell lines as in a murine model. Also, a retrospective study showed that RAI uptake was better preserved in NMTC patients treated with digoxin for cardiologic indications than in matched patients who were not treated with digoxin. In this prospective single-center open-label study we investigated whether treatment with digoxin could re-induce clinically relevant RAI uptake in patients with metastasized RAI refractory NMTC.

Methods: Eight NMTC patients with metastasized RAI refractory NMTC with at least one measurable target lesion of ≥1 cm, without a direct indication for systemic treatment and without contraindications for digoxin treatment were included between November 2022 and June 2023. Before treatment a baseline [123I]NaI-scintigraphy was performed. Thereafter, patients were treated for 3 weeks with digoxin with starting doses dependent on age and weight. For safety reasons, the usual therapeutic range for digoxin was aimed for; 0.5-2.0 ng/mL. After 1 week, the blood concentration of digoxin was measured and the digoxin dose was adjusted if necessary. After 3 weeks, a new [123I]NaI-scintigraphy was performed. If this second scintigraphy showed clinically relevant RAI uptake, a [131I]NaI-treatment would be performed within 1 week. Digoxin treatment was stopped after the second [123I]NaI-scintigraphy or after [131I]NaI-treatment in case of successful reinduction of RAI-uptake.

Results: Seven patients (5 papillary carcinoma and 2 oncocytic carcinoma) completed the digoxin treatment and were evaluable. An eighth patient discontinued the study because of an digoxin-unrelated emergency indication for a CT with iodinated contrast agent. None of these 7 patients showed clinically relevant RAI-uptake after digoxin treatment. Digoxin treatment was generally tolerated well. No digoxin-related serious adverse events occurred during the study. Increased fatigue was the only adverse event occurring in more than one patients, presenting in 4 out of 7 evaluable patients.

Conclusion: Contrary to results from preclinical trials, in this study digoxin treatment does not reinduce RAI uptake in patients with metastasized and RAI refractory NMTC. Future studies are needed to identify effective redifferentiation strategies for patients not eligible for kinase inhibitors.