Redifferentiation therapy in unresectable or metastatic radioactive iodine refractory thyroid cancer: an International Thyroid Oncology Group statement

In patients with follicular cell-derived thyroid cancer that have distant metastases and no iodine uptake, redifferentiation-ie, the restoration of tumoural 131I uptake with systemic therapy-is now possible. The use of mitogen-activated protein kinase (MAPK) inhibitors for a short period of time before the administration of high activity 131I shows promising results with iodine uptake restoration and tumour response. Redifferentiation has been used in patients with BRAF-mutated and RAS-mutated tumours in prospective trials and in the case of patients with RET or NTRK fusions. The iodine uptake restoration ranges from 33% to 95%, and tumour response rates from 11% to 80%. There is substantial variability between trials with regards to inclusion criteria, duration of redifferentiation drug therapy, activity of radioactive iodine, and use of dosimetry. Randomised studies are missing to clearly establish the effectiveness and applicability of redifferentiation. Thus, long-term studies are needed to establish the most effective redifferentiation protocols. The objectives of this Review are to: (1) provide a comprehensive review of the available results from prospective trials and case reports, including results regarding the restoration of radioiodine uptake and treatment efficacy (morphological and biological); (2) describe the differences in redifferentiation trial design between studies and discuss their potential impact on treatment efficacy; (3) describe the implications and limitations of dosimetry; and (4) outline the key questions to be addressed in future redifferentiation trials.