How to manage radioiodine-refractory thyroid cancer in the era of precision medicine.

Differentiated thyroid cancer has a favourable clinical course. However, a minority of patients with distant metastases lose the ability for radioiodine uptake. In case of refractoriness, the implementation of local therapies, that is radiofrequency/cryoablation or embolization, stabilizes metastasis and delays disease progression. A wait-and-see strategy can be a viable option in slow disease progression. On the other hand, in symptomatic patients with progressive disease, the alternative is systemic therapy with tyrosine kinase inhibitors. Three multi-kinase inhibitors have been approved for this indication: lenvatinib and sorafenib as a first-line option and cabozantinib as a second-line option. Next-generation sequencing allows identification of somatic genetic alterations in tumour tissue, some of which are druggable. Thus, additional selective inhibitors have been approved: larotrectinib and entrectinib for NTRK + tumours, selpercatinib and pralsetinib for RET + tumours, and crizotinib, alectinib and lorlatinib for ALK + tumours. Such a personalized approach increases clinical benefit whilst minimizing adverse events. Future studies should focus on the combination of tyrosine kinase inhibitors and immune-checkpoint inhibitors; currently, there is no strong evidence that redifferentiation strategies add clinical benefit in terms of overall survival or progression-free survival.