Clinical Indications for Treatment with Multi-Kinase Inhibitors in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer

SIMPLE SUMMARY: Differentiated thyroid cancer generally has an indolent, slow-growing nature. The disease gradually progresses in some of the patients and can ultimately develop into life-threatening conditions. Multi-kinase inhibitors including sorafenib and lenvatinib demonstrated prolonged progression-free survival compared with the placebo in pivotal phase 3 trials for patients with radioactive iodine-refractory, progressive disease. However, the overall survival benefit was not confirmed because of the cross-over design of the trials. Therefore, the initiation of treatment with multi-kinase inhibitors should be carefully considered according to the patients and their disease conditions. In this review, we comprehensively describe the currently reported factors that can be potential indications, and further attempt to provide a simplified list of indications for the initiation of multi-kinase inhibitor treatment in patients with radioactive iodine-refractory differentiated thyroid cancer. ABSTRACT: Differentiated thyroid cancer is usually a slow-growing disease, even if the patients develop distant metastasis. For recurrent or metastatic disease, radioactive iodine therapy is a standard treatment. However, the disease gradually progresses in some of the patients and can ultimately develop into life-threatening conditions. For patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RR-DTC), multi-kinase inhibitors (MKIs) including sorafenib and lenvatinib prolonged progression-free survival compared with placebo in pivotal randomized phase 3 trials, although the benefit in overall survival has not been clearly confirmed, possibly because the patients who received placebo were permitted to cross-over to lenvatinib upon disease progression. Moreover, the adverse events related to MKIs were not negligible. Therefore, the optimal timing of MKI initiation has long been controversial, and physicians should consider various patient and disease factors. Herein, we comprehensively review the clinical factors that can be helpful in determining the initiation of MKIs for patients with RR-DTC.