Abstract
Simple SummaryDifferentiated 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.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.
Highlights
In the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines, lenvatinib is recommended as the preferred treatment over sorafenib because of the higher objective response rate reported for lenvatinib (64.8%) compared with sorafenib
The results of RIFTOS multi-kinase inhibitors (MKIs) demonstrated that 2–3 years of the watch and wait approach is acceptable in some asymptomatic radioactive iodinerefractory differentiated thyroid cancer (RR-differentiated thyroid cancer (DTC)) patients, it still cannot provide an indication for starting MKIs at present
Dose reductions (73.6% vs. 63.9%), dose interruptions (86.8% vs. 79.4%), and treatment discontinuation (19.0% vs. 11.0%) were more likely in older patients than younger patients. These results indicate that when the patient is older than 65 years with progressive disease, the initiation of lenvatinib might be considered with careful management of adverse events
Summary
The incidence of distant metastasis at diagnosis is less than 5% in DTC, the incidence of recurrence is approximately 15% during follow up, and these recurrent or metastatic diseases can cause thyroid cancer-related death [10,11,12]. When the patients are refractory to RAI, the 10-year survival rate drops to 10–29% [15]. For patients with RAI-refractory differentiated thyroid cancer (RR-DTC), systemic therapy with multi-kinase inhibitors (MKIs) is a standard option when local treatment options have been exhausted. The phase 3 DECISION trial demonstrated evidence that sorafenib has benefit in progression-free survival (PFS) in patients with RR-DTC compared with placebo (median PFS 10.8 months vs 5.8 months; hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.45–0.76, p < 0.0001) [20]. In the phase 3 SELECT trial, lenvatinib demonstrated prolonged PFS compared with placebo in patients with RR-DTC (median PFS 18.3 months vs. 3.6 months, HR 0.21; 99% CI 0.14–0.31, p < 0.001) [24]
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