Efficacy of redifferentiation therapy in radioactive iodine refractory thyroid cancer: a systematic review and meta-analysis

Purpose: To systematically review and meta-analyze the efficacy of redifferentiation therapy in patients with radioactive iodine (RAI)-refractory thyroid cancer. Methods: PubMed and Scopus databases were comprehensively searched up to January 2026 to identify clinical studies evaluating patients with RAI-refractory thyroid cancer who received targeted therapies to restore radioiodine uptake. Eligible studies reported either the rate of successful iodine re-uptake or treatment response evaluated according to RECIST 1.1 criteria. The primary endpoint was the pooled rate of successful redifferentiation, while secondary endpoints were objective response rate (ORR) and disease control rate (DCR), each stratified by redifferentiation status. Results: Fifteen studies comprising 234 patients (cohort sizes: 3-33) were included. The pooled rate of successful redifferentiation was 51% (95% confidence interval, CI: 30%-71%), with no significant publication bias. Treatment response according to RECIST 1.1 was evaluated in 11 studies (93 patients). The pooled ORR was 28% (95% CI: 13%-44%) in redifferentiated patients compared to 8% (95% CI: 0%-44%) in non-redifferentiated individuals (P = 0.33). The pooled DCR was significantly higher, reaching 93% (95% CI: 79%-100%) in redifferentiated patients compared to 54% (95% CI: 15%-91%) in non-redifferentiated patients (P = 0.04). Conclusions: In patients with RAI-refractory thyroid tumors, redifferentiation therapy using mitogen-activated protein kinase inhibitors successfully restores radioiodine avidity in approximately half of the cases. Although short-term disease control rates are promising, statistically significant prognostic differences and long-term survival benefits remain to be demonstrated in larger, standardized trials with extended follow-up.