Keywords
Cell Differentiation
Proto-Oncogene Proteins B-raf
MAP Kinase Signaling System
Iodine
Radioisotopes
How to Cite
Abstract
Background: Radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) has a poor prognosis. Constitutive MAPK activation, frequently driven by BRAF V600E or RAS alterations, suppresses thyroid-specific genes and sodium-iodide symporter expression. Short-course BRAF and/or MEK inhibition before RAI aims to restore iodine avidity.
Methods: We conducted a systematic review and meta-analysis in accordance with PRISMA 2020. PubMed, Embase, CENTRAL, ClinicalTrials.gov, and Google Scholar were searched from inception through March 31, 2025, for prospective studies of short-course BRAF and/or MEK inhibition undertaken with the protocolized intention of restoring RAI uptake before therapeutic RAI (PROSPERO: CRD1371813). Random-effects models with REML estimation and logit transformation were used for proportions. Risk of bias was assessed with ROBINS-I and certainty with GRADE.
Results: Five non-randomized single-arm studies (N=72) met the revised eligibility criteria; four studies (n=48) contributed to the primary meta-analysis. The pooled proportion with restored detectable RAI uptake was 62.3% (95% CI 47.8%-74.8%; I²=0%). When the therapeutic dosimetric threshold reported by Ho et al. was used, the pooled estimate was 57.8% (95% CI 44.0%-71.5%). Excluding Ho et al., it yielded 63.5% (95% CI 45.7%-81.4%). No included study published a hazard ratio for progression-free survival; progression-free and overall survival were therefore synthesized narratively. Adverse-event rates were not pooled because attribution, grading, and exposure duration differed across studies. No treatment-related deaths were reported. Certainty of the evidence was very low for all outcomes.
Conclusions: Short-course MAPK inhibitor-based redifferentiation can restore RAI uptake in selected patients with RAI-refractory DTC, but uptake is a surrogate outcome and does not establish survival benefit. The evidence is insufficient to determine whether efficacy differs by mutation subtype. Controlled, biomarker-stratified trials using standardized imaging and clinically relevant outcomes are needed.
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