OBJECTIVES: Differentiated thyroid cancer (DTC) patients are offered multiple targeted therapeutics, but it is unclear which pharmaceutical therapies are the most effective and safe. We conducted a systematic review to investigate the efficacy and safety of targeted treatments.

METHODS: A comprehensive searches of MEDLINE®, Embase®, Evidence-based Medicine Reviews, and grey literature were conducted. All records were screened against predefined inclusion criteria. All included studies were extracted and evaluated using NICE's critical appraisal checklist.

RESULTS: A total of 18 studies from 5,334 publications were eligible. Two studies assessed treatments in the DTC population, while 16 studies addressed the radioactive iodine-resistant (RAIR) sub-population. DTC patients treated with nintedanib had a small increase in median progression-free survival (PFS) compared to placebo (3.71 vs 2.86 months). Selumetinib with radioactive iodine had a minor effect on complete remission rates (40 vs. 38%), but its higher adverse event profile raised concerns. However, the landscape for RAIR-DTC changes substantially. Clinical benefits were seen with donafenib, lenvatinib, anlotinib, apatinib, cabozantinib, cediranib, dabrafenib+trametinib, sorafenib, paazopanib, and vandetanib, ranging from 2% (intermittent pazopanib) to 69.9% (lenvatinib), However, five studies failed to reach the median overall survival (OS), suggesting that longer survival is possible. Furthermore, cabozantinib significantly improved PFS when compared to placebo, with anlotinib reaching a remarkable 40.54 months. Adverse events (mainly grade 1-2) were reported across all studies, with hypertension, diarrhea, and hand-foot skin reactions being the most common. In spite of its exceptional efficacy, lenvatinib caused an adverse event rate of 75.9% (grade 3).

CONCLUSIONS: Despite modest progress in the general DTC population, lenvatinib has revolutionized RAIR-DTC treatment by delivering a higher response rate and extended survival, although with a higher adverse event risk. Therefore, further DTC research needs to be conducted both in the broader population and in the RAIR-DTC population.