Predictors of Response and Survival to Multikinase Inhibitors in Radioiodine Resistant Differentiated Thyroid Cancer

Abstract

Sorafenib and lenvatinib are the only multikinase inhibitors (MKIs) approved for the treatment of radioactive iodine refractory differentiated thyroid cancer (RR-DTC). Although they have been demonstrated to improve progression free survival and overall response rate, the risk of toxicities is very high, worsening patients' quality of life. Therefore, predicting MKI treatment outcomes in the setting of RR-DTC is very challenging for optimizing patients' management. The current review provides an overview of the predictive factors for the response and survival of sorafenib and lenvatinib in RR-DTC. In this setting, a systemic therapy should be considered after conducting a multidisciplinary discussion aimed at evaluating the risk-benefit ratio of the treatment and taking into account several clinical, biochemical, and molecular factors. Age, performance status, and cancer-related symptoms are the most important clinical markers to be considered prior to starting MKI treatment, together with tumor burden. Some tissue and circulating biomarkers have been investigated, those involved in the angiogenic pathways being the most promising. Finally, prospective clinical trials aimed at evaluating predictive markers for therapeutic response are needed for tailoring patient management and allowing more appropriate treatment choices.

Keywords: differentiated thyroid cancer; lenvatinib; multikinase inhibitors; predictive marker; predictors; radioiodine resistance; response to treatment; sorafenib; survival.

Figure 1

Molecular pathways of multikinase inhibitors (MKIs) in radioactive iodine refractory differentiated thyroid cancer. The MKIs (sorafenib, lenvatinib) block signaling from the tyrosine kinase receptors, preventing cell survival, growth, proliferation and angiogenesis. Abbreviations: AKT, protein kinase B; FGFR, fibroblast growth factor receptor; HIF, hypoxia-inducible factor; MAPK, mitogen activated protein kinase; mTOR, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; PI3K, phosphoinositide 3-kinase; RAF, rapidly accelerated fibrosarcoma kinase; RAS, rat sarcoma protein; RET, rearranged during transfection receptor protein; TGF, tumor growth factor; VEGFR, vascular endothelial growth factor receptor. The signaling pathways inhibited by the indicated drugs are represented by crossed-out arrows.