Questions and Controversies in the Clinical Application of Tyrosine Kinase Inhibitors to Treat Patients with Radioiodine-Refractory Differentiated Thyroid Carcinoma: Expert Perspectives.

Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

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The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Déclaration de conflit d'intérêts

The authors declare the following potential conflicts-of-interest: all authors, honoraria and defrayment of travel and lodging expenses in connection with membership in the Eisai GmbH Advisory Board. Besides the foregoing, the authors declare the following potential conflicts of interest: FAV, consultancy fees from Jubilant Draximage and Sanofi Genzyme, speaker honoraria from Sanofi Genzyme, research support from Eisai; HA, lecture fees from Eisai, GE, Norgine, Novartis, Pfizer, and Sirtex; IBr, support from Bayer AG, Eisai GmbH, and ROTOP Pharma GmbH; AB, none; AD, none; CD, none; CK, honoraria for presentation, Novartis, advisory board membership, Eisai, Ipsen, Merck, travel support, Ipsen, Medac; UK, none; MCK, honoraria from Eisai, AstraZeneca, Bayer, Exelixis, GE Healthcare, Lilly, and Sanofi Genzyme, advisory board membership, Eisai, Exelixis, travel support, Eisai, Exelixis, GE Healthcare, Ipsen, Novartis; ML, research support from Exelixis; CR, none; KS, none; HSW, none; AZ, travel assistance from Eisai, honoraria, travel assistance, and advisory board membership, Johnson & Johnson, research support from Future Diagnostics, MSD, Shire, travel assistance from Gesellschaft für Qualitätssicherung Hessen, stock ownership in Fresenius; MS, none;. Eisai GmbH, Frankfurt, Germany supported the expert panel meetings the content of which is summarized in this paper. Eisai GmbH also provided medical writing support in the development of this manuscript, and defrayed journal page charges for the accepted manuscript. Robert J. Marlowe, ISMPP CMPP™, Spencer-Fontayne Corporation, Jersey City, NJ helped draft, edit, and organize the manuscript, and partly handled manuscript submission logistics.