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Multikinase inhibitors: a new option for the treatment of thyroid cancer

Nature Reviews Endocrinology volume 7, pages 617–624 (2011)Cite this article

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Abstract

Thyroid cancer typically has a good outcome following standard treatments, which include surgery, radioactive iodine ablation and treatment with TSH-suppressive levothyroxine. Thyroid cancers that persist or recur following these therapies have a poorer prognosis. Activation of mitogenic and angiogenic signaling pathways occurs in these cancers, and preclinical models have shown that inhibition of key kinase steps in these pathways can have antitumoral effects. Several of these kinase inhibitors have now been tested in phase II and phase III trials, with modestly encouraging results. Some promising data exist for the use of vandetanib (also known as ZD6474), motesanib, axitinib, cabozantinib (also known as XL184), sorafenib, sunitinib, pazopanib and lenvatinib (also known as E7080) in progressive thyroid cancer of medullary, papillary and follicular subtypes. These drugs are generally well-tolerated, although dose-limiting toxicities are common, and a few (probable) treatment-related deaths have been reported. Additional phase III trials will be needed to conclusively show that treatment benefit exceeds risk. Drug resistance can occur via activation of alternate mitogenic signals (pathway switching), as has been reported for the use of kinase inhibitors in other malignancies, such as melanoma. The hypothesis that combinations of kinase inhibitors targeting different pathways might produce better results is currently being tested in several clinical trials.

Key Points

  • Only one phase III trial of kinase inhibitors in patients with thyroid cancer, using vandetanib in progressive medullary thyroid cancer, has been completed to date

  • Patients with progressive medullary or differentiated thyroid cancer should be enrolled in ongoing clinical trials of kinase inhibitors

  • In the absence of clinical trial data, 'off-label' use of registered kinase inhibitors should be considered

  • Patients receiving kinase inhibitors should be carefully monitored for serious adverse events, including hand–foot syndrome, hypertension, perforated viscus, tumor bleeding, keratoacanthoma and hypothyroidism

  • Some kinase inhibitors are selective for particular cancer genotypes (for example, vemurafenib in melanoma patients with the BRAF Val600Glu amino acid substitution), but more research is needed before molecular testing becomes routine

  • The levels of classic tumor biomarkers, such as calcitonin or thyroglobulin, generally decrease with treatment, but correlation with radiological responses has not always been demonstrated; new biomarkers, such as soluble VEGFRs, are being evaluated

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Figure 1: Schematic diagram of the kinase signaling cascade involved in thyroid tumorigenesis.

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Authors and Affiliations

  1. Cancer Genetics Unit, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, 2065, NSW, Australia

    Matti L. Gild, Martyn Bullock, Bruce G. Robinson & Roderick Clifton-Bligh

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All authors researched the data for the article and reviewed and/or edited the manuscript before submission. M. L. Gild, M. Bullock and R. Clifton-Bligh provided a substantial contribution to discussions of the content and contributed equally to writing the article.

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Correspondence to Roderick Clifton-Bligh.

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Gild, M., Bullock, M., Robinson, B. et al. Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nat Rev Endocrinol 7, 617–624 (2011). https://doi.org/10.1038/nrendo.2011.141

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