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Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy

Nature Reviews Clinical Oncology volume 6, pages 219–228 (2009)Cite this article

Abstract

Despite their inherent selectivity, targeted therapies such as tyrosine kinase inhibitors (TKIs) can cause unusual adverse effects. Sunitinib and sorafenib are multitargeted TKIs that have been demonstrated to induce hypothyroidism and thyroid dysfunction. Retrospective studies indicate that sunitinib can induce hypothyroidism in 53–85% of patients, and in prospective studies this complication has been reported in 36–71% of patients. Sorafenib has been reported to be responsible for hypothyroidism in 18% of patients with metastatic renal-cell carcinoma. Furthermore, imatinib and sunitinib seem to increase the requirement of levothyroxine in hypothyroid patients. The management of thyroid dysfunction and possible related symptoms, such as fatigue, represents a challenge to oncologists. We propose a diagnostic and therapeutic algorithm for the management of TKI-related hypothyroidism. Prospective trials are needed to define the incidence of overt and subclinical hypothyroidism and thyroid dysfunction during therapy with sunitinib, sorafenib and potentially other TKIs. The safety and efficacy, and optimal dosing and timing of starting replacement therapy in patients affected by TKI-related hypothyroidism need accurate appraisal and should be evaluated prospectively in appropriately designed trials.

Key Points

  • The reported incidence of sunitinib-induced hypothyroidism is 53–85% and 36–46% in retrospective or prospective studies, respectively, and 18% in patients treated with sorafenib

  • Mechanisms of hypothyroidism induced by TKIs include drug-induced atrophy of the thyroid through inhibition of its vascularization, drug-induced thyroiditis, reduced synthesis of thyroid hormones, progressive depletion of the thyroid's functional reserve and inhibition of the thyroidal iodine uptake

  • Whether TKI-related hypothyroidism is mediated by inhibition of the VEGF pathway or of other molecular pathways is unknown

  • In patients treated with sunitinib or sorafenib, routine thyroid function testing at baseline, and measurement of serum thyroid stimulating hormone level on day 1 at the start of every new treatment cycle is recommended

  • Levothyroxine is the standard treatment for overt hypothyroidism and is recommended in some patients with subclinical hypothyroidism; overt or subclinical hypothyroidism per se does not justify the withdrawal of TKI therapy

  • Thyroid function test should be included in routine toxicity assessment of TKIs under clinical evaluation; however, the clinical relevance of early diagnosis of hypothyroidism in patients with TKIs is still controversial

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Figure 1: Flow chart to show the proposed decision-making sequence for the management of hypothyroidism in patients receiving tyrosine kinase inhibitors.

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Authors and Affiliations

  1. Medical Oncology Division, San Filippo Neri Hospital, Rome, Italy

    Francesco Torino & Raffaele Longo

  2. Catholic University, Rome, Italy

    Salvatore Maria Corsello

  3. Endocrinology Unit, Regina Elena Institute, Rome, Italy

    Agnese Barnabei

  4. Medical Oncology Division, San Filippo Neri Hospital, Rome, Italy

    Giampietro Gasparini

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Correspondence to Giampietro Gasparini.

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Torino, F., Corsello, S., Longo, R. et al. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol 6, 219–228 (2009). https://doi.org/10.1038/nrclinonc.2009.4

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