HYPOTHYROIDISM AND TYROSINE KINASE INHIBITORS

Hypothyroidism related to tyrosine kinase inhibitors

An emerging toxic effect of targeted therapy

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. Axitinib induced hypothyroidism in preclinical studies, but this result has not yet been reported in clinical trials. 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. Dr Francesco Torino from the Medical Oncology Division, San Filippo Neri Hospital, Rome, Italy and colleagues proposed a diagnostic and therapeutic algorithm for the management of TKI-related hypothyroidism in the latest issue of Nature Reviews Clinical Oncology.

Several possible mechanisms that lead to sustained TKI-related thyroid toxic effects have been suggested, but pharmacological and preclinical data are lacking. Understanding whether sunitinib-related or sorafenib-related hypothyroidism is dependent on the drug's direct mechanism of action (i.e. inhibition of VEGFR-2, KIT, BRAF, RET etc.), or because of indirect effects on other targets (mechanism-independent toxic effects) will be important to optimize therapy. Accurate studies on the mechanism-dependent and mechanism-independent toxic effects of new cancer drugs in clinical settings will not only lead to safer treatment with targeted agents, but could also provide the opportunity to achieve a better therapeutic index in individual patients. Unfortunately, the majority of published studies on hypothyroidism as an adverse effect of TKIs are observational. A common problem shared by all the studies is the small number of patients evaluated, which reduces the statistical power of each single study and the reliability of the conclusions.

Prospective trials are needed to explore the incidence of overt and subclinical hypothyroidism and thyroid dysfunction during therapy with sunitinib, sorafenib and other TKIs. To this aim, epidemiological and biological features of thyroid function should be carefully tested. TSH levels progressively rise with age. The prevalence of subclinical hypothyroidism might, therefore, be significantly overestimated unless an age-specific range for TSH is used. In future studies biological correlative features (such as the role of key genes for thyroid function) would help to define the molecular mechanisms of TKI-induced damage of thyroid function.

It would be of interest to compare the incidence of thyroid toxic effects induced by TKIs when used as first-line treatment to that following sequential therapy. If thyroid dysfunction is more frequent in patients after second-line or third-line treatments, a 'summation effect' related to the sequential treatments might be responsible. In addition, because TKI-related hypothyroidism seems to be a long-term adverse effect, the investigational use of TKIs in the adjuvant setting should take into account this issue, and monitoring thyroid function in patients treated with sunitinib or sorafenib should be mandatory.

The clinical relevance of overt hypothyroidism, the value of thyroid hormone replacement in individuals with abnormal TSH after TKI therapy, and the correct timing of replacement therapy need to be defined more accurately and should be evaluated prospectively with appropriately designed clinical trials. To this aim, a closer collaboration between oncologists and endocrinologists will improve the majority of the above issues and improve the therapies used and quality of life for patients with cancer.