Cabozantinib-induced thyroid dysfunction: a review of two ongoing trials for metastatic bladder cancer and sarcoma.
BACKGROUND
Thyroid dysfunction is a common adverse event associated with tyrosine kinase inhibitors (TKI), but its underlying pathophysiology is unclear. Cabozantinib is a novel TKI currently Food and Drug Administration approved for advanced medullary thyroid cancer and tested in clinical trials on solid tumors including prostate, liver, bladder, breast, and ovarian cancer.


METHODS
We analyzed the thyroid function of patients enrolled in two phase 2 clinical trials using cabozantinib at the National Institutes of Health Clinical Center. Two cases of thyroiditis associated with cabozantinib therapy are presented in detail, and a systematic review of the literature on TKI-associated thyroid dysfunction is also discussed.


RESULTS
Between September 2012 and September 2013, 33 patients were treated with cabozantinib, and follow-up thyroid function tests were available for 31 (20 males, 11 females; age 59±1 years). Thyroid dysfunction was recorded in the majority of patients (93.1%), with a predominance of subclinical hypothyroidism. Two cases showed a biphasic pattern of thyroid dysfunction characterized by a transient thyrotoxicosis followed by hypothyroidism. Color Doppler demonstrated an increase in vascularization during the thyrotoxic phase, but no uptake was visualized on nuclear medicine imaging. A systematic review of the literature resulted in the identification of 40 original manuscripts, of which 13 were case series and 6 were case reports describing TKI-associated thyroid dysfunction.


CONCLUSIONS
TKI therapy often results in clinically significant thyroid dysfunction. Cabozantinib treatment commonly results in thyroid dysfunction varying from subclinical hypothyroidism to symptomatic thyrotoxicosis. Early detection and characterization of cabozantinib-associated thyroid dysfunction and close follow-up are essential to provide adequate management of this common adverse event.
1 National Institute of Diabetes and Digestive and Kidney Diseases, Diabetes, Endocrine, and Obesity Branch, National Institutes of Health , Bethesda, Maryland.
Sahzene
S
Yavuz
Andrea B
AB
Apolo
Shivaani
S
Kummar
Jaydira
J
del Rivero
Ravi A
RA
Madan
Thomas
T
Shawker
James
J
Reynolds
Francesco S
FS
Celi
D000328:Adult; D000368:Aged; D000813:Anilides / Q000009:adverse effects* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000009:adverse effects* / Q000627:therapeutic use*; D012509:Sarcoma / Q000188:drug therapy*; D013959:Thyroid Diseases / Q000188:drug therapy* / Q000209:etiology; D013961:Thyroid Gland / Q000000981:diagnostic imaging; D013971:Thyrotoxicosis / Q000503:physiopathology; D018608:Ultrasonography, Doppler; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
D000813:Anilides; D000970:Antineoplastic Agents; D011725:Pyridines; C558660:cabozantinib; D011505:Protein-Tyrosine Kinases