Thyroid dysfunction in patients treated with tyrosine kinase inhibitors, sunitinib, sorafenib and axitinib, for metastatic renal cell carcinoma.
OBJECTIVE
Targeted drugs are generally associated with a lower toxicity than conventional systemic cytotoxic drugs and, thus, are administered for long periods. As a result, unusual adverse effects, including thyroid dysfunction, have become important clinical issues.


METHODS
We retrospectively collected the data and compared the incidence and the time of onset of thyroid dysfunction in 33 patients (M/F: 26/7, age: 34-77) with metastatic renal cell carcinoma treated with the small-molecule tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib and axitinib in Yamagata University Hospital, Japan, from 2005 to 2010.


RESULTS
The incidence of thyroid dysfunction tended to be higher in patients treated with axitinib (6 of 6: 100%) than in those treated with sunitinib (9 of 15: 60%) or sorafenib (6 of 12: 50%) (P= 0.1113). The median thyroid dysfunction-free survival evaluated using the Kaplan-Meier product-limit method with the log-rank test was significantly shorter in patients treated with axitinib than in those treated with sunitinib/sorafenib (3 vs. 16 weeks, P=0.0198). A multivariate Cox regression model for thyroid dysfunction-free survival with several probable confounding factors as co-variables showed that patients treated with axitinib were more likely to have thyroid dysfunction than the others (hazard ratio: 4.53, 95% confidence interval: 1.40-14.63, P=0.0116).


CONCLUSIONS
Patients treated with the tyrosine kinase inhibitors developed thyroid dysfunction frequently. Furthermore, those treated with axitinib developed thyroid dysfunction significantly more and at a faster rate than the others. Therefore, when the tyrosine kinase inhibitors, especially axitinib, are used, close monitoring of thyroid function is recommended, at least for the initial 1-2 months, to avoid clinical symptoms derived from thyroid dysfunction.
Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Yamagata, Japan. mdaimon@med.id.yamagata-u.ac.jp
Makoto
M
Daimon
Tomoyuki
T
Kato
Wataru
W
Kaino
Kaoru
K
Takase
Shigeru
S
Karasawa
Kiriko
K
Wada
Wataru
W
Kameda
Shinji
S
Susa
Toshihide
T
Oizumi
Yoshihiko
Y
Tomita
Takeo
T
Kato
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects; D000077784:Axitinib; D001557:Benzenesulfonates / Q000009:adverse effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects*; D007191:Indazoles / Q000009:adverse effects*; D007211:Indoles / Q000009:adverse effects*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000009:adverse effects*; D011758:Pyrroles / Q000009:adverse effects*; D000077157:Sorafenib; D000077210:Sunitinib; D013959:Thyroid Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000401:mortality; D013961:Thyroid Gland / Q000187:drug effects / Q000503:physiopathology; D013971:Thyrotoxicosis / Q000139:chemically induced
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000077784:Axitinib; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib