Sorafenib-Induced Destructive Thyroiditis

Dear Editor:

Sorafenib (Nexavar; Bayer Pharmaceuticals Group, Montville, NJ) is an orally active tyrosine-kinase inhibitor (TKI) whose spectrum of inhibition includes Raf kinase; vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor β; c-Kit protein; and RET receptor tyrosine kinases. It is used to treat advanced renal cell carcinoma and hepatocellular carcinoma (HCC) (1,2). The most common adverse events are diarrhea, rash, fatigue, hand–foot skin reactions, and hypertension. High prevalence of thyroid dysfunction, mostly hypothyroidism, occurs with sunitinib (Sutent; Pfizer Ltd., Sandwich, United Kingdom), a TKI with a similar mechanism of action. In the absence of data on sorafenib, we started routinely analyzing thyroid function during sorafenib. Here we report the first case of overt thyrotoxicosis caused by sorafenib-induced destructive thyroiditis.

A 60-year-old Korean man with chronic hepatitis B virus (HBV) infection underwent liver surgery to remove a 3.5-cm nodule of HCC with microscopic vessel invasion. He was initially treated with lamivudine and adefovir dipivoxil, with sustained virological response (HBV-DNA < 12 UI/mL). Three years later he presented with multiple liver and peritoneal tumors consistent with second primary HCC. Sorafenib, 400 mg twice daily, was started after freezing a baseline serum sample. There was no history of thyroid disease, autoimmune disease, or medications that affect thyroid function, including interferons. After 4 weeks he developed fatigue, hand–foot skin reaction, dysphonia, and moderate weight loss. He was a tired-appearing man but with no apparent distress, normal, dry skin, and erythrodysesthesia of the palmar and plantar surfaces. Thyroid function tests, which were normal at baseline, showed thyrotoxicosis (Supplemental Fig. S1, available online at www.liebertonline.com). Urine iodine was normal (195 μg/day; normal range, 150–300). Serum thyroglobulin was 39 μg/L prior sorafenib treatment but 399 μg/L after 1 month, suggesting destructive thyroiditis. This was confirmed by an ultrasonography scan showing a diffusely hypoechoic gland of normal volume (Supplemental Fig. S2A, available online at www.liebertonline.com). An echo-color Doppler showed reduced vascularization (Supplemental Fig. S2B, available online at www.liebertonline.com), and 99mTc pertechnetate thyroid scintigraphy demonstrated markedly decreased uptake of radioiodine (0.2%; normal range, 0.5%–4%). Serum antibodies against thyroglobulin, thyroid peroxidase, and thyrotropin (TSH) were negative at baseline and at month 1.

Treatment with 25 mg/day of prednisone + 40 mg/day of propanol was adopted and the original dosing of 800 mg/day of sorafenib could be maintained with a partial tumor response at month 4 of therapy. When prednisone was tapered down every 10 days over 12 weeks serum TSH remained below normal and free thyroxine levels remained elevated, but there were no symptoms and/or signs of thyrotoxicosis such as heat intolerance, tachycardia, or anxiety. Free triiodothyronine levels normalized at week 8. At week 15, TSH and free thyroxine levels normalized, and prednisone and propanolol were withdrawn. At week 18 TSH rose to the hypothyroid range with a plateau level of about 10 mU/L, with normal free thyroid hormones and no hypothyroid symptoms (Supplemental Fig. S1). We reported this adverse event to the Italian pharmacovigilance center in November 2009 (number 107996).

While the clinical benefit of sorafenib is undisputed, its administration is complicated by a significant rate of mild to moderate adverse events. Hypothyroidism has been reported in 18% of patients treated with sorafenib for renal cell carcinoma with a median time of appearance of 1.8 months (3). Consistently, in our series of 38 consecutive patients with HCC treated with sorafenib, 5 (13%) developed a subclinical hypothyroidism (TSH levels, 7.41 μIU/mL; range, 6.38–8.94 μIU/mL) (data not shown). Moreover, here we report the first description of sorafenib-induced thyrotoxicosis. Surprisingly, sorafenib-associated thyroid dysfunction was not reported in two registration trials in patients with advanced HCC (2,4). We speculate that sorafenib-induced hypothyroidism could have the same basis as sunitinib-induced hypothyroidism, including reduced synthesis of thyroid hormones related to inhibition of thyroid peroxidase activity, destructive thyroiditis, and inhibition of thyroid uptake of iodine (5). Nevertheless, thyroid toxicity occurs more frequently in patients receiving the TKI sunitinib (up to 85% of cases) than in those taking sorafenib, possibly indicating different pathogeneses. In contrast, sunitinib-induced mild thyrotoxicosis with undetectable TSH levels and normal free thyroid hormones is less frequent, and overt thyrotoxicosis unusual (6).

Thus, thyroid dysfunction is a class-specific adverse event of TKIs. The picture of overt hyperthyroidism after short-term sorafenib administration, and subsequent hypothyroidism, adds to the complex symptoms in HCC patients. TKI-induced fatigue is a main cause of sorafenib dose reduction or discontinuation. Since early detection and treatment of thyroid dysfunction permits sorafenib treatment to be maintained, strict surveillance of thyroid function is necessary in all patients with advanced HCC under sorafenib therapy.