Sorafenib therapy decreases the clearance of thyrotropin

Abstract

Objective: Thyroid function abnormalities are common during treatment with tyrosine kinase inhibitors such as sorafenib. Suggested causes are direct effects on thyroid tissue and increased extrathyroidal metabolism of serum thyroxine and 3,5,3-triiodothyronine. We postulated that tyrosine kinase inhibitors may affect the peripheral metabolism of TSH as well. The effect of sorafenib on TSH clearance was studied. Design: In a study of athyreotic patients on TSH suppression therapy, TSH concentrations were measured after recombinant human TSH (rhTSH) injections before and after 26 weeks of sorafenib therapy. Methods: Before and after the last week of sorafenib therapy, 20 patients with progressive differentiated thyroid carcinoma received a standard dose regimen of two injections 0.9 mg rhTSH on two consecutive days. TSH concentrations were measured 48 h (TSH 48 h ) and 96 h (TSH 96 h ) after the first rhTSH injection. The area under the curve (TSH-AUC), reflecting TSH content between 48 and 96 h following rhTSH administration, was calculated. Results: TSH 48 h levels (120.5 mU/l before vs 146.3 mU/l after; PZ0.029), TSH 96 h levels (22.0 mU/l before vs 35.5 mU/l after; PZ0.001), and TSH-AUC (142.7 vs 186.8 mU/l; PZ0.001) were significantly higher after sorafenib treatment. Higher sorafenib doses were associated with increased changes in TSH 96 h and TSH-AUC. In two patients, TSH levels after sorafenib therapy exceeded 200 mU/l. Conclusions: Sorafenib therapy is accompanied by higher rhTSH levels, probably due to a decreased TSH clearance. Further studies are recommended to clarify whether a decreased clearance of TSH is sorafenib specific.

ENDOCRINE SIDE-EFFECTS OF ANTI-CANCER DRUGS: Thyroid effects of tyrosine kinase inhibitors

“…In the phase II trial conducted by Wells et al (33) in 330 patients with advanced or metastatic MTC, a rise of TSH was described in 49.3 and 17.2% of patients with vandetanib and placebo respectively. As most patients are supposed to be thyroidectomised, this elevated TSH level is probably related to a modification of the metabolism of L-T 4 or to an interference with TSH metabolism or the pituitary or hypothalamic feedback loop (34). An increase of TSH was also observed in 17 athyreotic patients with advanced or metastatic MTC with a mean and median increase of 5.1-and 7.3-fold the baseline level (35).…”

“…It may be caused by a decrease of T 3 and/or T 4 , inhibition of pituitary MCT8 or a negative effect on pituitary capillaries. In athyroid patients treated with sorafenib, TSH clearance is reduced (34).…”

Selective use of sorafenib in the treatment of thyroid cancer

“… 47 The hypothesis for this phenomenon includes: 1) a MCT8 inhibition, the most prominent thyroid hormone transport protein, leading to an impairment of the levothyroixine absorption in the intestine 91 and/or reducing the pituitary and hypothalamic thyroid hormone feedback, 91 2) an enhancement in peripheral T4 and T3 metabolism due to increase in deiodinase 3 activity, 92 and 3) a reduction in thyroid-stimulating hormone clearance. 93 A destruction of the thyroid gland due to capillary dysfunction related with VEGFR inhibition has been described, 94 but it only applies for patients treated with sorafenib for other neoplasias such as hepatocarcinoma or renal cell carcinoma who conserved the thyroid. Transient hyperthyroidism has also been reported in this group of patients.…”