We found that patients with mRCC who take TKI drugs with hypothyroidism complications have longer PFS. TKI-induced hypothyroidism could act as a role to predict the prognosis in patients mRCC. TKIs-induced hypothyroidism, meanwhile, can help urologists and oncologists evaluate the efficacy of the TKI drugs to some degree.
The cause of hypothyroidism in patients with mRCC caused by the use of TKI drugs is very complicated. The VEGF and VEGFR are expressed in normal thyroid cells and thyroid follicles, which are mediated by thyrotropin to some extent[15, 16]. TKI drugs inhibit the formation of VEGF and VEGFR expressed in normal thyroid cells. At the same time, the thyroid is rich in capillaries, and its growth needs to be mediated by VEGF receptors on the surface of vascular endothelial cells, but TKI drugs inhibit the expression of VEFG and inhibit the formation and growth of capillaries. Insufficient blood supply leads to thyroid atrophy and decline in function. Besides, the inhibition of thyroid peroxidase activity caused by TKI drugs leads to a decrease in thyroid hormone synthesis.
There is evidence that TKI drug may heighten anti-tumor immunity by regulating tumor microenvironment and increasing the expression of interferon (IFN)-γ, which may be beneficial to T cell activation and helper T cell type 1 cell-mediated response. However, the activation of immune system may also be the pathophysiological mechanism of acquired hypothyroidism. Moreover, lymphocytic thyroiditis was found in patients with thyroid dysfunction during TKI drugs treatment . In the above hypothesis, hypothyroidism and efficacy of TKI are two different manifestations in the treatment of mRCC.
We found that the following factors may cause changes in thyroid function as well. There is a transition period to avoid the influence of thyroid function, although some patients received cytokine therapy before applied TKI drugs in the literature included in the meta-analysis. The dose of TKI drugs used by different patients will be adjusted according to condition, which might be related to hypothyroidism. And most patients underwent repeated CT scans with intravenous iodinated contrast media every eight weeks. Iodine-containing contrast media can temporarily increase serum TSH.
It is worth saying that the emergence of hyperthyroidism is not the eventual purpose. On the contrary, we should treat it in time in the course treatment. But it is controversial that the treatment of hypothyroidism based on serum TSH or clinical symptoms of hypothyroidism. Torino et al. documented that patients should receive thyroid hormone replacement therapy whenever thyrotropin exceeds 10 µ IU / mL. However, it is also found that some patients with obvious symptoms of hypothyroidism should be actively treated even if the concentration of TSH is not greater than 10 µ IU / mL[24, 25]. There is a flexible question about the timing of intervention for hypothyroidism. Clinicians should consider comprehensively the wishes of patients, clinical symptoms and serum TSH levels.
Some shortcomings are presented in our study. First of all, the definition of hypothyroidism is not consistent completely in the included literature. Besides, our research has incorporated more retrospective literature. Of course, some advantages exist in our research. First, we carefully read the literature that may meet the standard, and when we find that the literature data that meet the standard is insufficient, we improve the relevant data by contacting corresponding authors or using the statistical methods of Tierney and others to ensure that they do not lose any articles that meet the conditions. And, researchers strictly select qualified articles according to our standards.