Thyroid dysfunction and tyrosine kinase inhibitors in renal cell carcinoma

Abstract

The most recent World Health Organization classification of renal neoplasms encompassed nearly 50 distinctive renal neoplasms. Different histological subtypes have different clinical outcomes and show different responses to therapy. Overall, the incidence of kidney cancer has increased worldwide in the last years. Although the most common type of kidney cancer is localized renal cell carcinoma (RCC), with a 5-year survival rate of 85%, about one third of patients present advanced or metastatic disease at diagnosis, with a 5-year survival rate of only 10%. Multi-targeted receptor tyrosine kinase inhibitors (TKIs, sunitinib and sorafenib), the anti-VEGF MAB bevacizumab in association with interferon-a, and the mTOR inhibitors are now approved for the treatment of mRCC. Recently, the novel agents pazopanib and axitinib have also demonstrated efficacy in mRCC patients. Several recent retrospective and prospective trials have suggested that some of their adverse events, such as hypertension, hypothyroidism, and hand foot syndrome (HFS) may act as potential biomarkers of response and efficacy of treatment. In this review, we analyzed the studies that have suggested a relationship between hypothyroidism onset and a better outcome of mRCC patients treated with TKIs. The biological mechanisms suggesting and explaining this correlation are not well known and different speculative theories have been considered in order to investigate the clinical link between hypothyroidism occurrence and the prolonged therapy with TKIs in solid tumors. Furthermore, the management of this unexplained side effect is very important to maximize the efficacy of therapy in mRCC patients because there is a clear and consistent relationship between drug dose and efficacy of treatment. Certainly, other studies are needed to clarify whether a better outcome is associated with hypothyroidism induced to TKIs in patients with mRCC.

Tyrosine receptor kinase B silencing inhibits anoikis-resistance and improves anticancer efficiency of sorafenib in human renal cancer cells

“…However, it presented only partial response rates partly due to dose-related adverse events and clinical toxicities (7,36,37). In this study, TrkB silencing enhanced anti-proliferative, pro-apoptotic and anti-invasive effects of sorafenib at a sub-threshold concentration in anoikis-resistant ACHN cells through inhibiting the activity of Akt and ERK.…”

“…As a multi-targeted TKI, sorafenib was the first targeted agent approved for the treatment of mRCC and significantly prolonged median progression-free survival in a randomized phase Ⅲ trial for advance RCC (4-6). However, complete or long-term remissions are rarely accomplished due to intolerance of dose-related side-effects (7). Identifying novel target molecules is hence necessary to improve the clinical outcome for mRCC treatment.…”

Nebenwirkungsmanagement von Tyrosinkinaseinhibitoren in der Urologie

“…Der genaue Mechanismus der TKI-induzierten Hypothyreose ist noch nicht geklärt. Diskutiert werden neben einer durch eine Thyreoiditis induzierten fokalen Zellapoptose auch eine endotheliale Dysfunktion, ein Rückgang der gefensterten Kapillaren, ein Rück-gang der Jodaufnahme sowie ein Rück-gang der Schilddrüsenhormonprodukti-on [14,32].…”

“…Hypothyreose unter Pazopanib oder Sorafenib ist seltener als unter Sunitinib und wurde in den entsprechenden Zulassungsstudien nicht als häufige Nebenwirkung aufgelistet [32,36] …”

“…Axitinib · Cabozantinib · Pazopanib · Sorafenib · Sunitinib Unter Axitinib ist die TSH-Erhöhung häufig, wobei schwerwiegende Komplikationen aufgrund einer Schilddrüsen-unterfunktion selten sind [32,39]. TSHVeränderungen korrelieren mit der Axitinib-Exposition und treten v. a. ab dem 3.…”