Pazopanib, Cabozantinib, and Vandetanib in the Treatment of Progressive Medullary Thyroid Cancer with a Special Focus on the Adverse Effects on Hypertension

Abstract

Medullary thyroid cancer (MTC) is a rare malignancy with a poor prognosis. First line therapy is surgery, which is the only curative method of the disease. However, in non-operable cases or with tumor progression and metastases, a systemic treatment is necessary. This form of cancer is often insensitive to conventional chemotherapy, but the use of tyrosine kinase inhibitors (TKIs), such as pazopanib, cabozantinib, and vandetanib, has shown promising results with an increase in progression-free survival and prolonged lifetime. Therefore, we focused on the pharmacological characteristics of TKIs, their mechanism of action, their application as a secondary treatment option for MTC, their efficacy as a cancer drug treatment, and reviewed the ongoing clinical trials. TKIs also act systemically causing various adverse events (AEs). One common AE of this treatment is hypertension, known to be associated with cardiovascular disease and can therefore potentially worsen the well-being of the treated patients. The available treatment strategies of drug-induced hypertension were discussed. The mechanism behind the development of hypertension is still unclear. Therefore, the treatment of this AE remains symptomatic. Thus, future studies are necessary to investigate the link between tumor growth inhibition and hypertension. In addition, optimized, individual treatment strategies should be implemented.

Keywords: VEGF; antiangiogenesis; hypertension; medullary thyroid carcinoma; tyrosine kinase inhibitors.

Figure 1

Chemical structures and modes of action of pazopanib, cabozantinib, and vandetanib. The red T-arrows indicate inhibition on receptor signaling. AKT: Protein kinase B; BAD: BCL2 associated agonist of cell death; c-Kit: stem cell growth factor receptor, EGFR: epidermal growth factor receptor; ERK: extracellular regulated kinase, MAPK: mitogen activated protein kinase, MEK: methyl ethyl ketone, MET: methionine, MDM2: mouse double minute 2, mTOR: mammalian target of rapamycin, NF-kB: nuclear factor kappa B, PDGFR: platelet derived growth factor receptor, PI3K: phosphoinositide 3 kinases, RAF: rapidly accelerated fibrosarcoma, RAS: rat sarcoma, RET: rearranged during transfection, STAT: signal transducers and activators of transcription.

Figure 2

Effects of sorafenib on vascular stiffness. Patients treated with sorafenib showed an increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP) as well as an elevation of the pulse wave velocity (both indicated by yellow areas). Sorafenib was administered to patients continuously at a dose of 400 mg twice daily. The data is based on a subset of patients enrolled onto a phase II randomized discontinuation clinical trial [41]. Parts of the figure were drawn by using pictures from Servier Medical Art.