Toxicity of cancer therapy: what the cardiologist needs to know about angiogenesis inhibitors

Abstract

Clinical outcomes for patients with a wide range of malignancies have improved substantially over the last two decades. Tyrosine kinase inhibitors (TKIs) are potent signalling cascade inhibitors and have been responsible for significant advances in cancer therapy. By inhibiting vascular endothelial growth factor receptor (VEGFR)-mediated tumour blood vessel growth, VEGFR-TKIs have become a mainstay of treatment for a number of solid malignancies. However, the incidence of VEGFR-TKI-associated cardiovascular toxicity is substantial and previously under-recognised. Almost all patients have an acute rise in blood pressure, and the majority develop hypertension. They are associated with the development of left ventricular systolic dysfunction (LVSD), heart failure and myocardial ischaemia and can have effects on myocardial repolarisation. Attention should be given to rigorous baseline assessment of patients prior to commencing VEGFR-TKIs, with careful consideration of baseline cardiovascular risk factors. Baseline blood pressure measurement, ECG and cardiac imaging should be performed routinely. Hypertension management currently follows national guidelines, but there may be a future role forendothelin-1 antagonism in the prevention or treatment of VEGFR-TKI-associated hypertension. VEGFR-TKI-associated LVSD appears to be independent of dose and is reversible. Patients who develop LVSD and heart failure should be managed with conventional heart failure therapies, but the role of prophylactic therapy is yet to be defined. Serial monitoring of left ventricular function and QT interval require better standardisation and coordinated care. Management of these complex patients requires collaborative, cardio-oncology care to allow the true therapeutic potential from cancer treatment while minimising competing cardiovascular effects.

Keywords: cardiac risk factors and prevention; heart failure; pharmacology; translational cardiovascular science.

Figure 1

Estimated incidence of various cardiovascular toxicities associated with TKI therapy. [2]–[5], [9] LVSD – Left ventricular systolic dysfunction; MI – Myocardial infarction

Figure 2

Mechanisms of action VSPIs. There are four main groups of VSPIs: 1) Monoclonal antibodies against VEGF: Bevacizumab was the first VSPI approved for use in a variety of solid tumours. It selectively binds to VEGF to inhibit its interaction with VEGF receptors 2) Small molecule inhibitors of intracellular tyrosine kinases (e.g. sunitinib, sorafenib): these agents are not VEGFR-2-specific but also inhibit a variety of other receptor tyrosine kinases. This increases anti-cancer efficacy but may also contribute to cardiovascular toxicity. 3) VEGF 'trap' (e.g. aflibercept): this recombinant fusion protein comprises VEGF- binding regions of VEGFR-1 and -2 4) Monoclonal VEGFR antibodies (e.g. ramirucimab): these target VEGFR2 receptors, to prevent VEGF-A binding.

Figure 3

Changes in systolic and diastolic Blood Pressure. Change in mean blood pressure as measured by teletransmitted results of home monitoring in patients with metastatic renal-cell carcinoma treated with two cycles of sunitinib at a dose of 50 mg daily for 4 weeks (shaded area), followed by 2 weeks without treatment. The results are shown separately for patients who were normotensive (Panel A) and those who were hypertensive (Panel B) before starting sunitinib treatment. (Azizi M et al. N Engl J Med 2008;358:95-97, with permission).