Vascular Toxicities of Cancer Therapies: The Old and the New--An Evolving Avenue

Abstract

Since the late 1990s, there has been a steady decline in cancer-related mortality, in part related to the introduction of so-called targeted therapies. Intended to interfere with a specific molecular pathway, these therapies have, paradoxically, led to a number of effects off their intended cancer tissue or molecular targets. The latest examples are tyrosine kinase inhibitors targeting the Philadelphia Chromosome mutation product, which have been associated with progressive atherosclerosis and acute vascular events. In addition, agents designed to interfere with the vascular growth factor signaling pathway have vascular side effects ranging from hypertension to arterial events and cardiomyocyte toxicity. Interestingly, the risk of cardiotoxicity with drugs such as trastuzumab is predicted by preexisting cardiovascular risk factors and disease, posing the question of a vascular component to the pathophysiology. The effect on the coronary circulation has been the leading explanation for the cardiotoxicity of 5-fluorouracil and may be the underlying the mechanism of presentation of apical ballooning syndrome with various chemotherapeutic agents. Classical chemotherapeutic agents such as cisplatin, often used in combination with bleomycin and vinca alkaloids, can lead to vascular events including acute coronary thrombosis and may be associated with an increased long-term cardiovascular risk. This review is intended to provide an update on the evolving spectrum of vascular toxicities with cancer therapeutics, particularly as they pertain to clinical practice, and to the conceptualization of cardiovascular diseases, as well. Vascular toxicity with cancer therapy: the old and the new, an evolving avenue.

Keywords: angina pectoris; chemotherapy; complications, cardiovascular; coronary vasospasm; drug therapy; endothelial cells.

© 2016 American Heart Association, Inc.

Figures

Figure 1

Simplified spectrum of vascular disease/toxicity induced by chemotherapeutics

Figure 2

Algorithm for the comprehensive assessment of cancer patients undergoing chemotherapy with vascular toxicity risk (reproduced, with permission from John Wiley & Sons publications, from Ref. 60).

Figure 3

Example of a case of accelerated peripheral arterial disease of a 32-year-old female without any cardiovascular history but Philadelphia chromosome-positive acute lymphoblastic leukemia. She underwent treatment with dasatinib and subsequently ponatinib, and computed tomography angiography of the abdomen right after treatment did not show any arterial disease (baseline). However, significant changes were noted 20 months later when she presented with critical left limb ischemia. Besides stenosis of the right external iliac artery, near occlusion of the left external iliac artery is noticeable. In fact, diffuse peripheral arterial disease was present. A confounding factor the patient developed acute graft-versus-host-disease but subsequent positron emission tomography imaging remained negative for vasculitis and the interventional report was consistent with atherosclerosis.

Figure 4

Illustration of the risk of cardiovascular events with nilotinib (panel A, according to reference 135) and ponatinib (panel B, based on information provided in the Iclusig REMS (Risk Evaluation and Mitigation Strategy) data sheet at http://www.iclusigrems.com).

Figure 5

Illustration of the pericyte structure within the capillary microcirculation of the heart.

Figure 6

Schematic presentation of pericyte-endothelial-myocardial interaction. AC = adenylate cyclase, Ang-1 = angiopoietin 1, IP = prostacycline receptor, M2 = muscarinic receptor, NO = nitric oxide, NOS = NO synthase, NRG-1 = neuregulin-1, sGC = soluble guanyl cyclase, PDGR = platelet-derived growth factor, PDGRR = PDGR receptor, VEGF = vascular endothelial growth factor, VEGFR = VEGF receptor.