Vascular toxic effects of cancer therapies

Abstract

Cancer therapies can lead to a broad spectrum of cardiovascular complications. Among these, cardiotoxicities remain of prime concern, but vascular toxicities have emerged as the second most common group. The range of cancer therapies with a vascular toxicity profile and the clinical spectrum of vascular toxic effects are quite broad. Historically, venous thromboembolism has received the greatest attention but, over the past decade, the arterial toxic effects, which can present as acute vasospasm, acute thrombosis and accelerated atherosclerosis, of cancer therapies have gained greater recognition. This Review focuses on these types of cancer therapy-related arterial toxicity, including their mechanisms, and provides an update on venous thromboembolism and pulmonary hypertension associated with cancer therapies. Recommendations for the screening, treatment and prevention of vascular toxic effects of cancer therapies are outlined in the context of available evidence and society guidelines and consensus statements. The shift towards greater awareness of the vascular toxic effects of cancer therapies has further unveiled the urgent needs in this area in terms of defining best clinical practices. Well-designed and well-conducted clinical studies and registries are needed to more precisely define the incidence rates, risk factors, primary and secondary modes of prevention, and best treatment modalities for vascular toxicities related to cancer therapies. These efforts should be complemented by preclinical studies to outline the pathophysiological concepts that can be translated into the clinic and to identify drugs with vascular toxicity potential even before their widespread clinical use.

Fig. 1 |. Spectrum of vascular toxic effects of cancer therapies.

A number of cancer drugs (detailed in TABLES 1,2) can cause various vascular diseases, including coronary artery disease, myocardial infarction, stroke, systemic and pulmonary hypertension, vasospasm and thrombosis.

Fig. 2 |. Mechanisms of ischaemia in patients with cancer.

Ischaemia can be precipitated in patients with cancer by various mechanisms, leading to functional or structural alterations in the blood vessels. Increased vasoconstriction can be caused by vascular smooth muscle cell hyper-reactivity, which is classically seen with 5-fluorouracil therapy, and/or endothelial dysfunction, which can be provoked by various and sometimes concomitantly administered chemotherapeutics. Thrombotic occlusion, either partial or complete, can be caused by superficial erosion or by atherosclerotic plaque rupture. Erosion entails the loss of the endothelial monolayer, and multiple chemotherapeutics exert a cytotoxic effect on endothelial cells. This endothelial damage is often coupled with impairment of repair mechanisms, such as inhibition of the proliferation and migration of neighbouring endothelial cells or a reduction in the number of circulating endothelial progenitor cells (EPCs). Atherosclerotic plaque rupture is fostered by plaque inflammation, which also contributes to plaque development and growth and thereby to progressive luminal narrowing. Inflammation is stimulated by increased cytokine levels, for example, as a result of the expansion of some haematopoietic clones through a process called clonal haematopoiesis, or by disinhibition of immune checkpoints on inflammatory cells, mainly the programmed cell death 1–programmed cell death 1 ligand 1 (PD1–PDL1) axis, with immune checkpoint inhibitor therapy. BiTE, bispecific T cell engager; CAR, chimeric antigen receptor; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

Fig. 3 |. Risk of arterial thromboembolic events in patients with cancer.

Outline of the risk of arterial thromboembolic events relative to the time of cancer diagnosis in patients in the US Medicare system. A vulnerable and high-risk period of arterial thromboembolic events can be defined as illustrated, particularly for the cancer types listed. Baseline risk factors and long-term risk dynamics remain to be defined. The plot was generated using data from REFS^,. HR, hazard ratio; MI, myocardial infarction.

Fig. 4 |. Pathophysiological processes contributing to atherosclerosis in patients with cancer.

Somatic mutations can lead to alterations in the haematopoietic stem cell (HSC) clones in the bone marrow, such as mutations in TET2, which, through a process termed clonal haematopoiesis, ultimately leads to the generation of a macrophage pool with greater inflammatory activity. In addition, stress, via β₃-adrenergic receptor activation, leads to activation of HSCs and increased proliferation. These cells circulate in the blood and seed into the spleen, where they proliferate and continue to mature. The end effect is an increased infiltration of inflammatory cells into atherosclerotic plaques. Both of these processes — stress as well as somatic mutations and clonal haematopoiesis — can also contribute to and result in malignancies. Cancer therapies can affect the bone marrow, for example, leading to bone marrow suppression as well as mutations and derangements of bone marrow cells. ANS, autonomic nervous system; CVD cardiovascular disease.