Vascular disease during cancer therapy

Presentations

Three principal presentations of arterial vascular toxicities can be differentiated: acute vasospasm, acute thrombosis, and accelerated atherosclerosis ( Fig. 17.1 ). A summary of the pertinent aspects is provided in Chapter 8, Table 8.3 .

Acute vasospasm is one of the most classic presentations, as it emerged with one of the drugs first associated with vascular toxicities: 5-FU. Several reports have outlined chest pain episodes with ST segment elevation that resolve with vasodilator therapy. Alteration of coronary vasoreactivity, predisposing to coronary vasospasm has been shown in invasive provocation studies and relates mechanistically to changes in protein kinase C signaling and calcium handling in vascular smooth muscle cells (hypercontractility). Sympathetic innervation (catecholamines), molecular vasoconstrictors, and endothelial dysfunction play a contributing role. Severe complications that can evolve as a consequence of profound and prolonged coronary vasospasm include myocardial infarction, arrhythmias such as ventricular tachycardia and ventricular fibrillation to the point of sudden cardiac death, and cardiac dysfunction, even Takotsubo cardiomyopathy, with presentations of heart failure and even shock (“5-FU cardiotoxicity”). Other drugs that can induce coronary vasospasm include the oral prodrug of 5-FU capecitabine, paclitaxel, cisplatin, bleomycin, vascular endothelial growth factor (VEGF) inhibitors, such as sorafenib, and Bcr-Abl inhibitors, such as dasatinib.

Acute thrombosis is the second principal presentation of vascular toxicity in those with cancer. Almost intuitively these patients have been considered to be at a higher thrombotic risk relating to a procoagulant state. Indeed, evidence is emerging that supports a higher risk not only of venous but also of arterial thromboembolic events. The risk is seemingly highest just around the time of diagnosis and abates over two years, most profoundly within the first 12 months. The risk is highest with advanced (stage III and IV) cancers and those of the gastrointestinal tract and the lung, similar to venous thromboembolism. Intriguingly, for instance, gastric adenocarcinomas (especially undifferentiated and advanced stages) have been shown to express von Willebrand factor (vWF), thereby adding to platelet activation. Cancer cells can also express a number of other platelet agonists, such as adenosine diphosphate and thromboxane A2, and platelets can contribute to cancer growth and spread (“platelet-cancer loops”). One of the classic examples of a chemotherapeutic associated with thrombosis is cisplatin. vWF and circulating endothelial cells increase in patients undergoing cisplatin-based therapy, reflecting endothelial injury and apoptosis. ^, A number of agents, such as cisplatin, also suppress local (in-growth of surrounding endothelial cells) and remote (endothelial progenitor cells) regenerative capacity. This generates the unfortunate constellation of induction of endothelial injury and reduction of endothelial repair capacity. The fact that no underlying plaques and thus no potential for plaque rupture was noted in patients developing acute coronary thrombosis on cisplatin supports the view that erosions account for in situ thrombosis. These patients are also at risk for systemic thrombotic complications as thrombus burden can be high. Other drugs associated with acute thrombosis include mainly VEGF inhibitors.

Accelerated atherosclerosis in patients with cancer used to be thought of only in the context of radiation therapy. Radiation is a potent injurious stimulus that can induce and enhance the atherosclerotic disease process as outlined in Chapter 26 . A central element is injury to the endothelium (though radiation also injures the vascular smooth muscle layer of media and induces inflammation in the media). Drug therapies that have recently emerged to be potentially contributing to vascular disease include immune checkpoint inhibitors. These have been shown, at least experimentally, to reactivate giant cell arteritis, which is an adventitial inflammation that affects the entire arterial wall and can even lead to complete luminal obstruction. The most aggressive forms of arterial disease with any cancer therapeutics have been reported with nilotinib and ponatinib as progressive arterial occlusive disease with acute ischemic events of the peripheral lower extremity, the visceral, the cerebral, and the coronary circulation. Standard atherosclerotic cardiovascular disease risk prediction models support the view that these two drugs, indeed, accelerate atherosclerosis rather than leading to alternative forms of accelerated arterial disease such as vasculitis. ^, Endothelial injury is thought to be a key element underlying the pathophysiology of progressive arterial occlusive disease. ^, Both drugs inhibit the VEGF signaling pathway, as well as the Abl signaling pathway in endothelial cells, and it may be this combination that yields the detrimental momentum. Pan-VEGF receptor inhibition does lead to accelerated (but not necessarily unstable/vulnerable) atherosclerosis in a rodent model, but there have not been many clinical reports of events. Finally, patients undergoing cisplatin-based therapy may not only be vulnerable to acute thrombotic events and abnormal vascular reactivity but also to more accelerated atherosclerosis, especially if they underwent concomitant radiation therapy as seen in those with testicular patients.