Vascular Toxicity in Cardio-Oncology: The Intersection of Cardiac and Cancer Care Widens

Much of the research focus of cardio-oncology has gravitated towards chemoradiation therapies and their association with cardiomyopathy, with well-known culprits such as anthracycline and targeted therapies such as anti-HER2 agents (trastuzumab). However, as Campia and colleagues have demonstrated in their essential AHA Scientific Statement¹, there are other vasculotoxic effects in both traditional and newer cancer treatments that have been relatively underappreciated. Recognizing the significant impact on short and long term cardiovascular morbidity and mortality, this review of known vasculotoxic effects of cancer therapies warrants much attention and further study in light of a growing cancer patient and survivor population. While many agents have historically been known to cause cardiovascular toxicity, (ie, the acute vasospastic presentation related to fluoropyrimidine administration, or the thrombotic complications associated with platinum based therapies), the mechanisms of the collateral damage caused to the cardiovascular system continue to be somewhat elusive, and poorly quantified. In addition, the authors describe potential consequences of cancer-related and treatment-related metabolic abnormalities including increased long-term atherosclerotic vascular risk and development of other disease states, such as diabetes mellitus.

One important core objective of cardio-oncology has been to investigate and understand the physiologic cross talk of oncologic treatments, and how their adverse effects may yield insights into the pathophysiology of traditional forms of cardiovascular disease. There are already hints of overlap in inflammatory mechanisms that could promote both cardiovascular disease and cancer. For instance, the Canakinumab Antiinflammatory Thrombosis Outcomes Study, which studied the effects of interleukin-1β in reducing cardiovascular events, also made a striking observation that its use was associated with a lower incidence of lung cancer and related mortality^2,3. Discoveries of overlap in pathophysiology between cardiovascular and oncologic disease states can open both fields to development of therapeutics with novel mechanisms of action.

This document is a comprehensive survey of the relatively limited data of vascular sequelae across the spectrum of anticancer treatments, ranging from chemotherapeutic and radiation therapy to more modern targeted therapies. More importantly, it highlights that there is still much we do not understand about the mechanisms of vascular toxicity. These gaps in knowledge will only continue to grow given the rapid proliferation of cancer agents that is outrunning our ability to study their cardiovascular effects, and it is imperative that clinical and research cardio-oncology infrastructure be established to keep up with an increasing influx of potentially cardiotoxic treatments. Although the growth and interest in the multidisciplinary field of cardio-oncology continues to gain momentum on an international scale, it pales in comparison to the whirlwind speed of cancer drug development, particularly with immunotherapy. An estimated 63 cancer drugs launched within the past 5 years, and global spending on cancer medication increased from $96 billion in 2013 to $133 billion globally in 2017⁴. As of 2017, it was estimated that there were more than 240 immunooncology medicines and vaccines in development⁵.

While there are expert consensus statements from various Societies regarding optimal surveillance strategies for long-term vascular toxicity^6,7, there is limited data in the literature and these remain largely expert opinions. From a clinical standpoint, numerous questions remain unanswered about when, and how often, patients undergoing chemoradiation and/or targeted therapies should be screened for vascular toxicity, and when aggressive therapy (such as antiplatelet, statin, antihypertensive agents, revascularization) should be initiated, regardless of traditional atherosclerotic vascular risk factors. Such questions should be the focus of efforts in assembling wide scale registries, risk stratification models, strategies to optimize referrals in systems of care, and randomized control trials.

Acute cardiovascular toxicity can impede administration of potentially life-saving and life-prolonging cancer therapies. A prominent example is the acute hypertensive effect that can occur with administration of tyrosine kinase inhibitors, which is sometimes seen with vascular endothelial growth factor signaling pathway (VEGF) inhibitors used in gastrointestinal and genitourinary malignancies⁸. While limited in data, there is evidence to suggest that a hypertensive response is a possible marker of antitumor response⁹ and aggressive hypertension treatment can enable continuation of the cancer therapy with significant benefit for the patient¹⁰. These observations could be the basis of the penultimate cardio-oncological clinical trial—a randomized clinical trial testing the of efficacy different antihypertensive agents in controlling the effects of VEGF inhibitors, in both controlling blood pressure during treatment and evaluating for signals in cancer and cardiovascular-related events and survival.

Another example is the rare, but highly fatal, fulminant myocarditis that has been described with immune checkpoint inhibitors¹¹. While immunotherapy is overwhelmingly a revolutionary advance in the war against cancer, awareness must be raised about adequate detection and recognition of these adverse effects due to their high mortality. There are on-going efforts to develop a multicenter registry to collect and quantify these events¹², but more work needs to be done. These are just a small fraction of toxicity scenarios that warrant extensive investigation into which patients are at risk, as well as potential cardioprotective strategies to prevent and treat these events, so that lifesaving cancer treatment can potentially continue.

Recognizing metabolic abnormalities related to cancer and chemoradiation therapy is critical due to the associated increase in cardiovascular burden in these patients. For example, bone marrow transplant survivors have increased rates of cardiovascular risk factors including diabetes mellitus and hyperlipidemia¹³. These potential metabolic consequences of cancer treatment can have tremendous implications for long-term cardiovascular events particularly in patients with long survivorships. It is crucial to recognize which therapies are likely to cause significant metabolic abnormalities so that we can screen high-risk patients and provide timely treatment.

The incredible advances made in cancer treatments in a relatively short period of time have resulted in disease stability and meaningful clinical response in many patients even with advanced cancer states. Analogously, oncologists are starting to treat and view cancer in the same vein as how cardiologists treat “incurable” disease states such as congestive heart failure, complex coronary artery disease: as a chronic disease state, albeit with more expensive pharmacology. As people live longer and cancer therapeutics improve, it is inevitable that increasing numbers of patients with live with coexistent cardiovascular and cancer disease. Engaging and collaborating with our oncology colleagues in identifying and screening for cardiovascular events with all cancer treatment agents is critical for optimal patient care and the advancement of the field.

Currently there are over 15.5 million Americans with a history of cancer, and this number is projected to reach more than 20 million by 2026¹⁴; if cancer drug development continues on its exponentially explosive trajectory and is successful in improving survival, this projection may prove to be an underestimate. However, the field of cardio-oncology must continuously work on the insurmountable task of bridging the translational gap between understanding mechanisms of cardiotoxicity and identifying those at risk of developing it, strengthening relationships across the aisle with hematology/oncology, defining and designing registries to quantify the effects of both old and the unending tidal wave of new therapies, and ultimately transforming the field from a reactionary science to a preventative science.

This document should serve as a glimpse into a realm of cardiovascular disease that is underappreciated by the cardiovascular community as a whole, but is more common than one would think. With the increasing number of cancer survivors amongst the general population, all cardiologists, not just cardio-oncologists, should take heed to this statement. It remains a long road towards understanding the spectrum of effects of cancer treatment, but it is also an exciting one, with the potential for much discovery and collaboration, and most importantly, the ability for us to improve the overall health and quality of life of the cancer patient.