The effects and long-term outlook of cancer therapies on cardiovascular structure and function in childhood cancer survivors

Cancer is the leading cause of death by disease among United States children and adolescents. Although cancer incidence among children and adolescents has remained relatively constant over the last few decades, enhanced technological innovation, diagnostic techniques, and improved treatment approaches have led to an improvement in overall survival rate for all cancers. Moreover, the increase in childhood cancer survivorship has resulted in a new area of concern among healthcare professionals. Childhood and adolescent cancer survivors are more likely to develop cardiovascular and metabolic diseases than have a reoccurrence of cancer. Therefore, healthcare professionals need to be aware of the long-term consequences of cancer treatments to ensure a cancer survivor is free of future disease for years to come. While the exact mechanisms by which these cancer treatments cause cardiovascular and metabolic dysfunction are largely unknown, vascular dysfunction and its modulation of cardiovascular disease (CVD) progression among childhood cancer survivors is an avenue of research that has gained increased attention. Current cancer regimens typically employ multi-modal treatments, which can include surgery, radiation therapy, and/or multi-agent chemotherapy. Certain chemotherapeutic agents have been implicated in both early onset cardiotoxicity and the late development of cardiac abnormalities. In particular, repetitive administration of anthracyclines, as well as cyclophosphamides, has been shown to have cardiotoxic effects. Indeed, abnormalities in left ventricular structure and function have been observed with cumulative doses of these agents, leading to cardiac-related diseases such as cardiomyopathy and congestive heart failure. Cancer patients who undergo irradiation of the head and neck have been found to have a higher risk of developing significant carotid stenosis and increased carotid intima-media thickness. In addition, cancer patients who undergo thoracic irradiation have been found to develop inflammation and fibrotic lesions within the heart, increasing the risk of CVD. Research from our laboratory in young adult survivors of childhood acute lymphoblastic leukemia has demonstrated that vascular function is reduced some 25 years after these individuals had undergone chemotherapy. Additional studies in children who survived central nervous system tumors, solid tumors or leukemia, demonstrated that individuals who received chemotherapy had reductions in brachial artery function. In addition, leukemia survivors who received chemotherapy also had reduced carotid compliance and distensibility compared to healthy controls. Time since diagnosis was found to have no effect on endothelial dysfunction, suggesting the declines in vascular structure and function may be present early on in survivorship. Thus, monitoring cardiovascular risk factors in childhood cancer survivors of all ages is critical to ensuring long-term survival. In the following chapter we will discuss the burdens of childhood cancer survivorship and the consequences of different treatment therapies on the incidence of CVD. In addition, this chapter will explore potential monitoring methods and the need for consistent cardiovascular monitoring of childhood cancer survivors regarding their cardiovascular health.