Effects of cancer therapies on vascular structure and function in childhood cancer survivors

Cancer is the leading cause of death by disease among United States children 1 to 14 years of age. Although the incidence of children diagnosed with all forms of cancer has remained relatively constant over the last few decades, the survival rate has increased dramatically due to significant advances in treatment. Although free of cancer, these childhood cancer survivors are now at increased risk for a variety of chronic health problems including cardiovascular disease and related metabolic abnormalities. Current cancer therapies typically employ multi-modal treatments, which include surgery, radiation therapy, and/or multi-agent chemotherapy. Certain chemotherapeutic agents have been implicated in both early onset cardiotoxicity and late development of cardiac abnormalities. In addition, repetitive administration of anthracyclines, as well as cyclophosphamid-es, has been shown to have cardiotoxic effects. 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. To date, little research exists on the effects of chemotherapy on the peripheral vasculature. It has been hypothesized that dysfunction of the peripheral vascular endothelium may be the biomarker for the development of cardiovascular disease. Research from our laboratory in young adult survivors of childhood acute lymphoblastic leukemia have 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 distensiblity compared to healthy controls. Time since diagnosis had no effect on endothelial dysfunction, suggesting the declines in vascular structure and function are likely established early in the course of survivorship. Thus, monitoring cardiovascular risk factors in childhood cancer survivors of all ages in critical to ensuring long-term survival. The results of these studies demonstrate that early in life, childhood cancer survivors have arterial changes indicating increased risk for premature atherosclerosis and cardiovascular disease. Therefore, it is reasonable to advocate that efforts should be directed at monitoring and managing cardiovascular risk factors in childhood cancer survivors. In addition, future studies are needed to determine the exact mechanism by which chemotherapy causes endothelial dysfunction, as well as potential therapies aimed at reducing the decline in vascular function in cancer survivors. Cancer is the second most common cause of death in the United States, exceeded only by heart disease, and accounts for 23% of all annual deaths (U.S. Mortality Public Use Data Tape, 2003; Cancer Facts & Figures 2014). Approximately 50% of men and 33% of women will develop cancer during their lifetime (Ehrman et al., 2009), with cancer mortality being higher in men compared to women for every racial and ethnic group. In 2014, it is expected that there will be approximately 1,665,540 newly diagnosed cancer cases and 585,720 cancer deaths (roughly 1,600 people per day) in the United States alone. At this rate, cancer is set to become the leading cause of death in the United States within the next 25 years with an annual estimated economic burden of $205 million (Ehrman et al., 2009; Cancer Facts & Figures 2014). Although the rate of diagnosed cancer cases is growing, there is a silver lining. Enhanced technological innovation, diagnostic techniques, and improved treatment approaches over the past few decades have lead to an improved 5-year relative survival rate for all cancers diagnosed of 68% between 2003 and 2009, up from 49% survival rate reported during 1975-1977 (Cancer Facts & Figures 2014). This increase in cancer survivors, however, has resulted in a new area of concern among healthcare professionals. Specifically, childhood and adolescent cancer survivors are more likely to develop cardiovascular and metabolic diseases than have a reoccurrence of cancer (Mertens et al., 2001; Mertens, 2007). The consequences of cancer treatment, often referred to as late effects, are critical to be aware of and monitor to ensure a survivor is free of future disease for years to come. And while the exact mechanisms by which these 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. The following chapter will discuss the burdens of cancer survivorship and the consequences of different treatment therapies on the vasculature, specifically physiology and function as they relate to the vascular endothelium. Indeed, the vascular endothelium is an organ that not only acts as a barrier between the vessel wall and the bloodstream, but also more importantly contributes to the maintenance of vascular tone and homeostasis. Understanding the effect of cancer therapies on the endothelium is vital to accessing the damage these therapies have on vascular health. Additionally, therapeutic approaches to readily and cost-effectively evaluate vascular function and structure among childhood cancer survivors will also be discussed. These assessment techniques may help healthcare professionals? better monitor CVD progression and the presence of related abnormalities among this population of survivors. While the burdens of adult cancer are indeed evident, we will discuss the consequences of their treatment in limited context given the difficulty in assessing the independent therapeutic effects on subsequent health outcomes.