The primary focus of this study was to determine the risk of development of CVRFs and CVRFC after exposure to various cancer therapeutic modalities. Radiation therapy as opposed to chemotherapy was more strongly associated with the development of CVRFs, even after adjusting for other treatment exposures and demographic/lifestyle factors. In particular, exposure of large amounts of the torso to radiation, as in TBI and abdominal plus chest radiation, was strongly associated with many of the subsequent self-reported CVRFs and CVRFC. This may be due to radiation effects on either individual organs or the combined effects on multiple chest and abdominal organs.
In regards to chemotherapeutic exposures, moderate doses of anthracyclines were independently associated with hypertension, even after adjusting for other treatment exposures and demographic/lifestyle factors. In analysis of demographic and lifestyle factors adjusted for treatment exposures, a striking progressive increase in prevalence of each CVRF and CVRFC was noted with older attained age at time of completing the questionnaire. Self-reported sedentary lifestyle remained associated with most CVRFs and CVRFC, independent of other demographic and treatment factors. These findings suggest that, although factors known to be associated with CVRFs in the general population (i.e. age, sedentary lifestyle) remain important in cancer survivors, risk of developing CVRF/CVRFC is also increased by selected prior therapeutic exposures. However, because many primary care clinicians do not know the specific cancer treatment modalities their patients received, CVRF and CVRFC was reported by cancer diagnoses and compared to siblings. The associations of cancer diagnoses with CVRFs were not independent findings. Rather, these associations were likely dictated by the key cancer treatment exposures and underlying demographic data, such as older age at follow-up.
In the general U.S. population, the prevalence of obesity and other adverse cardiovascular traits that make up the metabolic syndrome have increased dramatically among both adults and children in recent years (26
). Development of any of these traits during childhood or adolescence tracks into adulthood (28
), and the presence of such traits increases the risk of future cardiovascular morbidity. A search of the literature (MEDLINE search terms “cancer survivor/survivorship”, “metabolic syndrome”, and/or “cardiovascular risk”, English-language through December 2008; and selected bibliographies) identifies a variety of reports featuring both national survey data (31
)as well as single institutional studies (32
)including those that recruited a subset of CCSS participants (8
). These studies suggest that cancer survivors may be at particularly increased risk of developing components of the metabolic syndrome, though not all demonstrated an increased risk of meeting the criteria for a diagnosis of MetS. Similarly, our study did not show an overall significantly increased risk of our metabolic syndrome surrogate (i.e. CVRFC), although most survivor groups were at increased risk of one or more component traits compared with siblings. However, given the heterogeneity of childhood cancer cohorts, one advantage of our study compared with prior reports is our much larger sample size, which allowed more meaningful stratification by treatment, and demographic characteristics. The underlying pathophysiology that predisposes towards development of CVRFs in the cancer survivor and the general population may be different. For example, obesity, considered by many to be the pathophysiologic driver of CV risk in the general population, was not more common overall in survivors compared with siblings, at least when determined using BMI. Other measures of central adiposity such as waist circumference and visceral fat content were not available to us, but have been noted to be increased in some, but not all, cancer survivor populations (8
). However, even in the absence of obesity, other exposures and outcomes unique to cancer survivors may predispose towards the development of CVRFs. Chest and abdominal radiation may lead to an increased risk of cardiac and renal dysfunction including hypertension, possibly secondary to direct vascular injury and fibrosis (36
). Growth hormone deficiency, often seen following cranial radiation and TBI, is associated with dyslipidemia, central adiposity, and altered carbohydrate metabolism (8
). Many of these metabolic changes are inter-related and complex. For example, the growth hormone deficient state has been associated with both increased and reduced insulin sensitivity (37
). Interpretation of the data can be difficult as obesity per se blunts the growth hormone response to provocative testing in otherwise normal individuals. These exposures, along with selected chemotherapy effects (e.g. acute pancreatitis following asparaginase; insulin resistance associated with chronic high-dose steroid therapy) may ultimately contribute to an increased risk of diabetes (39
). Other chemotherapy agents, such as anthracyclines, have long been associated with an increased risk of cardiac dysfunction (13
), although anthracyclines specifically have not previously been associated with hypertension. Some studies of adult cancer patients have reported an association between platinum agents and hypertension (41
), although this was not observed in our analysis.
This study has several methodological limitations. The first is the creation of a definition for MetS that paralleled other definitions but accommodates the data available in the CCSS cohort. We tried to remain true to the four basic categories of risk: obesity, hypertension, abnormal lipids and impaired glucose metabolism. MetS and its components are often under-recognized since these traits can be silent medical problems that require a visit to a physician, a physical exam and laboratory analysis to be diagnosed. Although 89% of survivors and siblings reported a healthcare visit in the two years preceding completing the questionnaire, we are unable to ascertain if blood pressure, lipid analysis and glucose metabolism tests were done at the time of the visit. Also our method of ascertainment required treatment for a CVRF and many survivors and siblings might have unrecognized or untreated CVRFs. There is potential bias in that survivors may have been more closely screened for CVRF and treated at a lower threshold because of their healthcare providers’ awareness of their risk for CV disease. Another limitation is the self-reported heights and weights used for the calculation of BMI. However, because height and weight values were self- reported by both the survivors and siblings in this analysis, the likelihood of differential measurement bias is reduced (42
). Self-reported medication histories obtained through questionnaires may be subject to misclassification and recall bias, but previous studies have demonstrated reasonable agreement between medication self-report and medical records or pharmacy records. Better recall accuracy has been associated with anti-hypertensive medications, statins and other chronic care medications compared with analgesics or antidepressants (43
). In addition questionnaires designed to ask about medications for a specific indication, such as the CCSS questionnaire, are more sensitive than those with open-ended questions (44
). Accuracy was improved through confirmation that self reported medications were correctly classified in the designated drug categories (e.g., medication for high blood pressure or hypertension, pills or insulin injection for diabetes and medication to lower cholesterol or triglycerides, as well as review of all medications listed under other prescribed drugs). However, the use of self report of medications as a proxy for disease is not standard and may result in underestimates and overestimates of the component traits of MetS.
Data on cardiovascular events were available from the baseline and first follow-up questionnaires. Realizing that the MetS components are often insidious diseases that can be present for months or years prior to diagnosis, there is likelihood that CVRFs ascertained in the Follow-Up 2003 questionnaire may have been present at the time of baseline and Follow-Up 2000 questionnaire. We analyzed the association of CVRFs ascertained at the Follow-Up 2003 questionnaire with the self report of cardiovascular events at earlier time points and found a significant association. At the time of this evaluation, the CCSS cohort is still a relatively young adult cohort. We anticipate that the frequency of CVRFs, CVRFC and CV events will increase with age. As the CCSS cohort ages, it will be important to continue to ascertain these outcomes to assess for stronger associations of demographic, lifestyle and treatment factors with CVRFs and clustering. It will also be important to ascertain the risk for subsequent development of CV events in survivors who a priori are identified to have CVRFC.
The presence of metabolic syndrome and its component parts are associated with significant morbidity and mortality from cardiovascular disease in the general population (48
). Many of the recognized risk factors for the development of CV disease: obesity, hypertension, dyslipidemia and physical inactivity are amenable to behavioral/lifestyle and pharmacologic interventions. Ongoing follow-up in this cohort will show if the prevalence and severity of chronic health conditions remains disproportionately high in cancer survivors compared to the general population. It is hoped that the results of this study will encourage clinicians to emphasize to pediatric cancer survivors the importance of maintaining regular healthcare. In light of the high prevalence of chronic health conditions including cardiac disease and associated increased rates of death, it behooves all healthcare providers to be proactive in the early recognition and treatment of CV risk factors in this population. (1