Racial Differences in 20-Year Cardiovascular Mortality Risk Among Childhood and Young Adult Cancer Survivors

Introduction

The incidence of childhood and adolescent/young adult (AYA) cancers has been increasing since 1975. ¹ Concurrently, as treatments have advanced, survival has improved, with 5-year relative survival rates at ∼80%.^2,3 Importantly, childhood and AYA survivors are at increased risk for competing causes of death, particularly cardiovascular disease (CVD) death, compared to the general population. For example, among 20,483 survivors in the U.S. Childhood Cancer Survivorship Study (CCSS) cohort, Armstrong et al. found a sevenfold higher risk of CVD death among survivors of childhood cancer compared to matched controls. ⁴ European studies have reported similar findings with risk of CVD death ranging from twofold to sixfold higher in comparison with the general population.^5–7 The risk for CVD does not diminish with time, with significantly increased risks among survivors demonstrated throughout the lifespan. ⁸

Data on risk of CVD mortality among childhood and AYA cancer survivors by cancer type are limited. In a CCSS study, the highest excess risks of CVD death compared to the general population were found in survivors of kidney tumors (Standardized Morality Ratio [SMR]: 12.7, CI: 6.3–22.8), Ewings sarcoma (SMR: 12.0, CI: 5.2–23.6), and Hodgkin lymphoma (SMR: 11.9, CI: 9.1–15.3). ⁴ In an analysis of risk of CVD death by AYA cancer type, Henson et al. found that survivors of Hodgkin lymphoma, acute myeloid leukemia, genitourinary cancers, non-Hodgkin lymphoma, lung cancer, and other leukemias had the greatest likelihood of CVD death compared to the general population (p < 0.0001 for all). ⁹

Multiple factors, including cardiotoxic treatments, health behaviors, and psychosocial status contribute to the increased risk of CVD mortality among survivors of childhood and AYA cancers. ¹⁰ Evidence suggests that several of these factors may differ by race,^11,12 though racial differences in CVD risk and mortality are not well studied in this population. Only one study, to our knowledge, has assessed risk of cause-specific mortality among Black and White survivors of childhood and AYA cancers, showing that Blacks had higher risks of all-cause and nonrecurrence/nonexternal-cause late mortality, compared to Whites. ¹³ However, no study has determined racial differences in risk of CVD mortality among survivors of childhood and AYA cancers and ascertained whether these differences vary across cancer type and time from diagnosis. This is important given the need to identify and follow subgroups of survivors at the highest risk of long-term effects. A recent position article from the CCSS highlighted the need for research to define and understand racial differences in morbidity among survivors of childhood cancer. ¹⁴ To this end, we utilized data reported to The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries from 1973 to 2011 to assess racial differences in risks of any death and CVD death by common cancer type among Black and White survivors of childhood and AYA (diagnosed before age 34) cancers at 5, 10, and 20 years postdiagnosis.

Methods

Cases were obtained using SEER*Stat software publically available from the National Cancer Institute. ¹⁵ Case data were obtained from the November 2013 SEER incidence database. ¹⁶ A total of 4,524,108 cases were identified, with diagnoses from 1973 to 2011 reported to SEER for the nine original SEER registry areas. Childhood and AYA cancers were categorized by primary cancer type defined according to ICD-0–3/WHO 2008 Adolescent and Young Adult classification (SEER AYA recode): Leukemias (01–04), Hodgkin Lymphoma (06), Non-Hodgkin Lymphoma (05), central nervous system (CNS) and Other Intracranial and Intraspinal Neoplasms—all behaviors (07–16), Germ Cell and Trophoblastic Neoplasms (26–28), Thyroid (31), Melanoma (29), Other (17–25, 30, 32–56), which included all other cancer types diagnosed in this population.

Cases were excluded if age at diagnosis was 35 years or greater (4,253,284 cases), the case was based solely on autopsy or death certificate data (733 cases), the case was not an individual's primary tumor (11,732 cases), the case was not ICCC classified or was in situ (89,214 cases), state death certificate or cause of death data were not available (2013 cases), or available follow-up time postdiagnosis was less than 1 month (2816 cases). After exclusions, 164,316 cases were included in the study, with analysis of racial differences limited to comparison between Black and White survivors.

Causes of death were obtained from the SEER registry. We defined CVD deaths as any of the following causes of death as coded in the SEER database (International Classification of Diseases, 10th Revision [ICD-10] codes): diseases of heart (I00–I09, I11, I13, I20–I51), cerebrovascular diseases (I60–I69), atherosclerosis (I70), and other diseases of arteries, arterioles, or capillaries (I72–I78).

Frequency counts and percentages for categorical variables, such as gender and cancer type were provided. Kaplan–Meier method and cumulative incidence curve using the competing risk model were applied for time-to-event analysis. Median time to event with 95% confidence interval (CI) was calculated. The log-rank test and Gray's test was used to evaluate the difference in time-to-event endpoints between patient groups for the usual survival analysis and the competing risk analysis, respectively.^17,18 Cox proportional hazards models were fitted to evaluate the effects of race on time-to-event outcomes. Statistical software SAS 9.3 (SAS, Cary, NC), S-Plus 8.2 (TIBCO Software, Inc., Palo Alto, CA) and R were used for all the analyses.

Results

Of the 164,316 cases included in the analysis, 133,932 were White, 16,060 were Black, 12,135 were of other races, and 2189 were of an unknown race. Table 1 shows the cases categorized by cancer type and race. There were 28,611 cases diagnosed at age 0–14 years and 135,705 cases diagnosed at age 15–34 years. The median follow-up times to all-cause death and CVD death were 15.1 and 10.3 years, respectively.

Table 2 shows racial differences in all-cause death. Black survivors had a higher risk of any cause death compared to White survivors (hazard ratio [HR]: 1.75, 95% CI: 1.70–1.79). This risk remained steady over time (5 years HR: 1.79, 95% CI: 1.73–1.84; 10 years HR: 1.76, 95% CI: 1.72–1.81; and 20 years HR: 1.76, 95% CI: 1.71–1.80). Compared to Whites, Black survivors of leukemias (HR: 1.46, 95% CI 1.35–1.58), Hodgkin Lymphoma (HR: 1.60, 95% CI: 1.43–1.78), Non-Hodgkin Lymphoma (HR: 1.32, 95% CI: 1.21–1.44), CNS (HR: 1.25, 95% CI: 1.14–1.36), and germ cell malignancies (HR: 1.57, 95% CI: 1.30–1.88) had a higher risk of death overall and at 5, 10, and 20 years postdiagnosis. A higher risk of all-cause death in Blacks compared to Whites was also found in survivors of thyroid cancer (HR: 1.98, 95% CI: 1.46–2.70), though differences were not observed at all time points studied.

Table 3 shows the risk of CVD death by race. Overall, Black survivors had a higher risk of CVD death compared to White survivors (HR: 2.13, 95% CI: 1.85–2.46), and this was sustained at 5 years (HR: 2.38, 95% CI 1.83–3.10), 10 years (HR: 2.59, 95% CI: 2.09–3.21), and 20 years (HR: 2.31, 95% CI: 1.95–2.74). Compared to Whites, Black survivors of Hodgkin lymphoma (HR: 1.55, 95% CI: 1.10–2.20), Non-Hodgkin lymphoma (HR: 1.71, 95% CI: 1.04–2.81), CNS malignancies (HR: 2.33, 95% CI: 1.37–3.94), thyroid malignancies (HR: 3.43, 95% CI: 1.75–6.73), and melanoma (HR: 8.16, 95% CI: 1.99–33.45) had a higher risk of CVD death. No racial differences in CVD risk were observed among leukemia and germ cell malignancy survivors. In addition, linear increase in CVD risk in Blacks compared to Whites was not observed over time.

Racial differences in risk of all-cause death stratified by age at diagnosis are shown in Tables 4 and 5. Table 4 shows racial differences in risk of all-cause death among those diagnosed at ages 0–14 years. There were racial differences overall (HR: 1.26, 95% CI: 1.18–1.35), with Black survivors of leukemias (HR: 1.61, 95% CI: 1.42–1.82), CNS cancers (HR: 1.41, 95% CI 1.25–1.60), and thyroid cancer (HR: 8.04, 95% CI: 2.41–26.79), at higher risks of all-cause death compared to White survivors in this age group. No racial differences were found in survivors of Hodgkin lymphoma, Non-Hodgkin lymphoma, germ cell cancers, or other cancers, and there were too few events to analyze among survivors of melanoma. Table 5 shows racial differences in risk of all-cause death among those diagnosed at ages 15–34 years. Racial differences were found overall (HR: 1.88, 95% CI: 1.83–1.93) and in each site-specific cancer assessed.

Table 6 shows racial differences in risk of CVD death among those diagnosed at ages 0–14 years. There were no racial differences in risk of CVD death in this age group, overall or by cancer type, with too few events for analysis among survivors of Hodgkin lymphoma, germ cell, thyroid, or melanoma malignancies. Table 7 shows racial differences in risk of CVD death among those diagnosed at ages 15–34. Overall, there was no statistical difference in risk of CVD death among survivors, however, differences were found among certain cancer types. Black survivors of leukemias (HR: 1.68, 95% CI: 1.19–2.39), Hodgkin lymphoma (HR: 1.74, 95% CI: 1.03–2.95), Non-Hodgkin lymphoma (HR: 3.00, 95% CI: 1.64–5.49), germ cell cancers (HR: 3.43, 95% CI: 1.75–6.74), thyroid malignancies (HR: 8.93, 95% CI: 2.18–36.60), melanoma (HR: 2.42, 95% CI: 1.98–2.96), and other cancers (HR: 2.36, 95% CI 2.04–2.72) had increased risks of CVD death compared to White survivors.

Discussion

In this study, Black survivors of childhood and AYA cancers were more likely to die of any cause compared to Whites; this racial difference was greatest at 20-years postdiagnosis. Black survivors were also more likely than White survivors to die of CVD, although this excess risk did not increase with time. When stratified by age at diagnosis, racial disparities in all-cause death were more pronounced and more widespread across cancer types among survivors diagnosed between ages 15 and 34 years, compared to survivors diagnosed between ages 0 and 14 years. When racial disparities in CVD death were stratified by age, no differences were seen among survivors diagnosed at ages 0–14 years, while disparities among survivors diagnosed at ages 15–34 years were similar to those found in the overall cohort. Compared to White survivors, Black survivors of melanoma, thyroid cancer, and CNS malignancies had the highest increased risk of CVD death, while there were no racial differences in risk of CVD death among survivors of leukemias or germ cell malignancies.

The increased risk of all-cause death in Blacks may be explained in part by racial disparities in treatment-related factors, socioeconomic status (SES), or follow-up care. Treatment completion impacts long-term survival, and Friedrich et al. found that low SES predicted treatment abandonment among childhood cancer patients. ¹⁹ Additionally, Black childhood and AYA acute lymphoblastic leukemia (ALL) patients are more likely to present with adverse prognostic features and less likely to receive recommended therapy. ²⁰ This may be secondary to a lower prevalence of health insurance coverage among Black young adults compared to Whites. ²¹ Lack of insurance also impacts the likelihood of childhood and AYA cancer survivors attendance in survivorship clinics, which affects identification and diagnosis of late effects.^22,23 Overall survival among childhood cancer survivors is also impacted by SES, with Acharya et al. finding a 21.7% difference in 5-year survival comparing White children with ALL living in the lowest poverty neighborhoods to Black children with ALL in the highest poverty neighborhoods. ²⁴

Racial disparities in behavioral risk factors may also contribute to differences in mortality. Specifically, obesity and lack of physical activity are associated with increased risks of overall mortality among cancer survivors.^25–28 Cox et al. found that male survivors of childhood cancer who did not exercise had a higher risk of death than survivors who exercised three or more times per week (odds ratio [OR]: 3.26, 95% CI: 1.90–5.61). ²⁹ In the childhood leukemia population, Orgel et al. found that increased body mass index (BMI) was associated with poorer overall survival, compared to a lower BMI (relative risk: 1.56, 95% CI: 1.32–1.86). ³⁰ Black survivors of childhood cancer have a higher prevalence of obesity than Whites, ³¹ and, in the pediatric ALL setting, Blacks are more likely than Whites to gain body mass throughout treatment. ¹¹ In reports from the CCSS, Black race predicted an inactive lifestyle and nonWhite race increased the risk of being insufficiently active.^32,33 Additionally, in a study that included childhood and AYA cancer survivors, Schootman et al. found that 19.5% of Black survivors met national recommended physical activity guidelines, compared to 29.5% of White survivors. ³⁴

Unique to this study, we found that Black survivors of childhood and AYA cancers had a higher risk of CVD mortality than Whites, with risks varying by cancer type and age at diagnosis. Black survivors of melanoma had the highest increased risk of CVD mortality compared to Whites. Similar to risk factors described above for all-cause death, disparities in behavioral risk factors and SES may contribute to racial differences in CVD mortality. Racial differences in psychosocial response and SES, both risk factors for CVD,^35–37 have been demonstrated among childhood and AYA survivors of thyroid cancer and those treated with CNS radiation.^38,39 Black AYA patients with Hodgkin's lymphoma are more likely to present with advanced stage disease compared to Whites, ⁴⁰ which may affect treatment length and cumulative dose of cardiotoxic radiation or chemotherapy regimens, potentially contributing to racial differences in CVD mortality among survivors. Nonwhite race has also been shown to predict low awareness of personal long-term risks among childhood cancer survivors, which impacts screening and treatment of competing risks such as CVD. ⁴¹ Additionally, White race has been associated with better rates of survivorship follow-up after childhood cancer. ⁴² Moreover, Caplin et al. found that areas with higher SES had higher rates of echocardiogram screening for CVD among childhood cancer survivors (OR: 1.12, 95% CI: 1.05–1.20). ⁴³

We observed no racial disparities in risk of CVD mortality among survivors of childhood and AYA leukemias. Prior investigations into racial differences, and late cardiovascular effects, have been primarily studied in the childhood leukemia population. This increased research focus may have helped to eliminate disparities in this group. Additionally, we observed no racial disparities in risk of CVD death among those diagnosed with cancer at ages 0–14 years. A Finnish study analyzing metabolic syndrome risk factors among survivors of childhood and AYA cancer found that, compared to siblings, survivors of AYA cancers were more likely to purchase lipid-lowering drugs (HR: 1.6, 95% CI: 1.04–2.5), but there were no differences between survivors of childhood cancer and their siblings. ⁴⁴ Another potential contributing factor to CVD mortality is adherence to cardiac late effects screening and early detection of CVD. Reppucci et al. found that 73.4% of survivors <18 years old adhered to echocardiogram screening guidelines compared to 57.3% of those aged 18 years and older (p = 0.0452). ⁴⁵ Taken together, these studies show that those diagnosed at a younger age may be less likely to develop CVD and more likely to identify it early, compared to patients diagnosed with cancer in adolescence or young adulthood, potentially mitigating racial disparities in this age group. Further research on the impact of age at diagnosis and cancer type on risk of CVD mortality is needed.

Risk-based screening guidelines from The Children's Oncology Group Late Effects Committee consider treatment, cancer type, medical conditions, and behavioral risk factors when determining frequency and type of cardiac surveillance.^46,47 Despite recommendations, not all at-risk survivors are being screened. A single institution study of children treated with anthracycline found that about 80% completed at least one echocardiogram following treatment. ⁴⁸ In addition to screening, long-term assessment of modifiable CVD risk factors and promotion of healthy behaviors, particularly physical activity, is needed among survivors of childhood and AYA cancer. Physical activity interventions in this population have been successful in inducing weight loss, increasing physical activity levels, increasing fitness, and improving metabolic risk factor profile,^49,50 though physical activity promotion is not widespread or standardized. Interestingly, there are racial differences in activity preference, with Saint Onge et al. finding that Blacks prefer team and fitness activities while Whites prefer facility-based exercise. ⁵¹ Additionally, Blacks are more likely than Whites to be ineligible for physical activity interventions due to lack of interest and no-shows. ⁵²

This study has several limitations and strengths. While the SEER registries are recognized as a definitive source of U.S. cancer data, information on specific chemotherapy and radiation regimens of cases is not available, therefore we could not determine whether therapy differences contributed to the racial differences in all-cause and CVD mortality. Additionally, there were small numbers of CVD deaths for certain types of cancer (i.e., melanoma) leading to significant, but wide, CIs that makes interpretation of results more difficult. A strength of this study is the large sample size, which permitted analysis of site-specific racial differences among childhood and AYA cancer survivors and thus broadened our understanding of competing risks of mortality in this population over a 20-year period.

In summary, Black survivors of childhood and AYA cancers have a heightened risk of all-cause and CVD mortality that varies by cancer type, compared to White survivors. Knowledge of at-risk populations is important to guide follow-up care, including surveillance recommendations and behavioral interventions. Given this data, a focus should be placed on strategies to mitigate risk factors common to both all-cause and CVD mortality. Cardioprotective drugs hold promise in protecting against both short and long-term effects of cardiotoxic treatment.^53–55 Furthermore, increasing amounts of physical activity may offset CVD risk. Among survivors of childhood Hodgkin lymphoma, Jones et al. found that vigorous exercise was associated with a lower risk of cardiovascular events over a median follow-up of 11.9 years, and that the association was independent of treatment and risk factor profile. ⁵⁶ Taken together, Black and White survivors of childhood and AYA cancers require greater access to preventative services and long-term survivorship monitoring.