Abstract
Background:
Survivors of childhood cancer have an increased risk of therapy-related cardiovascular disease (CVD). It is not known whether family history (FH) of CVD further increases risk of adverse cardiovascular outcomes among survivors.
Methods:
Family history of CVD was collected from 1,260 survivors (median age at diagnosis 8 years [range 0–23], age at last follow-up 35 years [18–66]) of childhood cancer in the St. Jude Lifetime Cohort Study. Multivariable risk models evaluated associations with CVD (CTCAE grade 2-4 events) and cardiovascular risk factors.
Results:
Among survivors exposed to chest-directed radiation and/or anthracycline chemotherapy (n=824): 7% reported a first-degree FH of heart failure (HF), 19% myocardial infarction (MI), 11% stroke, 26% atherosclerotic disease (MI and/or stroke), 62% hypertension, and 31% diabetes mellitus (DM). 18% of exposed survivors developed HF, 9% MI, 3% stroke, 11% atherosclerotic disease, 30% hypertension, and 9% DM. Having a first-degree FH of atherosclerotic disease was independently associated with development of treatment-related HF (RR 1.38, 95%CI 1.01-1.88, p=0.04) among exposed survivors. Risk for hypertension was increased among exposed survivors with a first-degree FH of hypertension (RR 1.55, 95%CI 1.26-1.92, p<0.0001) or of any cardiovascular disease (MI, stroke, or HF [RR 1.30, 95%CI 1.06-1.59, p=0.01]).
Conclusion:
Family history of CVD and cardiovascular risk factors independently increased risk of HF and hypertension among survivors of childhood cancer exposed to cardiotoxic therapies. Impact: These data show the importance of cardiovascular FH as a risk factor for cardiovascular disease in survivors of childhood cancer.
Introduction
Children diagnosed with a malignancy have 5-year survival rates greater than 83% as a result of therapeutic advances1. However, survivors have well-documented treatment-related late effects2,3. Cardiovascular disease is one of the most frequent causes of non-cancer morbidity and mortality4-10. Compared to the general population, survivors have higher rates of: 1) cardiovascular disease—specifically, myocardial infarction, stroke and heart failure; and, 2) cardiovascular risk factors—including, hypertension, obesity, diabetes mellitus and dyslipidemia5,7,9,11,12. Previous work identified that survivors were seven times more likely than the US population to die from cardiovascular-related events5. Known risk factors for the development of cardiovascular disease in survivors of childhood cancer include cumulative dose of anthracycline chemotherapy and chest-directed radiotherapy (RT), young age at anthracycline exposure, female sex, and black race5-8,13. More recently, attention has been given to the management of cardiovascular risk factors in the survivor population, as hypertension, diabetes, and obesity have been shown to potentiate risk of cardiovascular events among survivors9,14,15.
In the general population, Hunt and colleagues first described cardiovascular family history as a risk factor for cardiovascular disease in a large cohort study of > 90,000 Utah school children and their families. The importance of cardiovascular family history has since been replicated in other large series, such as the Newcastle Family History Study and the Framingham Offspring Study16-18. While much attention has been given to the significant cardiovascular risk conferred by a family history of early or premature cardiovascular disease, more recent studies show similar risk contribution from the presence of any first-degree family history of cardiovascular disease19,20. The occurrence of hypertension and diabetes in the general population can be similarly predicted by a family history of these conditions21,22. However, the independent contribution of cardiovascular family history towards the development of cardiovascular disease or traditional cardiovascular risk factors among survivors of childhood cancer is not known. It might have been predicted that in patients exposed to cardiotoxic therapies, the exposure would be so overwhelming that family history may not contribute to outcomes. Therefore, it is important to examine family history’s contribution to cardiovascular risk in both survivors who have been exposed to cardiotoxic therapy as well as those who have not.
Efforts to mitigate modifiable risk factors for cardiovascular disease in the survivor population may be improved with the addition of knowledge of cardiovascular family history. Therefore, we utilized the St. Jude Lifetime Cohort Study (SJLIFE) to examine the contribution of family history of cardiovascular disease and cardiovascular risk factors to the development of these same conditions among survivors of childhood cancer exposed and unexposed to cardiotoxic therapies.
Methods
Participants
Eligible participants were identified from the SJLIFE cohort, designed to characterize health outcomes among survivors of childhood cancer as they age23. Survivors eligible for this study were ≥18 years of age at evaluation, treated for childhood cancer at St Jude Children’s Research Hospital (SJCRH) between 1962 and 2007, ≥10 years post-diagnosis, and without a history of congenital heart disease. Females were not pregnant and ≥ three months postpartum. Study documents, materials, and methods were approved by the institutional review board. Participants provided written, informed consent prior to participation.
Diagnosis, Treatment, Demographics
Cancer diagnosis and treatment information were abstracted from medical records including cumulative doses of specific chemotherapy agents and radiotherapy. Total anthracycline dose (mg/m2) was the sum of doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone in doxorubicin equivalent doses24, 25. Radiotherapy records were centrally reviewed for the receipt of chest RT. In this analysis, participants were grouped as being exposed or unexposed to cardiotoxic therapy (anthracycline chemotherapy and/or chest RT; Table 1).
Table 1.
Characteristics of childhood cancer survivors exposed and unexposed to anthracyclines and/or chest-directed radiotherapy
| Survivors Overall (n=1260) |
Exposed Survivors* (n=824) |
Unexposed Survivors† (n=436) |
Exposed vs. Unexposed |
||||
|---|---|---|---|---|---|---|---|
| Median | Range | Median | Range | Median | Range | p-value | |
| Age at diagnosis (years) | 8 | 0-23 | 10 | 0-23 | 7 | 0-22 | <0.001 |
| Age at evaluation (years) | 35 | 18-66 | 36 | 19-62 | 34 | 18-66 | 0.19 |
| Time since diagnosis (years) | 26 | 10-51 | 26 | 10-50 | 27 | 10-51 | 0.34 |
| N | % | N | % | N | % | ||
| Sex | 0.05 | ||||||
| Male | 644 | 51.1 | 438 | 53.2 | 206 | 47.3 | |
| Female | 616 | 48.9 | 386 | 46.8 | 230 | 52.8 | |
| Race/ethnicity | 0.33 | ||||||
| Non-Hispanic White | 1052 | 83.6 | 699 | 84.8 | 353 | 81.0 | |
| Non-Hispanic Black | 179 | 14.2 | 106 | 12.9 | 73 | 16.7 | |
| Hispanic | 11 | 0.9 | 8 | 1.0 | 3 | 0.7 | |
| Other | 18 | 1.4 | 11 | 1.3 | 7 | 1.6 | |
| Primary Cancer Diagnosis | <0.001 | ||||||
| Acute lymphoblastic leukemia | 261 | 20.7 | 153 | 18.6 | 108 | 24.8 | |
| Acute myeloid leukemia | 45 | 3.6 | 40 | 4.9 | 5 | 1.1 | |
| Other leukemia | 12 | 1.0 | 1 | 0.1 | 11 | 2.5 | |
| Hodgkin lymphoma | 254 | 20.2 | 238 | 28.9 | 16 | 3.7 | |
| Non-Hodgkin lymphoma | 63 | 5.0 | 54 | 6.6 | 9 | 2.1 | |
| CNS tumor | 178 | 14.1 | 64 | 7.7 | 114 | 26.1 | |
| Wilms tumor | 100 | 7.9 | 74 | 9.0 | 26 | 6.0 | |
| Retinoblastoma | 45 | 3.6 | 4 | 0.5 | 41 | 9.4 | |
| Soft tissue sarcoma | 64 | 5.1 | 35 | 4.2 | 29 | 6.7 | |
| Neuroblastoma | 61 | 4.8 | 42 | 5.1 | 19 | 4.4 | |
| Osteosarcoma | 63 | 5.0 | 58 | 7.0 | 5 | 1.1 | |
| Ewing sarcoma | 52 | 4.1 | 51 | 6.2 | 1 | 0.2 | |
| Other | 62 | 4.9 | 10 | 1.2 | 52 | 11.9 | |
| Chemotherapeutic Exposures | |||||||
| Alkylating agents | 747 | 59.3 | 607 | 73.7 | 140 | 32.1 | <0.001 |
| Glucocorticoids | 472 | 37.5 | 349 | 42.4 | 123 | 28.2 | <0.001 |
| Asparaginase | 240 | 19.1 | 140 | 17.0 | 100 | 22.9 | 0.01 |
| Bleomycin | 101 | 8.0 | 84 | 10.2 | 17 | 3.9 | <0.001 |
| Cisplatin | 120 | 9.5 | 93 | 11.3 | 27 | 6.2 | <0.01 |
| Carboplatin | 67 | 5.3 | 52 | 6.3 | 15 | 3.4 | 0.03 |
| Vincristine | 798 | 63.3 | 582 | 70.6 | 216 | 49.5 | <0.001 |
| High dose methotrexate | 217 | 17.2 | 152 | 18.5 | 65 | 14.9 | 0.11 |
| Methotrexate | 442 | 35.1 | 318 | 38.6 | 124 | 28.4 | <0.001 |
| Mercaptopurine | 312 | 24.8 | 196 | 23.8 | 116 | 26.6 | 0.27 |
| Surgery | |||||||
| Thoracotomy | 59 | 4.7 | 51 | 6.2 | 8 | 1.8 | <0.001 |
| Amputation | 73 | 5.8 | 64 | 7.8 | 9 | 2.1 | <0.001 |
| Nephrectomy | 116 | 9.2 | 87 | 10.6 | 29 | 6.7 | 0.02 |
| Cardiotoxic Treatment Agent | |||||||
| Anthracycline only | 379 | 30.1 | 379 | 46.0 | 0 | 0.0 | |
| Anthracycline + Chest RT | 260 | 20.6 | 260 | 31.6 | 0 | 0.0 | |
| Chest RT only | 185 | 14.7 | 185 | 22.5 | 0 | 0.0 | |
| Neither | 436 | 34.6 | 0 | 0.0 | 436 | 100.0 | |
| Cardiotoxic Treatment Dose | |||||||
| Chest RT (median / IQR), Gy | 2600 | 2000-3500 | 2600 | 2000-3500 | - | - | |
| Anthracycline Dose (median / range), mg/m2 | 203.2 | 26.1-734.2 | 203.2 | 26.1-734.2 | - | - | |
| 1-200 mg/m2 (N / %) | 296 | 23.5 | 296 | 35.9 | 0 | 0.0 | |
| 201-350 mg/m2 (N / %) | 195 | 15.5 | 195 | 23.7 | 0 | 0.0 | |
| >350 mg/m2 (N / %) | 148 | 11.8 | 148 | 18.0 | 0 | 0.0 | |
Survivors who were treated with chest radiation and/or anthracyclines
Survivors who were not treated with chest radiation or anthracyclines; mg=milligram, m2=square meter, SD=standard deviation, IQR=interquartile range, kg=kilograms, cm-centimeters, Gy=gray.
Family History
A provider-administered family history questionnaire evaluated the presence and age at onset of cardiovascular disease or cardiovascular risk factors among all first- and second-degree relatives of each participant. The cardiopulmonary FH questionnaire was based on the Multi-Ethnic Study of Atherosclerosis (MESA) Family History Form (Supplemental Table A1). MESA investigated the prevalence, correlates, and progression of subclinical cardiovascular disease. Family history elements included in the analysis were first- and second-degree family history of: cardiovascular disease (myocardial infraction, stroke, or heart failure), atherosclerotic disease (myocardial infraction or stroke), early atherosclerotic disease (myocardial infraction or stroke occurring before age 55 in men and before age 65 in women)24, and cardiovascular risk factors (limited to hypertension or diabetes). Family history of hyperlipidemia was not present in the MESA study or in the current assessment, given the poor reliability of self-reporting of this diagnosis. Each relative’s sex and age at last birthday or age at death was recorded.
Cardiovascular Outcomes
At baseline and subsequent follow-up evaluations, participants completed a multi-item questionnaire that included age at onset of cardiac events, as well as comprehensive clinical assessment, including echocardiography, to classify cardiovascular outcomes using a modified version of the National Cancer Institute’s (NCI’s) Common Terminology Criteria for Adverse Events (CTCAE, version 4.03), Supplemental Table A225,26. We included three cardiovascular disease outcomes (myocardial infarction [MI], stroke, and heart failure) and two cardiovascular risk factors. CTCAE events are graded 1-5: mild (grade 1), moderate (grade 2), severe (grade 3), life-threatening or disabling (grade 4), and fatal (grade 5). We included stroke outcomes grade 2 (moderate neurologic deficit), grade 3 (severe neurologic deficit), and grade 4 (life threatening consequences requiring urgent intervention). We included heart failure outcomes grade 2 (resting ejection fraction [EF] between 40-50% or 10-19% absolute drop from baseline; asymptomatic), grade 3 (resting EF between 20-39% or >20% absolute drop from baseline; medication initiated), and grade 4 (resting EF <20%; refractory heart failure requiring IV medication or surgical intervention). For MI we included outcomes grade 3 (abnormal cardiac enzymes with ECG evidence of infarction) and grade 4 (life-threatening MI with hemodynamic instability). We excluded grade 2 MI as it describes mildly abnormal cardiac enzymes without ECG evidence of ischemia, rather than MI. We included hypertension and diabetes grades 2-4.
Statistical Analyses
Descriptive statistics characterized the study population, and compared survivors exposed and not exposed to anthracyclines and/or chest-directed RT with t-tests or Chi-square statistics as appropriate. Logistic regression analyses, stratified by exposure to cardiotoxic treatment, were used to examine univariable associations between family history and cardiovascular outcomes. Multivariable risk models were created based upon statistically significant associations (p<0.05) identified from univariable analysis and were adjusted for sex, race/ethnicity, and current age, as well as an exposure variable combining anthracycline dose and chest radiation exposure among exposed survivors (1-199 mg/m2 anthracycline alone, 200-349 mg/m2 anthracycline alone, 350+ mg/m2 anthracycline alone, chest RT - no anthracycline, chest RT - any anthracycline). Receiver operating curve analysis was conducted to evaluate the area under the curve (AUC) defined by models including family history variables as added to models evaluating treatment exposure27. SAS version 9.4 (Cary, N.C.) was used for all analysis. Cumulative burden curves were constructed among individuals with and without family history of cardiovascular disease or cardiovascular risk factors, evaluating the development of cardiovascular disease or risk factor over time3.
Results
Among 1,369 eligible survivors, 67 declined participation, 24 completed a survey only (did not return for clinical evaluation of cardiac outcomes), and 18 were lost to follow-up, resulting in enrollment of 1,260 participants (Figure 1)28. Survivors exposed (N=824) and unexposed (N=436) to cardiotoxic therapy (anthracycline chemotherapy and/or chest-directed RT) did not differ by median age (range): 36 (19 – 62) vs 34 (18 – 66) years, p=0.19; sex: 53.2% vs 47.3% male, p=0.05; race/ethnicity: 84.8% vs. 81.0% non-Hispanic white, p=0.33; or time since diagnosis: p=0.34. Survivors exposed to cardiotoxic therapy were older at diagnosis (p<0.0001), and were more likely to be survivors of lymphoma or bone tumors than those who were not exposed (Table 1).
Figure 1:
CONSORT diagram describing the eligible and participating study population
Among survivors exposed to cardiotoxic therapy, 7% reported a first degree relative with heart failure, 19% MI, 11% stroke, 26% with any atherosclerotic disease (MI and/or stroke), 62% hypertension, and 31% diabetes (Table 2). The proportions of survivors with a family history of cardiovascular disease or cardiovascular risk factors were similar between the exposed and unexposed groups. A first- or second-degree relative with a history of cardiovascular disease (myocardial infarction, stroke, or heart failure) was present in 73.9% of survivors exposed to cardiotoxic therapies and 75.9% of unexposed participants. A first- or second-degree relative with a history of cardiovascular risk factors (diabetes or hypertension) was present in 86.3% of survivors exposed to cardiotoxic therapies and 88.5% of unexposed participants, Supplemental Tables A3-4.
Table 2.
Prevalence of family history of cardiovascular disease and cardiovascular risk factors among survivors, exposed and unexposed to cardiotoxic therapy
| Family History | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MI | Stroke | Heart Failure |
HTN | DM | Cardiovascular Disease (MI, stroke, or heart failure) |
Athero- sclerotic Disease (MI or Stroke) |
Early* Athero- sclerotic Disease |
Cardiovascular Risk Factors (Diabetes or HTN) |
Cardiovascular Disease and/or Cardiovascular Risk Factors |
||||
| Early* | Ever | Early* | Ever | ||||||||||
| Exposed (n=824) | Any 1st degree relative | 11.7 | 18.7 | 7.2 | 11.0 | 6.6 | 62.3 | 31.0 | 28.2 | 25.9 | 17.1 | 68.5 | 73.4 |
| Father | 6.9 | 14.1 | 2.1 | 5.1 | 3.4 | 37.7 | 15.8 | 18.3 | 17.5 | 8.6 | 43.8 | 50.6 | |
| Mother | 4.0 | 4.9 | 3.4 | 4.7 | 2.6 | 37.4 | 15.5 | 10.3 | 9.0 | 6.8 | 42.8 | 46.1 | |
| Sibling | 1.7 | 1.9 | 1.7 | 1.7 | 0.9 | 17.7 | 6.1 | 4.1 | 3.3 | 3.0 | 21.1 | 22.5 | |
| Child | 0 | 0.0 | 0.2 | 0.2 | 0.1 | 0.1 | 0.4 | 0.4 | 0.2 | 0.2 | 0.5 | 0.9 | |
| Any 2nd degree relative | 21.4 | 46.8 | 12.5 | 35.1 | 14.9 | 50.7 | 41.0 | 66.1 | 62.3 | 29.3 | 64.3 | 82.7 | |
| PGF | 8.4 | 21.8 | 2.1 | 8.5 | 2.9 | 14.7 | 9.8 | 29.1 | 27.7 | 9.8 | 20.3 | 39.2 | |
| PGM | 2.9 | 7.2 | 3.6 | 10.0 | 3.3 | 16.9 | 12.9 | 17.8 | 15.7 | 6.0 | 24.6 | 34.6 | |
| MGF | 7.4 | 21.4 | 3.3 | 9.1 | 4.4 | 19.2 | 11.8 | 30.3 | 27.8 | 9.5 | 26.2 | 43.7 | |
| MGM | 5.5 | 10.9 | 5.2 | 14.7 | 6.2 | 28.4 | 17.0 | 26.3 | 22.6 | 9.5 | 37.0 | 47.9 | |
| Any 1st or 2nd degree relative | 29.5 | 55.1 | 18.1 | 42.1 | 19.5 | 77.9 | 56.8 | 73.9 | 70.3 | 39.2 | 86.3 | 94.4 | |
|
Unexposed (n=436) |
Any 1st degree relative | 13.5 | 22.3 | 6.7 | 11.9 | 6.7 | 65.4 | 33.0 | 31.4 | 28.2 | 18.4 | 71.1 | 75.2 |
| Father | 9.4 | 17.2 | 1.6 | 4.8 | 3.4 | 41.3 | 16.3 | 22.0 | 20.2 | 10.6 | 47.9 | 54.6 | |
| Mother | 3.0 | 4.8 | 3.4 | 5.5 | 3.2 | 38.1 | 16.5 | 10.6 | 8.9 | 6.2 | 42.0 | 45.0 | |
| Sibling | 2.1 | 3.0 | 1.8 | 2.1 | 0.7 | 19.3 | 7.1 | 5.5 | 4.8 | 3.7 | 22.7 | 25.4 | |
| Child | 0 | 0.0 | 0.2 | 0.2 | 0 | 0.5 | 0.2 | 0.2 | 0.2 | 0.2 | 0.7 | 0.9 | |
| Any 2nd degree relative | 21.3 | 46.1 | 16.3 | 34.9 | 15.1 | 48.6 | 42.4 | 66.3 | 62.4 | 31.7 | 63.5 | 81.9 | |
| PGF | 7.6 | 18.4 | 3.7 | 7.3 | 2.8 | 14.9 | 8.5 | 25.0 | 23.6 | 10.1 | 19.3 | 33.7 | |
| PGM | 2.3 | 6.4 | 3.7 | 9.2 | 3.7 | 18.4 | 12.8 | 17.0 | 14.0 | 5.7 | 26.4 | 35.1 | |
| MGF | 7.6 | 20.2 | 3.9 | 11.5 | 4.6 | 17.4 | 13.3 | 30.1 | 29.4 | 11.0 | 25.0 | 42.9 | |
| MGM | 6.2 | 11.0 | 5.1 | 12.2 | 5.5 | 23.4 | 17.2 | 25.2 | 21.3 | 10.6 | 33.3 | 45.4 | |
| Any 1st or 2nd degree relative | 31.0 | 57.6 | 21.3 | 42.7 | 20.4 | 80.1 | 58.7 | 75.9 | 72.3 | 43.4 | 88.5 | 94.3 | |
defined as MI or stroke occurring before age 55 in men and before age 65 in women
At last follow-up, 18% of exposed survivors had developed heart failure, 9% MI, 3% stroke, 11% any atherosclerotic disease (MI and/or stroke), 30% hypertension, and 9% diabetes. All cardiovascular outcomes were developed greater than two years from cancer diagnosis. Upon univariable analysis, the development of heart failure among participants who were exposed to cardiotoxic therapy was associated with first-degree family history of cardiovascular disease (RR=1.5, 95%CI 1.1-2.0), atherosclerotic disease (RR=1.5, 95%CI 1.1-2.0), early atherosclerotic disease (RR=1.4, 95%CI 1.0-1.9), any cardiovascular risk factor (RR=1.5, 95%CI 1.1-2.1), or first-degree family history of cardiovascular disease or cardiovascular risk factors (RR=1.6, 95%CI 1.1-2.3; Table 3). There was no association between family history of heart failure and development of heart failure in survivors. Furthermore, first-degree family history of any cardiovascular disease or cardiovascular risk factors was associated with an increased risk for hypertension and diabetes in exposed survivors. While few survivors unexposed to cardiotoxic therapies developed heart failure (n=15, 3%), MI (n=14, 3%), stroke (n=15, 3%), any atherosclerotic disease (n=30, 7%), hypertension (n=140, 32%), or diabetes (n=43, 10%), unexposed survivors with a first degree relative with heart failure (RR 9.4, 95%CI 3.6-24.5) and with a first degree relative with cardiovascular disease (RR 3.3, 95%CI 1.2-9.0) were at increased risk for heart failure. Among survivors not exposed to cardiotoxic therapy, hypertension was predicted by family history of hypertension (RR=1.6, 95%CI 1.1-2.2), and diabetes was predicted by family history of diabetes (RR=2.6, 95%CI 1.5-4.5). No differential effect based on high- or low-dose cardiotoxic exposure was observed for development of heart failure or atherosclerotic disease, Supplemental Tables A5-A8.
Table 3:
Univariable associations of 1st degree family history of cardiovascular disease with cardiovascular outcomes among survivors exposed and unexposed to cardiotoxic therapy
| Cardiovascular Outcomes | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Cardiovascular Disease | Cardiovascular Risk Factors | ||||||||||
| Atherosclerotic Disease (AD) | |||||||||||
| MI (N=73) | Stroke (N=24) | Heart Failure (N=145) | HTN (N=249) | Diabetes (N=75) | |||||||
| First Degree Family History among Survivors Exposed to Cardio- toxic Therapy (n=824) |
N | RR (95% CI) | N | RR (95% CI) | N | RR (95% CI) | N | RR (95% CI) | N | RR (95% CI) | |
| 1st⁰ FH of identical outcome | 12 | 0.9 (0.5-1.5) | 4 | 1.6 (0.6-4.6) | 9 | 0.9 (0.5-1.7) | 194 | 2.1 (1.6-2.8) | 35 | 2.0 (1.3-3.0) | |
| No FH | 61 | 1.0 | 20 | 1.0 | 136 | 1.0 | 55 | 1.0 | 40 | 1.0 | |
| 1st⁰ FH of CVD | 25 | 1.3 (0.8-2.1) | 8 | 1.3 (0.6-2.9) | 54 | 1.5 (1.1-2.0) | 105 | 1.9 (1.5-2.3) | 34 | 2.1 (1.4-3.2) | |
| No FH | 48 | 1.0 | 16 | 1.0 | 91 | 1.0 | 144 | 1 | 41 | 1.0 | |
| Early* 1st⁰ FH of AD | 16 | 1.4 (0.8-2.3) | 6 | 1.6 (0.7-4.0) | 32 | 1.4 (1.0-1.9) | 66 | 1.7 (1.4-2.2) | 21 | 1.9 (1.2-3.0) | |
| No FH | 57 | 1.0 | 18 | 1.0 | 113 | 1.0 | 183 | 1 | 54 | 1.0 | |
| 1st⁰ FH of AD | 24 | 1.4 (0.9-2.2) | 6 | 1.0 (0.4-2.4) | 50 | 1.5 (1.1-2.0) | 96 | 1.8 (1.5-2.2) | 30 | 1.9 (1.2-3.0) | |
| No FH | 49 | 1.0 | 18 | 1.0 | 95 | 1.0 | 153 | 1 | 45 | 1 | |
| 1st⁰ FH of CVRF | 55 | 1.4 (0.8-2.3) | 13 | 0.5 (0.2-1.2) | 111 | 1.5 (1.1-2.1) | 205 | 2.1 (1.6-2.9) | 59 | 1.7 (1.0-2.9) | |
| No FH | 18 | 1 | 11 | 1.0 | 34 | 1.0 | 44 | 1 | 16 | 1.0 | |
| 1st⁰ FH of CVD or CVRF | 59 | 1.5 (0.9-2.7) | 14 | 0.5 (0.2-1.1) | 118 | 1.6 (1.1-2.3) | 217 | 2.5 (1.8-3.4) | 64 | 2.1 (1.1-3.9) | |
| No FH | 14 | 1.0 | 10 | 1.0 | 27 | 1.0 | 32 | 1 | 11 | 1.0 | |
| First Degree Family History Among Survivors Unexposed to Cardio toxic Therapy (n=436) |
MI (N=14) | Stroke (N=15) | Heart Failure (N=15) | HTN (N=140) | Diabetes (N=43) | ||||||
| N | RR (95% CI) | N | RR (95% CI) | N | RR (95% CI) | N | RR (95% CI) | N | RR (95% CI) | ||
| 1st⁰ FH of identical outcome | 6 | 2.6 (0.9-7.4) | 1 | 0.5 (0.1-3.9) | 6 | 9.4 (3.6-24.5) | 105 | 1.6 (1.1-2.2) | 24 | 2.6 (1.5-4.5) | |
| No FH | 8 | 1.0 | 14 | 1.0 | 9 | 1.0 | 35 | 1.0 | 19 | 1.0 | |
| 1st⁰ FH of CVD | 7 | 2.2 (0.8-6.1) | 4 | 0.8 (0.3-2.4) | 9 | 3.3 (1.2-9.0) | 58 | 1.5 (1.2-2.0) | 17 | 1.4 (0.8-2.5) | |
| No FH | 7 | 1.0 | 11 | 1.0 | 6 | 1.0 | 82 | 1.0 | 26 | 1.0 | |
| Early* 1st⁰ FH of AD | 5 | 2.5 (0.9-7.2) | 2 | 0.7 (0.2-3.0) | 5 | 2.2 (0.8-6.3) | 35 | 1.5 (1.1-2.0) | 13 | 1.9 (1.1-3.5) | |
| No FH | 9 | 1.0 | 13 | 1.0 | 10 | 1.0 | 105 | 1.0 | 30 | 1.0 | |
| 1st⁰ FH of AD | 6 | 1.9 (0.7-5.4) | 4 | 0.9 (0.3-2.9) | 7 | 2.2 (0.8-6.0) | 53 | 1.6 (1.2-2.0) | 16 | 1.5 (0.8-2.7) | |
| No FH | 8 | 1.0 | 11 | 1.0 | 8 | 1.0 | 87 | 1.0 | 27 | 1.0 | |
| 1st⁰ FH of CVRF | 12 | 2.4 (0.6-10.7) | 11 | 1.1 (0.4-3.4) | 13 | 2.6 (0.6-11.5) | 109 | 1.4 (1.0-2.0) | 35 | 1.8 (0.8-3.7) | |
| No FH | 2 | 1.0 | 4 | 1.0 | 2 | 1.0 | 31 | 1.0 | 8 | 1.0 | |
| 1st⁰ FH of CVD or CVRF | 13 | 4.3 (0.6-32.3) | 11 | 0.9 (0.3-2.8) | 13 | 2.1 (0.5-9.3) | 117 | 1.7 (1.1-2.5) | 36 | 1.7 (0.8-3.7) | |
| No FH | 1 | 1.0 | 4 | 1.0 | 2 | 1.0 | 23 | 1.0 | 7 | 1.0 | |
CVD, cardiovascular disease; CVRF, cardiovascular risk factors; AD, atherosclerotic disease; MI, myocardial infarction; HF, heart failure; HTN, hypertension; FH, family history.
defined as MI or stroke occurring before age 55 in men and before age 65 in women
Multivariable analysis among patients exposed to cardiotoxic therapies, adjusting for sex, race/ethnicity, age at evaluation, and treatment, demonstrated that a family history of atherosclerotic disease in a first-degree relative was independently associated with an increased risk for treatment-related heart failure (RR 1.38, 95%CI 1.01-1.88; p=0.04; Table 4, Supplemental Table A9). Other family history elements showed a similar association with heart failure but did not achieve statistical significance. Having a first degree relative with hypertension (RR 1.55, 95%CI 1.26-1.92, p<0.0001), cardiovascular disease (RR 1.30, 95%CI 1.06-1.59, p=0.0103), cardiovascular risk factors (RR 1.58, 95%CI 1.24-2.01, p=0.0002), and cardiovascular disease or cardiovascular risk factors (RR 1.71, 95%CI 1.27-2.28, p=0.0003) increased risk for hypertension (Table 5). Among survivors not exposed to cardiotoxic treatments, family history was not associated with the development of heart failure, or hypertension in multivariable analyses (Supplemental Tables A10-A11). Among exposed and unexposed survivors, a family history of diabetes and other cardiovascular diseases/risk factors in first degree relatives was associated with the development of diabetes (Supplemental Tables A12-A13).
Table 4:
Multivariable risk association of first-degree family history with development of treatment-related heart failure among patients exposed to cardiotoxic therapy*
| N | RR | 95% CI | P value | |
|---|---|---|---|---|
| 1st⁰ FH of CVD | 54 | 1.27 | 0.93-1.74 | 0.13 |
| No FH of CVD | 91 | 1.00 | ||
| Early† 1st⁰ FH of AD | 32 | 1.23 | 0.88-1.73 | 0.23 |
| No FH of AD | 113 | 1.00 | ||
| 1st⁰ FH AD | 50 | 1.38 | 1.01-1.88 | 0.04 |
| No FH of AD | 95 | 1.00 | ||
| 1st⁰ FH of CVRF | 111 | 1.38 | 0.97-1.97 | 0.07 |
| No FH of CVRF | 34 | 1.00 | ||
| 1st⁰ FH of CVD or CVRF | 118 | 1.40 | 0.95-2.07 | 0.08 |
| No FH of CVD or CVRF | 27 | 1.00 |
FH, family history; AD, atherosclerotic disease; CVD, cardiovascular disease; CVRF, cardiovascular risk factor
adjusted for sex, race/ethnicity, current age, anthracycline chemotherapy and chest-directed radiotherapy
early is defined as MI or stroke occurring before age 55 in men and before age 65 in women
Table 5:
Multivariable risk association of first-degree family history with development of treatment-related hypertension among patients exposed to cardiotoxic therapy*
| N | RR | 95% CI | P value | |
|---|---|---|---|---|
| 1st⁰ FH of Hypertension | 194 | 1.55 | 1.26-1.92 | <0.0001 |
| No FH of same outcome | 55 | 1.00 | ||
| 1st⁰ FH of CVD | 105 | 1.30 | 1.06-1.59 | 0.0103 |
| No FH of CVD | 144 | 1.00 | ||
| 1st⁰ FH of CVRF | 205 | 1.58 | 1.24-2.01 | 0.0002 |
| No FH of CVRF | 44 | 1.00 | ||
| 1st⁰ FH of CVD or CVRF | 217 | 1.71 | 1.27-2.28 | 0.0003 |
| No FH of CVD or CVRF | 32 | 1.00 |
FH, family history; CVD, cardiovascular disease; CVRF, cardiovascular risk factor
adjusted for sex, race/ethnicity, current age, combined variable of anthracycline dose and radiotherapy exposure
The cumulative burden of cardiovascular outcomes and risk factors was greater among those with a family history of cardiovascular disease or risk factor (0.97 [95%CI 0.88-1.06] vs. 0.59 [95%CI 0.48-0.71] at 45 years from diagnosis; 0.91 [95%CI 0.83-1.00] vs. 0.58 [95%CI 0.46-0.70] at attained age of 50 years; Figure 2). Receiver operating curve analysis for models of treatment-exposed individuals identified that addition of family history of hypertension improved AUC for prediction of hypertension. Adding remaining model elements did not improve AUC (Supplemental Table A14).
Figure 2:
Cumulative burden analysis by age (A) and by years from diagnosis (B) showed higher rates of developing cardiovascular disease or risk factor among those with a family history of cardiovascular disease or risk factor. Cardiovascular disease events included CTCAE grades 2-4 for stroke or heart failure and grades 3-4 myocardial infarction. Cardiovascular risk factor events included CTCAE grades 2-4 for hypertension and diabetes.
CVD, cardiovascular disease; CVRF, cardiovascular risk factors.
Discussion
Long term survivors of childhood cancer are at increased risk of cardiovascular disease and cardiac-specific mortality due to exposure to therapies with known cardiovascular effects (anthracycline chemotherapy and chest-directed RT)7,14,29,30. Our study demonstrated, in a population of survivors of childhood cancer exposed to cardiotoxic therapies, yet still relatively young for development of heart disease, that: 1) development of heart failure is independently associated with a history of atherosclerotic disease (myocardial infarction and stroke) in a first-degree relative; and, 2) development of hypertension is independently associated with a history of hypertension or cardiovascular disease in a first-degree relative. The results also suggest, though the number of cardiac events was low, that an association exists between family history of cardiovascular diseases/risk factors and the development of heart failure and hypertension among survivors not exposed to cardiotoxic therapies, mirroring the known hereditary patterns of cardiovascular risk in the general population. Thus, in this analysis, family history of cardiovascular diseases/risk factors was an independent predictor of cardiovascular outcomes in survivors both exposed and unexposed to cardiotoxic therapies. This is important because family history remains predictive of cardiovascular outcomes even among survivors exposed to highly cardiotoxic treatment, showing that the effect of family history is independent and not overwhelmed by the receipt of cardiotoxic therapies. By identifying that family history is an independent predictor of heart failure, even in the setting of exposure to cardiotoxic therapy, these findings highlight the importance of obtaining and updating the cardiac family history among survivors of childhood cancer at any age. With the additive knowledge of cardiovascular family history in the survivor population, more attention can be paid to the early diagnosis and treatment of cardiovascular conditions, such as hypertension and heart failure, in order to mitigate poor outcomes commonly observed.
It is important to know whether the prevalence of family history of cardiovascular disease among survivors of childhood cancer is similar to that of the general population. The Multi-Ethnic Study of Atherosclerosis (MESA) questionnaire was utilized in this study to determine family history of cardiovascular disease. As such, this sample’s prevalence of and risk relative to cardiovascular disease could be compared to those identified by previous studies from MESA data, which cites a 36% prevalence of cardiovascular disease family history and a 16% prevalence of early cardiovascular disease family history20. These prevalence values are similar to those found in our sample (exposed survivors having 28.2% family history and 17.1% early family history and unexposed survivors having 31.4% family history and 18.4% early family history), suggesting that the family history of survivors of childhood cancer are not unlike other populations.
Surveillance parameters for adult survivors of childhood cancer are outlined in the Children’s Oncology Group (COG) Long-Term Follow-up Guidelines31. Although these guidelines include recommendations for screening and follow-up assessment of cardiovascular disease and cardiovascular risk factors among recipients of cardiotoxic therapies9, no recommendations regarding the ascertainment of cardiovascular family history are provided. The conclusions defined by this study provide evidence for the importance of obtaining the history of myocardial infarction, stroke, heart failure, hypertension, and diabetes among first-degree relatives.
This is important given the known cardiovascular risk imparted by family history of cardiovascular disease and premature cardiovascular disease in the general population, resulting in the American Academy of Family Physicians and American Academy of Pediatrics recommending ascertainment of family history of cardiovascular disease events (coronary death, myocardial infarction, stroke, or hospitalized coronary insufficiency) among first- and second-degree relatives24,32,33. These recommendations are informed by the Framingham Offspring Study, which included two-generation family history data collected between 1948 and 2001 of >5,000 offspring of participants of the original Framingham Heart Study. Offspring participants with at least one parent with premature cardiovascular disease (onset age <55 years in father or <65 years in mother) were more than twice as likely to develop cardiovascular events24. Similar findings have been replicated in larger, more contemporary cohorts, including the Physicians’ Health Study and the Women’s Health Study, informing this definition of premature family history of cardiovascular disease as the gold-standard for cardiovascular disease family history assessment19. Further studies of cardiovascular family history, however, provide evidence that a simplified definition (any first-degree relative with coronary artery disease) may be similarly predictive of familial cardiovascular risk17,20. The complex care of the childhood cancer survivor includes multi-system surveillance for cancer recurrence and treatment-related chronic conditions and may neglect the complete ascertainment of familial cardiovascular disease risk. Given the cardiovascular disease risk attributed to the presence of cardiovascular disease in first degree relatives of this relatively young population, coupled with knowledge of the high risk for early onset of cardiovascular disease in the survivor population, childhood cancer survivors should have early and serial cardiovascular family history assessment7,34.
Consistent with the association of cardiovascular disease with a family history of cardiovascular disease in the general population, we identified that among survivors, cardiovascular risk factors, specifically, hypertension and diabetes, are strongly associated with family history of these diagnoses21,22,35. Further, in the general population, longitudinal studies have established bi-directional associations between the presence of cardiovascular disease and hypertension/diabetes within personal and family histories21,22,35. As previously described, COG guidelines include assessment of hypertension and diabetes among childhood cancer survivors, given the known associations between cardiotoxic therapies and these outcomes. Our results show associations of family history of both cardiovascular disease and cardiovascular risk factors with the development of hypertension and diabetes. The information provided by this study provides additional evidence regarding the importance of prevention and successful treatment of hypertension and diabetes, now more so in survivors with a family history of cardiovascular diseases.
The study’s strengths include direct assessment of cardiac outcomes in a large population of long-term survivors, and interviewer-directed family history assessment, with detailed records of cancer therapy and relatively long interval of longitudinal evaluation. The main limitation of this study, however, is the inability to validate survivor-reported family history information. Previous studies have evaluated the reliability of self-reported family history. An evaluation of the Framingham Offspring Study, for example, found high positive predictive values (>75%) for self-reported family history of hypertension and diabetes but poorer such values for family history of premature heart attack or stroke (28% and 43%, respectively)36. Given these limitations, future investigations should define the accuracy and predictive value of this family history data through medical record validation. Additionally, future studies can utilize genetic risk scoring data that have been collected within this sample to strengthen evaluation of familial-based cardiovascular risk in this population. Another potential limitation is that all participants were treated for their childhood cancer at a single institution. Though previous evaluation of SJLIFE patients has shown participants to have similar exposures to that of other children treated in North America during this time period, these results may not be generalizable to all survivors3,23,37. Additionally, the study had a limited number of individuals in the unexposed group (n=430), compared to the exposed group (n=824), which may have affected the ability to achieve appropriate statistical power among unexposed individuals. A predominance of non-Hispanic white race/ethnicity is a known limitation of the dataset. Given the known effects of race on cardiovascular outcomes, future survivor datasets should be powered to evaluate these differences.
In summary, among survivors who received anthracycline chemotherapy or chest-directed RT, a history of myocardial infarction and stroke in a first-degree relative were independently associated with the development of heart failure. Additionally, the development of hypertension among exposed survivors was predicted by a history of cardiovascular disease and cardiovascular risk factors in a first degree relative. The results also suggest an elevated risk of heart failure, hypertension, and diabetes in survivors with family a history of cardiovascular disease and cardiovascular risk factors and no exposure to cardiotoxic therapies, as would be expected in the general population. These findings underscore the importance of cardiovascular family history screening among survivors of childhood cancer, which can start upon diagnosis of a malignancy and continue through the long-term follow-up period. With more robust collection of cardiovascular family history data and cardiovascular genetic risk factors, those caring for the survivor population may be able to better identify and intervene upon cardiovascular disease, attenuating the cardiovascular morbidity and mortality known to this population.
Supplementary Material
References
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