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Page 2 of 12 Baker et al. J Cancer Metastasis Treat 2020;6:24 I http://dx.doi.org/10.20517/2394-4722.2020.36

dyslipidemia), more than one-fourth (26%, 16/61) of patients had three or more of these risk factors at baseline
visit, and 49% (30/61) had two or more.

Conclusion: The results of this pilot study support the presence of modifiable CAD risk factors in this population of
sarcoma survivors. Evidence-based guidelines for high-risk survivors of rare cancers are needed.

Keywords: Coronary artery disease, cardiovascular disease, sarcoma, anthracycline, cancer survivor

INTRODUCTION
In 1973, the Southwest Oncology Group (SWOG) reported a phase II trial of 472 patients accrued in
17 months that demonstrated the clinical efficacy of an exciting new cytotoxic chemotherapy, doxorubicin
[1]
in treating patients with advanced breast cancer, Hodgkin’s lymphoma, and multiple types of sarcomas .
[2]
SWOG further reported findings of cardiac toxicity manifested as irreversible heart failure . In a
subsequent follow-up publication, the impact of cumulative dose on long-term effects, most notably
[3]
cardiac toxicity, leading to dose-limiting treatment schedules was described . The first attempt to diminish
this cardiomyopathy was also reported by SWOG in a randomized clinical trial reporting the benefit and
[4]
toxicity of doxorubicin administered as a bolus injection vs a continuous infusion over 96 h . The infusion
schedule was associated with less toxicity. The importance of anthracycline chemotherapy in pediatric and
adult populations was underscored, but was rapidly followed by the recognition that the long-term effects
were unknown, especially in pediatric populations. The launch of the landmark Childhood Cancer Survivor
Study in 1994 provided a powerful tool to account for the long-term effects of anthracycline chemotherapy
on the first cohort of pediatric patients, those treated between 1970 and 1986 . Following the example of
[5]
this important study, the focus has been on retrospective analysis and surveillance of the long-term effects
of treatment.

Anthracycline chemotherapy and chest radiation make cardiovascular disease (CVD) a leading cause of
[6-9]
morbidity and mortality among childhood cancer survivors . Cardiomyopathy secondary to cumulative
doxorubicin exposure has been a concern among oncologists, because it is often irreversible and fatal .
[10]
Over the years we have learned to prevent this cardiomyopathy by capping the dose and/or adding
[11]
dexrazoxane . More recently, the Childhood Cancer Survivor Study suggested that whereas the incidence
of cardiomyopathy decreases since the time of treatment, the incidence of coronary artery disease (CAD)
increases [12,13] . Cumulative incidence of CAD now significantly exceeds the cardiomyopathy by age 45 .
[13]
CAD is also associated with doxorubicin exposure, presumably by altering the innate immune pathway and
[14]
initiating CAD . CAD is associated with several modifiable risk factors and chronic diseases including
hypertension, dyslipidemia, tobacco use, metabolic syndrome, and diabetes. These chronic illnesses are
most often managed by family physicians and primary internists.

[7]
Effective management of these risk factors reduces the incidence of CAD . Exposure to anthracycline
chemotherapy and radiotherapy are recognized as CVD risk factors on par with hypertension and
diabetes, but are not included in cardiovascular risk prediction tools, nor is high-sensitivity C-reactive
protein (hsCRP), which Ridker and colleagues have identified as a key linkage of inflammation induced by
anthracycline and CAD, leaving individual practitioners to determine risk [15-18] . While the American College
of Cardiology/American Heart Association (ACC/AHA) guidelines on the management of cholesterol and
the guidelines for primary prevention of CVD recommend using the Pooled Cohort Equation to estimate
cardiovascular risk in the general population [19,20] , this and other risk calculators do not account for
anthracycline chemotherapy or chest radiation, key drivers of CAD risk in survivors of cancer, especially
in younger patients. Most risk-scoring systems do not include patients at or younger than age 40, which