Abstract B37: Evaluation of cardiovascular and musculoskeletal health in sarcoma survivors
Authors: Baker Laurence H. , Ploutz-Snyder Lori , Jalife Jose , Palmieri-Smith Rianna , Herron Todd , Murthy Venkatesh L. , Weinberg Richard L. , Reinke Denise 
Published: August 2018

Background: Children, teenagers, and young adult survivors of bone sarcoma have a 39-fold risk of developing a severe, life-threatening, or fatal chronic medical condition compared to their siblings. Heart disease is the most common and serious chronic illness observed in sarcoma survivors treated with doxorubicin (DOX). The commonest heart disease in these survivors is coronary artery disease (CAD). Long-term cardiotoxicity is a significant problem of DOX but the underlying pathogenesis and pathophysiology remains incompletely understood. Until recently, it was assumed that the DOX effect was limited to cardiomyopathy, but we now posit that DOX is also associated with CAD as well as with arrhythmias. Though commonly used, ejection fraction is not predictive of any of these acquired heart diseases. Better and earlier diagnoses are needed. We established a Sarcoma Survivorship Program to include patients at high risk of chronic illness who are at least two years free of disease after completion of treatment.

Methods: Every 6 months, patients electronically complete NIH's PROMIS (Patient-Reported Outcomes Measurement Information System) questionnaires (on Anxiety, Depression, Mobility, Pain Interference, Sleep Disturbance, and Physical Function). Detailed family history is documented. Chemotherapy doses are abstracted from original medical records. Data collected include blood pressure, lipid profile, high-sensitivity C-reactive protein (hs-CRP), basic metabolic panel, chemistries, renal and pulmonary function, and expert echocardiography. All patients signed an IRB approved informed consent.

Results: All patients had normal left ventricular ejection fractions (median= 60%), yet 8 (N=24) patients had an elevated high-sensitivity C-reactive protein suggesting increased risk of early CAD. 10 patients had untreated hypertension. More than half of our patients have a BMI &gt;25 and self-declare that they do not exercise. Our high rate of family history of heart disease (58%) in first-degree relatives raises the issue of genetic predisposition both to heart disease and sarcoma. We compared standardized cardiac risk assessments with mediastinal calcification and epicardial fat on serial chest CT scans. A 39-year-old man had a coronary calcium score &gt;400 Agatston units and scattered calcifications were remarkably found in 4 additional patients under the age of 40.

Conclusions: This survivorship phase of oncologic care represents a unique opportunity to improve the health and quality of life for sarcoma survivors as well as a new focus for translational research to understand mechanisms driving premature aging and chronic heart disease. We assess cardiomyocyte function (cell viability, organization, fibrosis, electrical coupling, and contractility) for survivors and matched sibling controls with cells from skin biopsy using 3D bioengineering techniques to culture and mature the phenotype from human stem cells. Altering lifestyle through weight management and increased physical aerobic and anaerobic exercise is the best approach to reducing coronary artery disease. Our team includes expert exercise physiologists to better understand mechanisms limiting exercise in patients with amputation or limb salvage surgeries and in turn develop individualized appropriate exercise regimens utilizing research methodologies used by NASA to improve the performance of our astronauts in space. These lab technologies are being prospectively applied into a patient population of sarcoma survivors to understand the extent and cause of physical limitation of amputation vs. limb-salvage surgery as well as to understand the mechanisms of acquired cardiac disease. We must improve our knowledge of the long-term cardiac risk associated with surviving a sarcoma to effectively counsel survivors and offer existing effective intervention strategies to prevent or minimize the impact of adverse late effects.

Citation Format: Laurence H. Baker, Lori Ploutz-Snyder, Jose Jalife, Rianna Palmieri-Smith, Todd Herron, Venkatesh L. Murthy, Richard L. Weinberg, Denise Reinke. Evaluation of cardiovascular and musculoskeletal health in sarcoma survivors [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B37.