Impact of Age at Diagnosis on Cardiotoxicity in High-Grade Osteosarcoma and Ewing Sarcoma Patients

Abstract

Background: Osteosarcoma and Ewing sarcoma patients face a significant risk of cardiotoxicity as defined by left ventricular dysfunction and heart failure (HF).

Objectives: This study sought to evaluate the association between age at sarcoma diagnosis and incident HF.

Methods: A retrospective cohort study was performed at the largest sarcoma center in the Netherlands among patients with an osteosarcoma or Ewing sarcoma. All patients were diagnosed and treated over a 36-year period (1982-2018) and followed until August 2021. Incident HF was adjudicated through the universal definition of heart failure. Determinants including age at diagnosis, doxorubicin dose, and cardiovascular risk factors were entered as fixed or time-dependent covariates into a cause-specific Cox model to assess their impact on incident HF.

Results: The study population consisted of 528 patients with a median age at diagnosis of 19 years (Q1-Q3: 15-30 years). Over a median follow-up time of 13.2 years (Q1-Q3: 12.5-14.9 years), 18 patients developed HF with an estimated cumulative incidence of 5.9% (95% CI: 2.8%-9.1%). In a multivariable model, age at diagnosis (HR: 1.23; 95% CI: 1.06-1.43) per 5-year increase, doxorubicin dose per 10-mg/m² increase (HR: 1.13; 95% CI: 1.03-1.24), and female sex (HR: 3.17; 95% CI: 1.11-9.10) were associated with HF.

Conclusions: In a large cohort of sarcoma patients, we found that patients diagnosed at an older age are more prone to develop HF.

Keywords: AYA, adolescent and young adult; CTX, cardiotoxicity; HF, heart failure; age; anthracyclines; cancer; cardio-oncology; heart failure; sarcoma.

Graphical abstract

Figure 1

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Diagram of Patient Selection All patients of the institutional Ewing sarcoma and osteosarcoma registries were considered for study participation. Patients are enrolled in these registries based on International Classification of Diseases-10th Revision diagnoses and have histologically confirmed disease. The study population was composed of 528 patients who were exposed to doxorubicin-containing chemotherapy regimens and were treated with curative intent.

Figure 2

Cumulative Incidence of HF at Follow-Up The estimated cumulative incidence of heart failure (HF) was 5.9%, but older adults (aged ≥40 years, dashed line) at diagnosis showed a higher cumulative incidence of HF compared with patients diagnosed at childhood or adolescents and young adults (solid line). Cumulative incidence curves were constructed and compared using Fine and Gray’s method.

Central Illustration

Age in Heart Failure Risk After Doxorubicin Treatment for Sarcoma In a large cohort of osteosarcoma and Ewing sarcoma patients, covering all age groups, we performed a retrospective study to assess the impact of age at sarcoma diagnosis on the risk of heart failure (HF) adjudicated according to the universal definition of HF. When adjusting for the cumulative doxorubicin dose, female sex, and the presence of traditional cardiovascular risk factors, older adults at diagnosis had a near 4-fold increased risk of HF compared with patients diagnosed at childhood or adolescent/young adult age. Age at diagnosis was not a significant predictor of all-cause mortality. The competing risk of death was strongly determined by cancer-related factors such as relapse.