NEWS & PERSPECTIVE
Refined insights into the relationship between anthracyclines and CHF
Since the introduction of anthracyclines, they have been associated with cumulative and dose-dependent cardiotoxicity.1 The updated European Society of Cardiology (ESC) guidelines endorse echocardiography (ECG) assessments at baseline and 12 months of treatment, with further surveillance if the cumulative dose reaches an equivalence of doxorubicin 250mg/m2.2 Of note, previous studies reported a cumulative decrease in left ventricular ejection fraction (LVEF).1 However, in a recent retrospective case-controlled report, there was no significant difference in the chronic heart failure (CHF) risk based on cumulative anthracycline dose, and that among cancer patients who were not treated with anthracyclines, the risk of CHF was also not statistically significant compared with healthy controls.2
Unlike its primary mechanism of deoxyribonucleic acid (DNA) damage in killing rapidly dividing cancer cells, anthracyclines damage cardiac tissues due to the formation of free radicals during their metabolism.1 The damage caused by anthracyclines leads to the death of cardiomyocytes, and therefore is irreversible.1 The efficacy of anthracyclines in cancer treatment is often limited by the threat of a progressive and irreversible HF with variable onset time, making it particularly relevant among survivors of pediatric cancers.1
In a recent retrospective case-controlled study, longitudinal data from the residents of Olmsted County of Minnesota in the United States were collected to describe the risk of CHF in cancer patients treated with anthracyclines.3 Participants were diagnosed with breast cancer (BC), Hodgkin lymphoma (HL), or non-Hodgkin lymphoma (NHL) during the period of January 1985 to December 2010, and were treated with chemotherapy with or without radiotherapy.3 Participants with cardiovascular (CV) risk factors were included, but patients with CHF at diagnoses were not.3 Those with cancer recurrence were censored at the time of recurrence and only the cumulative doxorubicin dose of the initial treatment counted towards the analysis.3 New-onset CHF was defined by the modified Framingham criteria, and was recorded in both in-patient and out-patient settings.3
A total of 812 patients were recruited and were matched 1:1.5 to 1,384 healthy controls in the comparison to the cohort adjusted for age, sex, diabetes, hypertension, hyperlipidemia, coronary artery disease (CAD), obesity, and smoking history.3 The median follow-up was 8.6 years [Interquartile range (IQR): 5.2-13.4] in the case group and 12.5 years (IQR: 8.7-17.5) in the control group.3 Overall, the mean age was 52.62 years, with 78% being female participants.3 There were more ever smokers in the study arm (43% vs. 21%; p<0.001) and a higher instance of CAD (5% vs. 2%; p<0.001) at baseline.3 Notably, the majority of participants in either group were white (93% and 92%).3 Participants of other races with different social determinants of health, allostatic load, and structural racism may have different CV and cancer outcomes.2
Cancer patients had a higher risk of CHF (HR=2.86; 95% CI: 1.90-4.32; p<0.001).3 However, the risk of CHF lost statistical significance among cancer patients not treated with anthracyclines (HR=1.78; 95% CI: 0.83-3.81; p=0.14).3 Unsurprisingly, patients receiving anthracyclines for their cancer had a higher risk of CHF compared with the healthy cohort (HR=3.25; 95% CI: 2.11-5.00; p<0.001).3 A higher cumulative incidence of CHF was observed compared with the comparator cohort across different time points at 1 year (1.81% vs. 0.09%), 5 years (2.91% vs. 0.79%), 10 years (5.36% vs. 1.74%), 15 years (7.42% vs. 3.18%), and 20 years (10.75% vs. 4.98%) (p<0.001).3 Remarkably, contrasting to the popular belief, there were no significant differences in the risk of CHF for patients receiving different anthracycline doses.3 Patients receiving <180mg/m2 had a similar risk of CHF when compared with those receiving a higher dose of 180-250mg/m2 (HR=0.54; 95% CI: 0.19-1.51) or ≥250mg/m2 (HR=1.23; 95% CI: 0.52-2.91).3 Further multivariable Cox regression was performed to identify the independent risk factors for CHF in cancer patients, including age, sex, cancer diagnoses, chest, or mediastinal radiation, and that the CV risk factors include CAD, hyperlipidemia, body mass index (BMI) >30, and ever smoking.3 Among these, age was the only independent risk factor associated with a significant increase in the risk of CHF (HR per 10 years=2.77; 95% CI: 1.99-3.86; p<0.001).3
The researchers concluded that there was a significantly greater risk of CHF for cancer patients treated with anthracyclines, but further prospective studies are required to develop surveillance models and susceptibility indexes for these patients.3
