The following are summary points from this review of anthracycline cardiotoxicity mechanisms, monitoring, and prevention:

1. Cancers responsive to anthracyclines include carcinoma (breast, small cell lung, bladder, esophagus, stomach, liver, and thyroid), leukemia (AML and ALL), lymphomas (Hodgkin’s and non-Hodgkin’s, cutaneous T-cell lymphoma), and sarcoma (osteogenic bone, soft tissue, and Ewing). Anthracycline-induced (doxorubicin, daunorubicin, epirubicin, idarubicin) cardiomyopathy is a disease spectrum ranging from development of heart failure (HF) with symptoms and clinical signs to asymptomatic decline in left ventricular ejection fraction (LVEF). Clinical HF may ensue in up to 5% of high-risk patients.
2. Cardiac event rates on anthracycline therapy are 7%, 18%, and 65% at cumulative doses of 150 mg/m², 350 mg/m², and 550 mg/m², respectively. Anthracycline chemotherapy was associated with an adjusted hazard ratio of 1.26 (confidence interval, 1.12-1.42) for development of congestive cardiac failure in 43,000 women (aged 66-70 years) with breast cancer over a median period of 53 months. In 2,625 cancer patients who received anthracycline (74% women; 51% breast cancer, and 28% non-Hodgkin’s lymphoma), incidence of cardiotoxicity was 9% with 98% of cases developing in the first year (median time 3.5 months). Pediatric populations receiving anthracycline chemotherapy remain at elevated risk of developing HF decades after receiving a cancer cure.
3. Mechanism of toxicity: The main mechanism is by inhibition of Toposiomerase 2β, which is active in quiescent non-proliferating cells including cardiomyocytes, resulting in activation of cell death pathways and inhibition of mitochondrial biogenesis, and is now thought to be the key mediator of anthracycline-induced cardiotoxicity.
4. Risk markers: These include cumulative dose, female gender, hypertension, valvular disease, baseline LV dysfunction, African-American ancestry, age >65 years or <18 years, renal failure, concomitant exposure to radiation and/or trastuzumab, and possibly genetic factors.
5. LVEF and global longitudinal strain (GLS): There is no consensus on how best to monitor cardiotoxicity; however, monitoring LVEF remains the basis for identifying cardiotoxicity—baseline measurements and ongoing monitoring for patients receiving >200 mg/m² is recommended. Delaying initiation of trastuzumab reduces incidence of LV dysfunction by 7% in one study and HF by 0.6%. A fall in GLS of 15% compared with baseline measurement is considered pathological and an early injury marker, which is predictive of LV systolic dysfunction.
6. Cardiac biomarkers: Cardiac troponin and B-type natriuretic peptide have shown promise as indicators of cardiotoxicity. In one study of 81 breast cancer patients, a combination of GLS and high-sensitivity troponin I had 93% sensitivity and 91% negative predictive value for future cardiotoxicity.
7. Anthracycline derivatives: Lipsomal encapsulated doxorubicin is associated with lower rates of HF and subclinical changes in LV dysfunction, but in the United States, its use is restricted to ovarian cancer, AIDS-related Kaposi sarcoma, and multiple myeloma after failure of at least one treatment.
8. Dexarazoxane: Dexarazoxane has been shown to prevent anthracycline cardiotoxicity by minimizing or completely preventing fall in LVEF and reducing release of cardiac biomarkers. However, it fell out of favor after concerns that it dampened the anti-mitochondrial activity of anthracyclines and was associated with a signal of increased secondary malignancies in survivors of childhood leukemia and lymphoma. A reappraisal of data has led to an extended indication in pediatric patients receiving >300 mg/m². Its clinical safety continues to be appraised.
9. Therapy and prevention: angiotensin-converting enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARBs) and beta-blockers are utilized for both treatment and prevention of cardiotoxicity (i.e., asymptomatic LV dysfunction and HF), on the basis of small randomized clinical trials. However, there are no robust data to recommend a specific regimen, and ongoing studies (ICOS-ONE, PROACT, Cardiac CARE) should shed light on key questions including: a) how long should ACEI/ARBs and/or beta-blockers be continued following recovery of LV function, and b) to what degree should these medications prevent future presentations of HF?
10. Primary prevention with statins: Preclinical studies suggest that statins could be protective in preventing anthracycline cardiotoxicity. Further randomized studies are needed to confirm these findings.

Keywords: Anthracyclines, Adrenergic beta-Antagonists, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Antibiotics, Antineoplastic, Biomarkers, Breast Neoplasms, Cardiomyopathies, Cardiotoxicity, Diagnostic Imaging, Doxorubicin, Geriatrics, Heart Failure, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Leukemia, Lymphoma, Multiple Myeloma, Natriuretic Peptide, Brain, Neoplasms, Primary Prevention, Sarcoma, Stroke Volume, Troponin I

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