Cancer patients receiving anthracycline therapy are at an increased risk of developing cardiotoxicity, including cardiomyopathy and congestive heart failure (CHF).
Anthracyclines are the most frequently implicated antineoplastic agents associated with cardiotoxicity. Anthracycline induced cardiotoxicity has been categorised into acute, early-onset chronic progressive, and late-onset chronic progressive and is usually not reversible. The risk of clinical cardiotoxicity increases with a number of risk factors including higher total cumulative doses. Anthracycline-induced cardiotoxicity typically manifests as a reduction in left ventricular ejection fraction (LVEF), cardiomyopathy, or symptomatic CHF.
Diagnostic criteria for cardiac dysfunction due to antitumour medication is defined as a decrease in LVEF >10% from baseline to a final LVEF <53% (lower limit of normal).rr
A meta-analysis of 8 trials showed that the use of anthracyclines was associated with a significantly increased risk of both clinical (odds ratio [OR] 5.43, 95% CI 2.34-12.62) and subclinical cardiotoxicity (OR 6.25, 95% CI 2.58-15.13). The rate of cardiac-related deaths, though infrequent, was also significantly higher when an anthracycline was used (OR 4.94, 95% CI 1.23-19.87).r
In a separate meta-analysis which included over 49,000 patients, the incidence of clinically overt cardiotoxicity and subclinical cardiotoxicity was 6% and 18% respectively after a median follow up of 9 years.r
- Acute anthracycline cardiotoxicity – occurs during or immediately after a single dose of an anthracycline and occurs in <1% of patients.r It may manifest as ventricular dysfunction, ECG abnormalities, arrhythmias and pericarditis-myocarditis syndrome. Most of these events are transient and normally resolve within a week and are not dose related.
- Early onset chronic progressive anthracycline cardiotoxicity – typically presents early, either during treatment or within one year after termination of treatment occurring in 1.6-2.1% of patients typically presenting as cardiomyopathy which can be progressive.r
- Late onset chronic progressive anthracycline cardiotoxicity – presenting at least one year after completion of treatment up to 20 years since the first dose. Occurring in 1.6-5% of patients manifestations include reduced LVEF, cardiomyopathy or symptomatic CHF.r Chronic cardiotoxicity is dose-related and the risk may be minimised by ensuring the total lifetime cumulative dose of an anthracycline administered to a patient is not exceeded.
- age <15 or >65 years
- cumulative anthracycline dose (e.g. >250 mg/m2 doxorubicin or equivalent)
- high-dose (>30 Gy) thoracic radiation therapy (particularly left-sided)
- lower-dose anthracyclines in combination with thoracic radiation therapy or trastuzumab (sequential therapy)
- intravenous bolus administration of anthracyclines
- previous, concurrent or planned treatment with other potentially cardiotoxic drugs may increase risk e.g. trastuzumab, paclitaxel, streptozocin, cyclosporin, dacarbazine, dactinomycin, etoposide, cyclophosphamide, ifosfamide, mitomycin, melphalan, vincristine, and bleomycin
Multiple cardiac risk factors (≥2):
- diabetes mellitus
- peripheral vascular disease
- sedentary lifestyle
Non-cardiac conditions that may increase cardiotoxicity risk:
- thyroid dysfunction
- electrolyte abnormalities
- chronic kidney disease
- very high or very low weight and possibly malnutrition, especially vitamin E deficiency
Prior heart diseases:
- borderline low LVEF (50-55%)
- history of:
- heart failure
- myocardial infarction
- clinically relevant cardiac arrhythmias (atrial fibrillation, prolonged QT interval, supraventricular tachycardia, ventricular tachycardia)
- moderate or severe valvular heart disease
- increase in cardiac biomarkers (troponins and natriuretic peptides) during and after administration
- increased length of time since completion of chemotherapy
Anthracyclines in breast cancer
For patients with risk factors for cardiac impairment, less cardiotoxic regimens should be considered e.g. TC (docetaxel/cyclophosphamide) or CMF (cyclophosphamide/methotrexate/fluorouracil). For those who require trastuzumab, a non-anthracycline containing chemotherapy regimen could be considered such as TCarboH (docetaxel/carboplatin/trastuzumab) or TCycloH (docetaxel/cyclophosphamide/trastuzumab).
Trastuzumab has been used concurrently with anthracyclines in the metastaticr and the neoadjuvant setting,r with cardiotoxicity rates up to 27%.r It is recommended that where this combination is used, extended administration is avoided (i.e. limited to 3 cycles) and patients counselled about the potential for increased risk of cardiotoxicity. Consideration should be given to closer cardiac monitoring in this setting. There is evidence that liposomal doxorubicin does not increase trastuzumab associated cardiotoxicity.r There is currently no data suggesting any difference in efficacy whether trastuzumab is given concurrently or sequentially with anthracyclines.