Chemotherapy-related Heart Failure

Chapter 1 - Cardiac Complications of Cancer and Anti-Cancer Treatment

Aetiology

One of the most common manifestations of cardiotoxicity associated with anti-cancer therapies is the development of left ventricular dysfunction (LVD) and overt heart failure (HF). According to the definition proposed by the Cardiac Review and Evaluation Committee, LVD is characterised by:

• A decrease in cardiac LV ejection fraction (LVEF), that is either global or more severe in the septum;
• Symptoms of congestive heart failure (CHF);
• Associated signs of CHF, including but not limited to S3 gallop, tachycardia or both;
• Decline in LVEF of at least 5% to below 55% with accompanying signs or symptoms of CHF, or a decline in LVEF of at least 10% to below 55% without accompanying signs or symptoms.

Two distinct forms are identifiable. Type I cardiac dysfunction, typically induced by cytotoxic agents, is due, at least in part, to oxidative stress on the cardiac muscle, resulting in free radical formation and cell death. It is irreversible and typically associated with significant ultrastructural changes at biopsy.

Type II, typically induced by biological agents, is associated with reversible myocardial dysfunction rather than structural damage. It is highly reversible (up to 79%) and generally not dose-related.

Anthracyclines and cytotoxics with cumulative dose-related cardiotoxicity: type I agents

Even if several cytotoxic agents have been associated with cardiac toxicity (see below), anthracycline-induced cardiotoxicity is the most studied, given their frequency of use and resulting morbidity.

It may present as acute, subacute or late. Acute toxicity occurs during or immediately after infusion, and includes arrhythmias sometimes accompanied by an acute, transient decline in myocardial contractility, which is usually reversible and not dose-dependent. Subacute toxicity occurs within a few weeks of treatment, and clinically resembles myocarditis with oedema and thickening of the LV walls, accompanied by diastolic dysfunction. These two forms are, however, rare (1%–4%).

The most important risk factor for late cardiac toxicity is cumulative anthracycline dose. The associated incidence of HF is about 3%–5% with a doxorubicin cumulative dose of 400 mg/m2, and 18%–48% with a cumulative dose of 700 mg/m2. For this reason, a cumulative doxorubicin dose of 450–550 mg/m2 is empirically considered as the highest allowed in clinical practice. Other anthracyclines, such as epirubicin, idarubicin and daunorubicin, induce cardiotoxicity less frequently (0.9%–3.3%), allowing administration of different cumulative doses (900–1000 mg/m2 for epirubicin, 100 mg/m2 for idarubicin, 600 mg/m2 for daunorubicin).The most significant cardiac effect of anthracyclines is chronic cardiac toxicity leading to LVD and congestive HF. Symptoms usually appear during the first post-treatment year, but may occur even after 10–20 years. Prognosis is poor, with a 50% 2-year mortality in untreated established LVD.

However, there is a considerable variability in the individual dose–response relationship for cardiac toxicity, and symptoms of CHF may also occur at lower doses. Additional risk factors for anthracycline cardiotoxicity include extremes of age, female gender, underlying cardiovascular (CV) diseases, and predisposing factors such as hypertension and smoking. Moreover, intravenous bolus administration and higher single doses of anthracyclines, concomitant use of cyclophosphamide, taxanes or trastuzumab, and previous mediastinal irradiation can increase the risk of developing cardiac toxicity. Liposomal anthracyclines are generally associated with a lower rate of cardiotoxicity compared to standard anthracyclines; for pegylated liposomal doxorubicin, which has been the most extensively studied, clear evidence shows a better cardiac safety profile. However, high cumulative doses of liposomal anthracyclines may still be associated with cardiac damage (Safra 2003).

The use of cardioprotectants such as dexrazoxane, which acts by chelating iron and decreasing iron-mediated free radical formation, has confirmed efficacy against anthracycline-related cardiac damage. Use of dexrazoxane, however, is recommended, both in the USA and in Europe, only for adult patients with advanced or metastatic breast cancer who have already received >300 mg/m2 doxorubicin, and who may benefit from continued doxorubicin-containing therapy.

Monoclonal antibodies and targeted agents not associated with cumulative dose-related cardiotoxicity: type II agents

Several targeted agents have been identified as causing type II cardiac dysfunction (Table 1), trastuzumab being one of the first shown to adversely affect cardiac function. In patients with advanced disease, the incidence of LVD ranges from 2%–7% when trastuzumab is used as monotherapy, to 2%–13% up to 27% when in combination with paclitaxel and anthracyclines plus cyclophosphamide, respectively. Trastuzumab-related cardiotoxicity includes various degrees of asymptomatic decreased LVEF or, less frequently, symptomatic CHF. Typically, it does not appear to be dose-dependent. Patients who develop cardiotoxicity generally improve once trastuzumab is discontinued, and retreatment is usually possible with a low incidence of LVD recurrence.

Risk factors include partially altered baseline LVEF values, elderly age, prior cardiac diseases, previous cardiotoxic treatments (including media-stinal irradiation and anthracyclines) and CV risk factors.

The temporary cardiomyocyte dysfunction caused by trastuzumab is probably secondary to inhibition of cardiomyocyte human ErbB2 signalling, thereby interfering with normal growth, repair and survival. Apart from HER2-targeting agents, other target agents, such as the antiangiogenic drugs sunitinib and bevacizumab and some tyrosine kinase inhibitors (TKIs) such as imatinib, are also known for their association with LVD.

Evaluation and Treatment

Prevention is the best approach to minimise chemotherapy-induced cardiotoxicity. Careful drug selection should be based on a detailed patient history focused on CV risk factors, pre-existing CV disorders and previous exposure to chemotherapeutic agents or mediastinal irradiation. The introduction of a drug-free interval between anthracyclines and trastuzumab, or the administration of anthracycline-free regimens, can lower the potential risk of cardiac damage. Additionally, patients should be encouraged to actively reduce CV risk through blood pressure (BP) control, lipid level reduction, smoking cessation and lifestyle modifications. Even so, careful serial monitoring of the LV, using Doppler echocardiography or gated radionuclide scan with multiple acquisitions (MUGA scan), is advisable. Serial evaluation should always be conducted using the same procedure.

The monitoring schedule can be adapted according to the drug, cumulative dose, length of treatment and CV risk profile of the patient. Generally, in the adjuvant setting, serial monitoring of cardiac function every 3 months has been proposed, while patients treated for metastatic disease can be monitored less frequently in the absence of symptoms.

An assessment of cardiac function is recommended 4 and 10 years after anthracycline therapy in patients who were treated at <15 years of age, or even older if the cumulative dose of doxorubicin is >240 mg/m2 or epirubicin >360 mg/m2.

Cardiospecific biomarkers, such as troponin I and brain natriuretic peptide (BNP) concentrations, have also been shown to be valid diagnostic tools for the early identification and monitoring of cardiotoxicity. They are minimally invasive and less expensive than echocardiography. Nevertheless, the standardisation of their use in clinical practice is still under debate.

If a decline in LVEF does occur, even in the absence of symptoms, early treatment with angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers and beta-blocker administration, unless contraindicated, should be considered.

When using anthracycline-containing regimens, a reduction in LVEF of ≥20% from baseline or a confirmed LVEF decrease <50% requires discontinuation of therapy, evaluation of medical LVD treatment and further clinical and echocardiographic re-evaluations. If LVEF declines to <40%, chemotherapy should be stopped and alternatives discussed.

When managing trastuzumab-related cardiotoxicity, “stopping/restarting” rules are usually effective, and their use is recommended (see below).