Adjuvant regimens including taxanes, however, do not seem to increase anthracycline cardiotoxicity. In the European Cooperative Trial in Operable breast cancer (ECTO), comparing doxorubicin (75 mg/m2) followed by CMF (cyclophosphamide, methotrexate, and 5-FU) with the combination of paclitaxel and doxorubicin (60 mg/m2) followed by CMF, the incidence of symptomatic cardiac events were similar between arms with and without paclitaxel.[33] In clinical trials, docetaxel has not been associated with increased cardiotoxicity when combined with doxorubicin or epirubicin.
Trastuzumab
Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene and a member of the erbB family of transmembrane tyrosine kinases. Approximately 20% to 25% of patients with breast cancer have tumors that overexpress the HER2 protein or amplify the HER2/neu gene; such alterations are associated with a more aggressive clinical course.[34] Trastuzumab, an anti-HER2 monoclonal antibody, represents the most significant improvement for treating this poor-risk group of patients.[35]
During the pivotal metastatic breast cancer trials of trastuzumab, cardiac dysfunction was observed in women treated with trastuzumab-containing chemotherapy regimens.[35,36] The incidence and severity of cardiac dysfunction was greatest among patients who received trastuzumab in combination with an anthracycline. Symptomatic or asymptomatic cardiac dysfunction was observed in 27% of patients who received concomitant anthracycline and trastuzumab therapy. The rate of cardiac events was much lower in patients given trastuzumab alone (4.7%), or with paclitaxel (13%).[36] Thus, trastuzumab appears to increase the susceptibility of the heart to anthracycline. Due to the high rate of cardiotoxicity, later trials have avoided administration of trastuzumab during anthracycline treatment.
Trials of adjuvant trastuzumab have incorporated careful monitoring of LVEF, and most now require a normal postanthracycline LVEF before initiating treatment with trastuzumab. In a combined analysis of the NCCTG N9831 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trials, 6.7% of patients who had completed anthracycline treatment had a lower LVEF or developed cardiac symptoms preventing the initiation of trastuzumab.[37] A lower LVEF before initiation of trastuzumab (P = .033), age ≥ 60 (P = .003), and use of antihypertensive medications (P = .005) increased the risk of trastuzumab-associated cardiac dysfunction following AC therapy.[7]
Monitoring
Both echocardiogram and multigated acquisition (MUGA) scan are methods used to monitor anthracycline-induced cardiotoxicity. Guidelines for monitoring the use of both modalities are available from the American Heart Association and American College of Cardiology. Because the two techniques cannot be compared directly, patients should always be assessed with the same technique when monitoring cardiac changes during treatment over time. MUGA is highly reproducible and able to detect a decline in LVEF in patients treated with anthracycline, but cumulative radiation exposure limits the applicability of this technique for frequent monitoring. Echocardiography is used regularly to monitor LVEF and is more widely available than MUGA. Unlike MUGA, it does not expose the patient to ionizing radiation. However, it is considered more prone to operator-dependent variability. Both modalities may overlook early changes that could identify patients at risk for anthracycline-related cardiotoxicity.
Newer imaging techniques have been evaluated to enhance earlier detection of subclinical myocardial changes in the course of anthracycline treatment. One modality is cardiac magnetic resonance imaging (MRI), which can measure morphologic and functional tissue changes, and has little between-test variability. The technique can visualize the site and extent of myocardial infarction by imaging of the associated edema as well as the necrotic area. Increased myocardial signal enhancement might be an early marker for myocardial changes independent of cardiac function.[38] Cardiac MRI thus has the potential to investigate cardiac function even before tissue changes that generally precede the functional alterations.
Myoscint cardiac scans using indium antimyosin antibody is another modality that may be useful in diagnosing early cardiac dysfunction and predicting toxicity. When cardiac myocytes are damaged, myosin is exposed and can be detected by antimyosin antibodies. Myoscint cardiac scan compares the heart to lung ratio uptake of indium-radiolabeled antimyosin antibodies. When LVEF measured by MUGA was compared with myoscint cardiac scan in patients who had been treated with high cumulative epirubicin doses, an increase in the heart-to-lung ratio preceded a decline in the LVEF.[39] More studies are needed to assess the utility of cardiac MRIs and myoscint scans in clinical practice, but these imaging modalities may be useful outcome measures in cardiac safety studies.
