Risk Factors
Risk Factors for Anthracycline-Induced Cardiotoxicity
A number of risk factors for the development of anthracycline-induced cardiotoxicity have been identified (Table 1). The strongest risk factor is cumulative dose. Other potential risk factors include age, preexisting cardiac risk factors, radiation therapy, and other chemotherapy agents. However, while some of these are known risk factors for the development of CHF in the general population, it is unclear from most studies whether they potentiate the effects of anthracyclines or whether their effects are simply additive.
Cumulative Dose
A high cumulative anthracycline dose is the most recognized risk factor for cardiac damage and remains the best predictor of subsequent cardiac dysfunction. This association was first observed by Von Hoff et al in a retrospective analysis showing that anthracycline toxicity and heart failure were dose-related, with the incidence of complications rising sharply as cumulative doses of doxorubicin(Drug information on doxorubicin) increase.[10] The estimated percentage of patients who developed CHF at a dose of 400 mg/m2 was 3%, increasing to 7% at 550 mg/m2 and to 18% at 700 mg/m2.[10] This led to a recommended limit on lifetime cumulative doxorubicin dose of 450 to 550 mg/m2.
Subsequent studies have confirmed this observation, but most did not control for competing causes of mortality or take into account the effect of time on the risk of cardiotoxicity.[19] This was addressed by Ryberg et al in a recent retrospective study of 1,097 patients with metastatic breast cancer treated with epirubicin(Drug information on epirubicin) over a 20-year period.[20] They first identified independent predictive factors for the development of cardiotoxicity and other causes of mortality, respectively. Using competing risk analysis, they were able to determine the maximum dose resulting in no more than a 5% rate of CHF for patients with different sets of risk factors. For a patient aged 40 years with no other risk factors for CHF, the recommended dose yielding a 5% risk of CHF at 2.5 years of treatment would be 806 mg/m2. If the same woman were 70 years old, the maximum cumulative dose drops to 609 mg/m2.[20] This analysis showed that maximum cumulative dosage of anthracycline would differ among patients depending on preexisting cardiac risk factors and other competing factors for mortality.
Age
An early study by Von Hoff has suggested that anthracycline-induced cardiotoxicity may be more pronounced with advancing age.[10] In a retrospective analysis of three clinical trials involving 630 patients who were treated with doxorubicin, Swain et al showed that patients more than 65 years old are 2.25 times more likely to experience anthracycline-induced CHF compared with patients less than 65 years old, but the effect is only pronounced after a cumulative dose of 400 mg/m2.[19] In addition, the number of CHF events that occurred in the subgroup analysis was small, and a non–anthracycline-treated comparison group was not included. Therefore, the interpretation of the findings is difficult.
Several studies have used the Surveillance, Epidemiology and End Results (SEER)-Medicare database to evaluate the risk of CHF following anthracycline administration in women with early-stage breast cancer,[21] finding over a twofold increase in the risk of cardiomyopathy and a 40% increase in CHF. These studies found that CHF was associated with advanced age, black race, increased number of comorbid conditions, and a prior history of cardiac conditions and cardiac risk factors.[21] The risk of CHF after anthracycline treatment in these studies appeared to be higher than the rate of CHF observed by other adjuvant breast cancer trials, where patients were generally younger.[7] While these studies were strengthened by large numbers of subjects and up to 10 years of follow-up, they were limited by a lack of anthracycline dose information in the database, and the outcomes of CHF being determined only through billing claims.
In the Danish study of metastatic breast cancer patients treated with epirubicin (described previously), Ryberg et al showed that age at the start of epirubicin treatment had a statistically significant association with risk of cardiotoxicity: The cardiotoxicity rate increased by 28.7% for every 10 years of age.[20] Using competing risk analysis, they were able to generate predictive models accounting for a number of known risk factors associated with risk, including age, prior cardiac disease, known cardiac risk factors, thoracic radiation, prior hormonal therapy, and prior cyclosphosphamide-based chemotherapy. As one would expect, some of these known risk factors for CHF in the general population are also associated with risk in patients treated with epirubicin. It is unclear from this analysis, however, if any of these factors potentiate the effects of epirubicin, or if their effects are purely additive.
Radiation Therapy
Given the role of radiation in reducing local recurrence and improving survival, a considerable number of women are treated with both local radiation and systemic anthracycline. Meta-analysis of randomized controlled trials by the Early Breast Cancer Trialists’ Group (EBCTG) confirmed that patients who received radiation had a higher risk of vascular mortality than those who did not, and that this association was strongest among older patients. As a result, concern over the synergistic effects of radiation and anthracyclines have been raised, with some small studies suggesting that left-sided radiotherapy with higher cumulative doses of an anthracycline may exacerbate the drug’s cardiac toxicity.[22,23]
In a study using the SEER-Medicare database, evaluating more than 45,000 breast cancer patients with up to 13 years of follow-up, Doyle et al did not find an increased risk of cardiac morbidity or CHF associated with radiation therapy or left-sided radiation therapy in patients treated after 1992.[24] In addition, radiation did not increase the risk of CHF in patients treated with anthracycline.[25] Recent studies have not observed increased CHF in breast cancer patients who received radiation therapy in combination with a standard dose of doxorubicin (60 mg/m2) given for four cycles.[26,27]
Preexisting Cardiac Risk Factors
People with preexisting cardiac risk factors are at increased risk for developing CHF in the absence of anthracycline therapy, and therefore, it is important to evaluate cardiotoxicity in the context of these cardiac risk factors and to understand how they interact with anthracycline treatment. In the study by Ryberg et al, cardiotoxicity was approximately threefold higher in patients with a condition predisposing to heart disease (such as hypertension, diabetes, obesity, thyrotoxicosis, and chronic obstructive lung disease), independent of the cumulative dose of epirubicin.[20]
Several other studies have suggested that patients with previous cardiac disease (coronary, valvular, or myocardial) and hypertension may have an increased risk of developing CHF when treated with an anthracycline.[6,12,28] However, none of these studies had specifically evaluated the interaction of preexisting cardiac conditions with treatment. Using SEER-Medicare data, one study evaluating 9,438 patients with non-Hodgkin’s lymphoma who had been treated with anthracycline-based therapy, showed that hypertension was the only preexisting cardiac risk factor that potentiated the effect of the anthracycline on the heart (hazard ratio = 1.8, P = .01).[29]
Taxanescetaxel (Taxotere) are active agents in the treatment of breast cancer. They are microtubule inhibitors that are thought to induce apoptosis and inhibit tumor angiogenesis. In multiple phase II trials, the combination of an anthracycline plus taxanes demonstrated high response rates in advanced breast cancer.[30] However, the incidence of cardiac adverse effects increased when cumulative doxorubicin doses exceeded 360 mg/m2.[30] The increase in cardiac toxicity is thought to be the result of taxanes stimulating the conversion of doxorubicin to the more potent cardiotoxic metabolite doxorubicinol inside human myocardium, and potentiating anthracycline-induced cardiotoxicity, especially at high, cumulative anthracycline doses. Slow infusion of paclitaxel(Drug information on paclitaxel) and doxorubicin[31] or increased time between doxorubicin and paclitaxel treatment decreased cardiotoxicity.[32] When combined with paclitaxel, the cumulative doxorubicin dose should not exceed 360 mg/m2.
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(Drug information on 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(Drug information on 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(Drug information on 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]
