Anthracyclines

The anthracyclines currently approved in the United States, doxorubicin (Adriamycin), daunorubicin (Cerubidine), epirubicin (Ellence), and idarubicin (Idamycin PFS), and a related compound, mitoxantrone, are key components of many chemotherapeutic regimens, having demonstrated efficacy in lymphomas and many solid tumors, including breast and small cell lung cancer (SCLC).³ This class of agents clearly is the most cardiotoxic to date, acutely producing arrhythmias, left ventricular (LV) dysfunction, and pericarditis, and chronically producing LV dysfunction and HF. The toxicity is strongly dose-related. Initial retrospective analyses suggested that the incidence of HF was 2.2% overall and 7.5% in patients receiving a cumulative dose of 550 mg/m². More comprehensive analyses, however, have suggested that the incidence is higher than this.⁴ The incidence rises significantly for cumulative doses above 400 to 450 mg/m² for doxorubicin (Fig. 69-1). Consequently, with most tumors, oncologists typically limit the dose to 450 to 500 mg/m².³ If anthracycline cardiomyopathy develops, it often appears within the first year of completion of therapy, with a median of 5 to 9 months, and continues to progress. Anthracycline-induced cardiomyopathy also may be of late onset, and, if so, it typically is chronic.

Risk factors for cardiotoxicity, in addition to doses above 450 mg/m², include advanced age, history of cardiac disease, and previous mediastinal irradiation (see Fig. 69-1 and Table 69-1). Predictors of cardiotoxicity based on assessment of LV function include a baseline LV ejection fraction (LVEF) less than 50% and a decline in LVEF of more than 10% during treatment to a level less than 50%. Diastolic dysfunction may be the first abnormality noted. Children are particularly susceptible to anthracycline cardiotoxicity; in one series, HF had developed in 5% at 15 years of follow-up, and the incidence increased to 10% for cumulative doses of 550 mg/m².⁵ In addition to dose and mediastinal irradiation, age at diagnosis and female sex are predictors for adverse outcomes in children. HF may become clinically evident years after treatment, when these children become adults.⁶

Endomyocardial biopsy is the most sensitive method to detect anthracycline cardiotoxicity, with typical findings of cytosolic vacuolization, lysis of myofibrils, and cellular swelling—features more typical of a necrotic form of cell death. Abnormalities on electron microscopy, however, have not been shown to correlate highly with risk for development of HF and often are present in patients receiving cumulative doses well below those associated with an increased risk of HF. In view of the technical skills required for the procedure and its inherent risks, endomyocardial biopsy is not a practical way to detect or to monitor patients with anthracycline cardiotoxicity, and serial determination of LV function, although insensitive, is the currently accepted method. Recently, the use of biomarkers of injury, most prominently hs-TnI (highly sensitive troponin I), has been reported to identify patients at risk of developing LV dysfunction. In one study, an elevated TnI level after anthracycline therapy was able to predict patients at risk for development of LV dysfunction, and prophylactic angiotensin-converting enzyme (ACE) inhibitor therapy limited LV dysfunction.^7,8 Novel imaging strategies such as peak systolic longitudinal strain ultrasound techniques also may prove to be helpful, with benefit additive to that of biomarkers, although more validation is needed before implementation of these strategies in the clinic.⁹

Other strategies have been used to limit anthracycline cardiotoxicity, including the use of epirubicin, a stereoisomer of doxorubicin. This agent produces less cardiotoxicity than doxorubicin at comparable doses, and 900 to 1000 mg/m² of epirubicin produces cardiotoxicity comparable to that seen with 450 to 500 mg/m² of doxorubicin. However, efficacy of the two agents appears to be comparable at equivalent doses. The use of ACE inhibitors was noted previously, but selected studies with angiotensin II receptor blockers and beta blockers also have suggested cardioprotective effects.¹⁰ At present, it probably is reasonable to use these therapies prophylactically in high-risk patients until more data are available.

In important developments, the cellular mechanisms leading to anthracycline cardiotoxicity are beginning to be identified. Doxorubicin binds both DNA and topoisomerase type II, and this ternary complex leads to DNA cleavage and cell death.¹¹ Zhang and co-workers found that the topoisomerase IIB isoform is the specific mediator that leads to doxorubicin-induced DNA double-strand breaks and transcriptome changes resulting in mitochondrial dysfunction and reactive oxygen species generation (long proposed to play a role in anthracycline cardiotoxicity).¹¹ Of note, deletion of topoisomerase IIB in mice largely prevented anthracycline-induced cardiotoxicity. Thus inhibition of topoisomerase IIB could prevent anthracycline-induced cardiotoxicity, although it remains to be seen whether manipulation of topoisomerase IIB might impair tumoricidal activity. Recent studies also have provided evidence of effects of anthracyclines on noncardiomyocyte cells including vascular endothelium, fibroblasts, and cardiac stem cells⁶ (Fig. 69-2).

These findings also may be consistent with the oxidized iron hypothesis that has led to the use of dexrazoxane (Zinecard), a chelator of intracellular iron, which may limit anthracycline cardiotoxicity.¹² However, concerns were raised in at least one trial that it might also reduce efficacy of the anthracycline. In 2011, the U.S. Food and Drug Administration (FDA) restricted use of the drug to adult patients with breast cancer who had received more than 300 mg/m² of doxorubicin or the equivalent.

A baseline determination of the patient’s LV function is indicated before initiation of anthracycline therapy, and this parameter should be monitored periodically thereafter, especially when the cumulative dose rises above 300 to 350 mg/m² for doxorubicin or above comparable doses for the other anthracyclines. The criteria noted earlier concerning risk factors, baseline LV function, and deterioration of LV function, in combination with dosage consideration, can be used for risk-stratification of patients for the development of HF. Use of hs-TnI measurements may improve predictive accuracy and may be particularly helpful in patients receiving high-dose chemotherapy. In those patients, an elevated TnI level predicted subsequent development of LV dysfunction with high sensitivity, albeit low predictive accuracy. A negative TnI assay result strongly predicted the likelihood that LV function would not deteriorate.⁸ Earlier studies of anthracycline cardiotoxicity have suggested a high mortality rate, but with more modern approaches to the management of patients with HF, the prognosis is better.

Taxanes

The taxanes, paclitaxel (Taxol) and its semisynthetic analogue docetaxel (Taxotere), disrupt microtubular networks as their mechanism of antitumor activity and are effective in breast cancer. Used alone, these drugs have relatively little cardiotoxicity, with occurrence of predominantly asymptomatic bradycardia and, much less often, heart block. However, when paclitaxel was given in close combination with high-dose doxorubicin, high rates of congestive heart failure (CHF) were observed (21%).¹³ This was found to be secondary to alteration of metabolism of doxorubicin by the taxanes. Further studies demonstrated that doxorubicin doses of less than 380 mg/m² and separating infusion of paclitaxel by up to 4 hours after doxorubicin administration decreased the risk of HF to less than 5%.¹⁴ Docetaxel given with anthracyclines is reported to only mildly increase risk of HF, thought to be secondary to differences in pharmacokinetics and pharmodynamics.¹³

Alkylating Agents and Antimetabolites

Alkylating agents and antimetabolites are classes of agents generally associated with low incidence of cardiotoxicity (see Table 69-1). Cyclophosphamide (Cytoxan) is relatively well tolerated when it is used at conventional doses, but in patients receiving conditioning regimens before autologous stem cell transplantation, which include high-dose cyclophosphamide, acute cardiotoxicity can occur.¹⁵ As opposed to the total cumulative dosage for anthracyclines, dosage in an individual course of treatment is more predictive for cyclophosphamide toxicity. Risk factors include previous anthracycline therapy and mediastinal irradiation and possibly previous imatinib therapy.¹ Clinically, patients may present with HF, myocarditis, or pericarditis. In one series of 17 consecutive patients receiving induction therapy, none of whom developed HF, LV dilation as revealed by cardiac magnetic resonance (CMR) was evident from the onset. Mechanisms underlying the toxicity are thought to be injury of both endothelial cells and myocytes, and a picture of hemorrhagic myocardial necrosis can emerge. Patients who survive the acute phase typically do not have residual LV dysfunction. High-dose ifosfamide (Ifex) induced HF in 17% of patients.

Cisplatin (Platinol)-based regimens are the cornerstone of therapy for testicular germ cell cancer, the most common malignant neoplasm in men 20 to 40 years of age; 80% of those with disseminated nonseminoma tumors achieve long-term survival. Thus, in addition to short-term toxicity, long-term toxicity is a concern in this group. Cisplatin is notable for causing hypertension, which is sometimes severe. Acute chest pain syndromes, including myocardial infarction (MI), also have been reported, possibly related to coronary spasm. Because cisplatin often is used in combination with bleomycin, an agent that can induce Raynaud phenomenon in approximately one third of patients, long-term vascular toxicity is particularly a concern. Indeed, after a median 10-year follow-up period after treatment with platinum-based regimens (cisplatin or carboplatin [Paraplatin]) versus radiation therapy, 6.7% of patients in the chemotherapy group and 10% of those in the irradiation group suffered a cardiac event, for a relative risk of 2.4- to 2.8-fold compared with patients treated with surgery only. Changes in the ratio of carotid intima-media thickness were detected as early as 10 weeks after a course of cisplatin-based chemotherapy. The morbidity data have led to calls for more conservative approaches in patients at low risk for cancer recurrence. Nephrotoxicity also is common.

Fluorouracil (Adrucil) is used in the treatment of many solid tumors, and regimens based on this agent have been the mainstay for treatment of colorectal cancer. Fluorouracil can cause acute ischemic syndromes ranging in severity from angina to MI; such syndromes can occur in patients without coronary artery disease (CAD) (approximately 1% of patients), although they are more common in patients with preexisting disease (4% to 5%). Overall, rates range from 0.55% to 8%, although more sensitive methods of detecting possible subclinical ischemia (ambulatory electrocardiographic monitoring) find much higher rates. Discontinuation of treatment with institution of standard antianginal therapies usually leads to resolution of symptoms, but ischemia often recurs if therapy is reinitiated. An alternative agent, capecitabine (Xeloda), is metabolized to fluorouracil, preferentially in tumor cells, suggesting that it may have less cardiotoxicity. However, one retrospective review (that excluded patients with “significant” cardiac disease) found an incidence of 6.5% for major cardiac events for the combination of capecitabine and oxaliplatin that included angina (4.6%), MI, ventricular tachycardia, and sudden death.¹ Vasospasm is thought to be the mechanism triggering ischemia, although thromboembolic events also are increased. Not clear at this point is whether prophylactic nitrates prevent ischemic events. Capecitabine monotherapy appears to be associated with a lower incidence of cardiac toxicity than fluorouracil monotherapy.

Proteasome Inhibitors

Bortezomib (Velcade) is an inhibitor of the proteasome system responsible for degrading improperly folded proteins and proteins that are no longer needed in the cell. The drug is approved for use in patients with multiple myeloma. The concept behind its use is that malignant cells have altered proteins regulating the cell cycle, leading to more rapid cell division and increased accumulation of damaged proteins as a result. Therefore the continued health of the malignant cell, as opposed to normal cells, may be more dependent on degradation of the damaged proteins. In support of this concept, proteasome inhibitors are more toxic to proliferating malignant cells in culture than to normal cells. Targets include activation of endoplasmic reticulum stress pathways leading to activation of proapoptotic factors and inactivation of survival factors. Cardiomyocytes have an active proteasome system, raising concerns that inhibitors may be cardiotoxic. However, in the phase III trials of bortezomib, HF developed in 5% of treated patients but also in 4% of patients in the dexamethasone arm of the trial.¹⁶ Higher rates have been reported, however, and mice treated with the agent exhibited significant LV dysfunction, ultrastructural abnormalities, and mitochondrial dysfunction.¹⁷

Other Agents

The cardiotoxicity of additional chemotherapeutic agents, including cytokines (interleukin-2 [IL-2], aldesleukin [Proleukin], and denileukin diftitox), interferons, and suberoylanilide hydroxamic acid, as well as topoisomerase inhibitors (etoposide and teniposide), purine analogues (pentostatin and cladribine), all-trans retinoic acid (ATRA), arsenic trioxide, and thalidomide and lenalidomide, is discussed in the online supplement for this chapter (Cardiovascular Complications of Additional Cancer Therapeutic Agents).