Researchers have also looked into serum markers such as troponin T and B‑type natriuretic peptide (BNP) for earlier detection of cardiotoxicity, but due to small sample sizes and short follow-up, their ability to predict either early or long-term toxicity have not been established.
Prevention and Management
Besides limiting the lifetime dose of doxorubicin to less than 450 to 500 mg/m2, several strategies have been developed to prevent and manage anthracycline-induced cardiotoxicity such as administration schedule, cardioprotectants, and new formulations (Table 2).
Administration Schedule
Several studies have indicated that high peak serum levels of anthracycline may increase the risk of cardiac injury, and administration schedules that result in lower serum drug levels may be cardioprotective.[40,41] For adults, continuous infusions of doxorubicin have been reported to be less cardiotoxic than bolus administration, as suggested by a meta-analysis comparing bolus infusion (up to 1 hour) with a longer infusion duration (varying from 6 to 96 hours).[42] Despite the possible benefit of prolonged doxorubicin infusion schedules, most doxorubicin is still given via bolus therapy, as the frequent need for hospitalization and placement of a central venous catheter make this approach less attractive to patients.
Liposomal Anthracyclines
Liposomal anthracyclines have been developed in an attempt to improve the cardiac safety profile of conventional anthracyclines. Due to their size, liposomes cannot escape the circulation through the tight capillary junctions found in normal tissue such as the heart, but can escape selectively through the weakened vasculature that feeds tumor cells.[43]
In several studies of women with metastatic breast cancer, monotherapy with liposomal products showed similar efficacy and reduced cardiotoxicity compared with conventional doxorubicin.[44,45] Liposomal products have also been evaluated in combination with trastuzumab in multiple phase II studies for patients with HER2-positive metastatic breast cancer, showing promising results with good efficacy and decreased risk of development of CHF. An ongoing randomized phase II multinational trial will evaluate the cardiotoxicity of doxorubicin-based and a liposomal doxorubicin (Doxil)-based adjuvant chemotherapy regimen in 180 women with early-stage breast cancer.[45]
Dexrazoxane
Dexrazoxane is the only US Food and Drug Administration (FDA)-approved cardioprotectant designed to decrease the effects of anthracyclines on the heart. It is an iron-chelating agent that reduces free-radical generation by anthracyclines, thereby preventing damage to cardiomyocytes. Dexrazoxane was approved for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer.[46] Current American Society of Clinical Oncology guidelines recommend its use for this indication only, and caution against its use in malignancies where doxorubicin has been shown to increase survival, because such agents are thought to reduce the efficacy of therapy.[47]
ACE Inhibitors/ARBs
The renin-angiotensin system plays an important role in the pathophysiology of hypertensive and ischemic heart disease in humans. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) can reduce left-ventricular afterload and slow the progression of left-ventricular dysfunction. Interestingly, studies in rats showed that concurrent use of ACE inhibitors with doxorubicin prevents the decline in cardiac function related to doxorubicin.[48]
