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Breast Cancer Research, Baylor Charles A. Sammons Cancer Center, Dallas, Texas, USA
Correspondence: Joyce O’Shaughnessy, M.D., Breast Cancer Research and Chemoprevention Research, US Oncology, Inc., 3535 Worth Street, Collins 5, Dallas, Texas 75246, USA. Telephone: 214-370-1795; Fax: 214-370-1850; e-mail: Joyce.O'Shaughnessy{at}usoncology.com
Conventional anthracyclines are among the most widely used agents for the treatment of breast cancer in both the adjuvant and metastatic settings. Considered a mainstay of therapy for several decades, conventional anthracycline-containing regimens have demonstrated benefits in terms of response rate, time to disease progression, and overall survival [1]. However, the clinical utility of these agents may be limited by their toxicity profiles, which include events such as myelosuppression, acute nausea and vomiting, alopecia, and cumulative cardiotoxicity [2, 3].
The overall risk of conventional anthracycline-induced cardiotoxicity is related to cumulative dose. In a retrospective study, Von Hoff and colleagues estimated that the cumulative percentage of patients developing conventional anthracycline-induced congestive heart failure (CHF) was 3% at a cumulative conventional doxorubicin dose of 400 mg/m2, increasing to 7% at 550 mg/m2 and to 18% at 700 mg/m2 [4]. However, the results of a recent analysis suggest that conventional anthracycline-induced CHF may occur at lower cumulative doses and with a somewhat greater frequency than previously observed [5]. In that study, CHF was reported at total cumulative conventional doxorubicin doses 
300 mg/m2 in 2% of patients, doses substantially lower than the currently accepted maximum lifetime cumulative dose of 450-550 mg/m2. The incidences of CHF were greater at 8% with the 450 mg/m2 and 26% with the 550 mg/m2 cumulative conventional doxorubicin doses.
More recently, researchers have focused on the development of liposomal anthracycline formulations in an effort to increase the therapeutic index of conventional anthracyclines. These liposomal formulations include liposomal daunorubicin (DaunoXome®; Gilead Sciences, Inc.; San Dimas, CA; http://www.gilead.com), liposomal doxorubicin (D-99, MyocetTM; Elan Pharmaceuticals; Princeton, NJ; http://www.elan.com), and pegylated liposomal doxorubicin (Doxil® is marketed and distributed in the U.S. by Ortho Biotech Products, Bridgewater, NJ; http://www.orthobiotech.com; Caelyx® is marketed outside the U.S. by Schering-Plough Corporation, Kenilworth, NJ; http://www.schering-plough.com). Generally, these agents exhibit efficacies comparable with those of conventional anthracyclines, but with better safety profiles and less cardiotoxicity [6–9]. Of the liposomal anthracyclines, pegylated liposomal doxorubicin is the most widely studied in patients with breast cancer, both as a single agent and in combination regimens. The demonstrated equivalent efficacy and significantly lower risk of cardiotoxicity with pegylated liposomal doxorubicin compared with conventional doxorubicin [7] have led to its recent approval in the European Union as a monotherapy for metastatic breast cancer in patients with greater cardiac risks with conventional anthracyclines, in addition to its U.S. compendium listing for patients with metastatic breast cancer. Moreover, recent evidence supports the use of pegylated liposomal doxorubicin as first-line treatment for patients with metastatic breast cancer because of its demonstrated equivalent efficacy and lower cardiac toxicity compared with conventional doxorubicin [7].
The comparable efficacies and better safety profiles of liposomal anthracyclines in metastatic breast cancer have sparked research interest in other breast cancer settings. Early studies have shown promise with liposomal doxorubicin and pegylated liposomal doxorubicin as neoadjuvant therapies in patients with locally advanced breast cancer [10]. The activities and tolerabilities of liposomal doxorubicin and pegylated liposomal doxorubicin in the metastatic and neoadjuvant settings provide the rationale for future study of these agents as adjuvant therapy for patients with early-stage breast cancer.
The better safety profiles and tolerabilities of liposomal anthracyclines have also created interest in the potential use of these agents in combination with novel biologic growth modulators, the most promising of which is the anti-HER2 monoclonal antibody, trastuzumab [11]. To date, combination treatment regimens of trastuzumab and the liposomal anthracyclines currently under investigation have shown better cardiac safety than that observed when trastuzumab was combined with conventional doxorubicin [12–15].
In this supplement, Dr. Rivera provides a clinical update on the efficacies and safety profiles of liposomal anthracyclines, both as single agents and in combination regimens for the treatment of metastatic breast cancer [8]. Dr. Campos discusses the role of liposomal anthracyclines in the metastatic and neoadjuvant breast cancer settings and also addresses the potential use of these agents in the adjuvant setting [10]. Dr. Safra focuses specifically on the cardiac safety of liposomal anthracyclines [9]. Finally, Dr. Wolff describes future directions and new treatment strategies in metastatic breast cancer, with emphasis on the combination of growth and survival pathway modulators and cytotoxic agents such as liposomal anthracyclines [11]. As progress continues in treating breast cancer, new agents and treatment combinations promise to further increase overall survival and quality of life in patients fighting this disease.
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