Anthracycline-induced cardiotoxicity and the cardiac-sparing effect of liposomal formulation

Abstract

The anthracyclines are a group of antibiotics that are among the most potent chemotherapeutic agents. They are highly effective against a broad spectrum of malignancies, including lymphoma, gastric cancer, small cell lung cancer, sarcoma, and breast cancer. Unfortunately, these agents also exhibit a well-recognized cumulative-dose related cardiotoxic profile that limits the extent to which they can be used safely. In clinical practice, most clinicians limit the cumulative dose of doxorubicin (the most widely used agent in this group) to 400-450 mg/m2, but considerable cardiac damage is now known to occur at cumulative dosages considerably below this level. Regimens using newer combinations of agents, the most widely studied of which is the monoclonal antibody trastuzumab, are known to augment the cardiotoxicity of anthracyclines. The application of nanotechnology to medicine involves the use of devices that will interact with the body at the molecular level. These methods can lead to target and tissue specific clinical application, often with minimal or reduced side effects. Liposomal preparations incorporate such technology, thereby altering some important characteristics of the parent compound and facilitating concentration at the tumor site. In the case of liposomal doxorubicin, cardiotoxicity is reduced significantly. This review summarizes the important information on the liposomal preparation of anthracyclines.

Figure 1

Electron micrographs showing examples of representative field of a high-grade biopsy (Billingham score of 3.0) obtained from a solid-tumor patient who received more than 400 mg/m² conventional doxorubicin. Severe diffuse damage to >35% of all cells was seen. Necrotic cell is shown with extensive myofibrillar loss (A). Another cell is seen with extensive vacuolization (B, center). Magnification is indicated by a bar in each frame. (Micrographs courtesy of Gerald Berry MD, Stanford University School of Medicine (Ewer et al 2004)).

Figure 2

Cumulative time to a cardiotoxicity endpoint, defined as a decrease in LVEF by more than 20 units to a value >50%, a decrease in LVEF by more than 10 units to a value <50%, or CHF. (A) Patients who received either NPLD alone or conventional doxorubicin alone (Dox) in a dose of 75 mg/m² every 3 weeks. From Harris L, Batist G, Belt R, et al 2002. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer, 94:25–36. Copyright © 2002 American Cancer Society. This material is reproduced with permission of Wiley-Liss, Inc., a subsidiary of John Wiley and Sons, Inc. (B) Patients who received cyclophosphamide 600 mg/m² every 3 weeks plus either NPLD (MC) or conventional doxorubicin (AC) in a dose of 60 mg/m² every 3 weeks. Reprinted with permission from Batist G, Ramakrishnan G, Rao CS, et al 2001. Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol, 19:1444–54. Copyright © 2001 American Society of Clinical Oncology.

Figure 3

Cardiac event-free survival for PLD versus conventional doxorubicin in a randomized comparison of 509 patients with metastatic breast cancer. Cardiac event was defined as a decrease in LVEF by more than 20 units to a normal value, a decrease in LVEF by more than 10 units to an abnormal value, or CHF Patients received either PLD 50 mg/m² every 4 weeks or conventional doxorubicin 60 mg/m² every 3 weeks. The cumulative anthracycline dose included exposure before entry onto trial plus the total amount received during the course of the study. Adapted with permission from O’Brien ME, Wigler N, Inbar M, et al. 2004. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol, 15:440–9. Copyright © 2004 Oxford University Press.