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The Oncologist, Vol. 8, Suppl 2, 17–24, August 2003
© 2003 AlphaMed Press

Cardiac Safety of Liposomal Anthracyclines

Tamar Safra

Institute of Oncology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

Correspondence: Tamar Safra, M.D., Institute of Oncology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel 64239. Telephone: 972-3-6974831; Fax: 972-3-6974828; e-mail: safrat{at}bezeqint.net


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Liposomal Anthracyclines
 MUGA Scan Recommendations
 Round-table Discussion
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Describe the cardiac toxicity profiles of conventional anthracyclines.
  2. Discuss the published data evaluating the cardiac safety of liposomal anthracyclines.
  3. Describe MUGA scan monitoring recommendations for patients treated with liposomal anthracyclines.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Liposomal Anthracyclines
 MUGA Scan Recommendations
 Round-table Discussion
 Conclusions
 References
 
Anthracyclines have demonstrated antitumor activity in a variety of cancers; however, irreversible cardiac damage is a major dose-limiting toxicity, restricting lifetime cumulative dose. The most successful strategy to improve the cardiac safety of anthracyclines to date involves liposomal encapsulation, which alters the tissue distribution and pharmacokinetics of these agents. The cardiac safeties of liposomal daunorubicin, liposomal doxorubicin (D-99), and pegylated liposomal doxorubicin have been studied in several clinical trials. The lack of published data comparing liposomal daunorubicin with conventional daunorubicin makes it difficult to draw meaningful conclusions regarding the relative cardiac safeties of these formulations. Studies indicate that the risk of anthracycline-induced cardiotoxicity is considerably lower with liposomal doxorubicin formulations than with conventional doxorubicin. Pegylated liposomal doxorubicin has been studied most extensively and has demonstrated the most significant reductions in risk for cardiotoxicity. Compared with conventional doxorubicin, pegylated liposomal doxorubicin has shown similar efficacy with a significantly lower incidence of cardiotoxicity and significantly fewer cardiac events. Although the long-term cardiac safety of these agents is unknown, data suggest that liposomal anthracyclines, particularly pegylated liposomal doxorubicin, may offer a significant clinical benefit for patients with higher risks for anthracycline-induced cardiotoxicity.

Key Words. Anthracyclines • Liposome • Doxorubicin • Drug toxicity • Breast neoplasms


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Liposomal Anthracyclines
 MUGA Scan Recommendations
 Round-table Discussion
 Conclusions
 References
 
Although conventional anthracyclines have been used extensively for the treatment of a variety of cancers, they can be associated with the development of substantial cardiotoxicity that is both cumulative and irreversible. Based primarily on clinical events reported retrospectively, the incidence of cardiotoxicity is approximately 7.5% at cumulative conventional doxorubicin doses up to 550 mg/m2 [1] and can be as high as 27% when similar cumulative doses are combined with other agents such as trastuzumab and cyclophosphamide [2]. A recent analysis of three phase III trials of patients (n = 630) treated with conventional doxorubicin in combination with other chemotherapeutic agents or radiation therapy suggests that conventional doxorubicin-associated cardiac events may occur more frequently and at lower cumulative doses than previously reported [3]. In that retrospective analysis, the estimated cumulative percentages of patients developing doxorubicin-related congestive heart failure (CHF) were 5% at a cumulative conventional doxorubicin dose of 400 mg/m2, 26% at a dose of 550 mg/m2, and 48% at a dose of 700 mg/m2. Moreover, CHF was reported at markedly lower cumulative conventional doxorubicin doses (<=300 mg/m2) than the currently accepted maximum lifetime cumulative dose (450-550 mg/m2).

The risk for cardiac damage may result in reluctance by oncologists to use conventional anthracyclines [4]. Patients initially responding to treatment with an anthracycline face the prospect of having to discontinue therapy after reaching dose levels near the maximum recommended cumulative dose (approximately 450-550 mg/m2), and anthracycline use may compromise quality of life in young patients who will live long after treatment has ended. Another limitation of anthracycline therapy is a problematic reexposure when disease recurs.

Anthracycline-induced cardiotoxicity manifests in several forms, ranging from acute arrhythmias and nonspecific electrocardiogram changes to decreases in left ventricular ejection fraction (LVEF) [4–6]. The most serious cardiac toxicity is cardiomyopathy, which can lead to permanent damage. The mechanisms by which these changes are believed to occur include the development of cardiomyopathy as the result of free radical damage to the myocytes [7, 8] and are related to high peak plasma anthracycline levels [9, 10]. Repeated damage to the mitochondria and defenses against free radicals are believed to contribute to cumulative cardiomyopathy [11].

Several factors increase the risk of developing irreversible cardiotoxicity. These include the extent of anthracycline exposure (patients who have received higher cumulative doses are more likely to experience cardiac problems), age (both elderly and very young patients have greater risks), a history of cardiac disease, and previous cancer therapies such as mediastinal radiation therapy, high-dose anthracycline infusion, and the concurrent use of chemotherapy regimens that include paclitaxel or trastuzumab [4, 7].

Current strategies for myocardial protection include the use of anthracycline analogs such as epirubicin. Although epirubicin cardiotoxicity occurs at a higher cumulative dose (>900 mg/m2, compared with 550 mg/m2 with conventional doxorubicin), a decrease in LVEF >=10% has been observed at cumulative epirubicin doses of 450 mg/m2 [4]. Another strategy involves the use of low-dose prolonged continuous infusion of conventional doxorubicin, which has also been shown to result in a lower incidence of cardiotoxicity compared with that seen in standard dosing controls [10]. Similarly, the administration of ICRF-187 (dexrazoxane), an agent that prevents free radical formation, improves the cardiac safety of anthracyclines significantly, though there is a possibility of a reduction in antitumor efficacy [12, 13]. There is no evidence to suggest that continuing therapy with a conventional or liposomal anthracycline and dexrazoxane prolongs response. A practical strategy that allows for the continuation of anthracycline therapy without appreciable risk of cardiotoxicity is liposomal encapsulation, which has been done in an effort to maintain efficacy and improve the safety of conventional anthracyclines [8]. More specifically, it is thought that at least two factors may contribute to the lower cardiotoxicity associated with liposomal anthracyclines: A) changes in tissue distribution with less drug exposure to sensitive organs, such as the heart muscle, and B) slow release of the drug, which may avoid high peak plasma concentrations [14].


   LIPOSOMAL ANTHRACYCLINES
Top
 Learning Objectives
 Abstract
 Introduction
 Liposomal Anthracyclines
MUGA Scan Recommendations
 Round-table Discussion
 Conclusions
 References
 
There are three liposomal anthracycline formulations currently under investigation in the U.S.: 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, L.P., Bridgewater, NJ; http://www.orthobiotech.com; Caelyx® is distributed outside the U.S. by Schering-Plough Corporation, Kenilworth, NJ; http://www.schering-plough.com). The cardiac safety profiles of each of these liposomal anthracyclines are described in detail in the following sections.

Liposomal Daunorubicin
Although liposomal daunorubicin is used more often in myeloid malignancies than in solid tumors, its cardiac safety profile is noteworthy for this discussion. Early clinical studies indicated that liposomal daunorubicin may have a more favorable cardiac safety profile than the conventional formulation [15–17]. However, evidence of cardiotoxicity has been observed at higher cumulative doses of liposomal daunorubicin (600-900 mg/m2) [18, 19].

O’Byrne and colleagues conducted a phase I dose-escalation study to determine the maximum tolerated dose, safety profile, and activity of liposomal daunorubicin in the treatment of metastatic breast cancer (MBC) [18]. Sixteen anthracycline-naïve patients received 2-hour infusions of liposomal daunorubicin given every 21 days. Dose escalation started with an initial dose of 80 mg/m2 and was increased to 100, 120, and 150 mg/m2 thereafter; cohorts of at least three patients were treated at each dose level, with no intrapatient dose escalation permitted. All patients had normal cardiac function at baseline, with LVEFs >50%. The maximum tolerated dose in that study was 120 mg/m2, with dose-limiting toxicities of prolonged grade 4 neutropenia or neutropenic pyrexia. Significant asymptomatic cardiotoxicity was reported in three patients. One patient, who had received a cumulative liposomal daunorubicin dose of 800 mg/m2, experienced a decrease in LVEF from 65% to 50%. Another patient, with a history of adjuvant conventional doxorubicin treatment (prior cumulative dose of 300 mg/m2) and a cumulative liposomal daunorubicin dose of 600 mg/m2, experienced a decrease in LVEF from 75% to 46%, and the third patient (who had received a cumulative liposomal daunorubicin dose of 960 mg/m2) experienced an LVEF decrease from 84% to 57%.

Fassas and colleagues conducted a phase I/II dose-escalation study of single-agent liposomal daunorubicin in patients with relapsed or refractory acute myeloid leukemia (AML) and a history of anthracycline treatment [19]. A total of 28 patients received escalating doses of 75, 100, 125, or 150 mg/m2 of liposomal daunorubicin for 3 consecutive days; cohorts of six patients were treated at each dose level. There was no evidence of cardiotoxicity at doses of 75, 100, or 125 mg/m2, up to a cumulative dose of 375 mg/m2. At the 150-mg/m2 dose level, two patients developed cardiotoxicity and died (one of whom had received a cumulative liposomal daunorubicin dose of 900 mg/m2), although the relationship to treatment was not disclosed. Of the 14 patients who completed 6 months of follow-up, LVEF dropped to below 45% in one patient, with no clinical signs or symptoms. The highest acceptable cumulative dose of liposomal daunorubicin in that study was identified as 750 mg/m2.

A lack of published clinical studies that compare the cardiac safety of liposomal daunorubicin with that of conventional daunorubicin makes it difficult to draw meaningful conclusions regarding the relative cardiac safeties of these formulations. Therefore, more studies are needed to determine the maximum tolerated cumulative dose of liposomal daunorubicin and to define further its cardiac safety.

Liposomal Doxorubicin (D-99)
While liposomal doxorubicin is still under investigation in the U.S., it is approved in the European Union in combination with cyclophosphamide as a first-line treatment for MBC. The majority of clinical trials have been conducted in MBC; however, liposomal doxorubicin is also being studied in other tumor types, including non-Hodgkin’s and AIDS-related lymphomas and Kaposi’s sarcoma [20, 21]. Several studies have been published that discuss the cardiac safety profile of liposomal doxorubicin in women with MBC [22–24]. Similar to what was observed with liposomal daunorubicin, higher doses of liposomal doxorubicin were associated with a greater risk for cardiotoxicity [24].

Harris and colleagues compared the cardiac safety of liposomal doxorubicin with that of conventional doxorubicin in 224 patients with MBC and a cumulative lifetime adjuvant conventional doxorubicin dose <=300 mg/m2 [22]. In that phase III study, patients received either liposomal doxorubicin, 75 mg/m2, or conventional doxorubicin, 75 mg/m2, as 1-hour infusions given every 3 weeks. Although the median time to progression was similar in both treatment groups (3.8 months for liposomal doxorubicin versus 4.3 months for conventional doxorubicin, p = 0.59), significant differences were noted with respect to cardiac safety. Patients who received liposomal doxorubicin experienced significantly fewer cardiac events than those receiving conventional doxorubicin (13% versus 29%, respectively, p = 0.0001), and significantly fewer patients treated with liposomal doxorubicin developed CHF (2% versus 8% of patients receiving conventional doxorubicin, p = 0.0001). The median cumulative doxorubicin dose at the onset of cardiotoxicity was significantly higher in patients treated with liposomal doxorubicin: 785 mg/m2 compared with 570 mg/m2 in patients receiving conventional doxorubicin (p = 0.0001, hazard ratio [HR] = 3.56).

The cardiac safety of liposomal doxorubicin has also been evaluated as part of a combined treatment regimen with cyclophosphamide [23]. A phase III study conducted by Batist and colleagues evaluated 297 patients with MBC who had received a cumulative lifetime doxorubicin dose of <=300 mg/m2. Patients received either liposomal doxorubicin, 60 mg/m2, or conventional doxorubicin, 60 mg/m2, in combination with cyclophosphamide, 600 mg/m2, every 3 weeks until disease progression or unacceptable toxicity occurred. Liposomal doxorubicin demonstrated efficacy comparable with conventional doxorubicin, but with a better cardiac safety profile. Specifically, the response rate was 43% in both treatment groups, while the median time to progression was 5.1 months in patients receiving liposomal doxorubicin and 5.5 months in patients receiving conventional doxorubicin (p = 0.82). Cardiotoxicity was noted in 6% of patients treated with liposomal doxorubicin, compared with 21% of patients treated with conventional doxorubicin (p = 0.0001). Although none of the patients receiving liposomal doxorubicin developed CHF, it was documented in five patients who received conventional doxorubicin (p = 0.02). The onset of cardiotoxicity was also identified to occur at significantly higher median cumulative doses with liposomal doxorubicin (estimated at >2,200 mg/m2) than with conventional doxorubicin (480 mg/m2, p = 0.0001, HR = 5.04).

Shapiro and colleagues investigated high doses of liposomal doxorubicin (135 mg/m2) with filgrastim (5 µg/kg) as first-line treatment for patients with MBC [24]. Fifty-two patients were enrolled in that study and received a median cumulative liposomal doxorubicin dose of 405 mg/m2 (range 135-1,065 mg/m2). Greater doses of liposomal doxorubicin did not improve efficacy and resulted in considerable cardiac toxicity. Cardiac events were observed in 38% of patients, and 13% developed CHF. One patient died of cardiomyopathy after a cumulative liposomal doxorubicin dose of 1,035 mg/m2.

These studies indicate that the activity of liposomal doxorubicin in MBC is similar to that of conventional doxorubicin, whether given alone or in combination, and that the risk of developing cardiotoxicity is significantly lower with liposomal doxorubicin [22, 23]. However, cardiac toxicity may be greater when higher doses are administered [24].

Pegylated Liposomal Doxorubicin
The first evidence of a better cardiac safety profile associated with pegylated liposomal doxorubicin was provided by a retrospective endomyocardial biopsy study conducted in 10 patients with Kaposi’s sarcoma [25]. Patients in that study received cumulative doses of pegylated liposomal doxorubicin of 440-880 mg/m2 or conventional doxorubicin of 174-671 mg/m2. The preliminary results were promising: the median Billingham scale biopsy scores were significantly lower in patients treated with pegylated liposomal doxorubicin (0.3 versus 3.0 with conventional doxorubicin, respectively, p = 0.002), suggesting a lower risk for developing cardiotoxicity.

The improved cardiac safety of pegylated liposomal doxorubicin has been confirmed in two larger scale studies [26, 27]. The first of these, conducted by Safra and colleagues, was a retrospective review of patients with solid tumors who had received pegylated liposomal doxorubicin in one of eight phase I or II studies [26]. Forty-two of the 237 patients included in those studies had received cumulative doses of pegylated liposomal doxorubicin ranging from 500-1,500 mg/m2 (median dose of 660 mg/m2), and seven of those patients had also received conventional doxorubicin prior to study entry. All patients had undergone clinical assessment of cardiac status that included determination of LVEF by multigated acquisition (MUGA) scan.

Following treatment with pegylated liposomal doxorubicin, the median change in LVEF was –2% (range from –15% to +9%). Although no clinical evidence of cardiac symptoms was observed at the 6-month follow-up visit, five patients experienced LVEF decreases >10%. No correlation was observed between cumulative dose of pegylated liposomal doxorubicin and change in LVEF (Fig. 1Go). In the six patients who underwent endomyocardial biopsy procedures after receiving cumulative doses of pegylated liposomal doxorubicin of 480-1,320 mg/m2, Billingham biopsy scores ranged from 0-1.5, with no cardiac symptoms present [26].



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  		Figure 1. Changes in LVEF with cumulative pegylated liposomal doxorubicin doses >=500 mg/m2 [26].

 
Further analyses indicated that there were no significant differences in the incidence of cardiotoxicity with respect to dose intensity, the number of prior treatment regimens, age, or survival time. The finding that three of seven patients with prior conventional doxorubicin exposure had LVEF decreases >=10% is important, as it may indicate that patients with histories of conventional doxorubicin treatment may have higher risks for cardiotoxicity if later challenged with a related agent. However, the small sample size of that study makes it difficult to interpret this particular finding. Thus, the authors concluded that the use of pegylated liposomal doxorubicin at cumulative doses >500 mg/m2 was associated with a considerably lower risk of cardiotoxicity than similar doses of conventional doxorubicin [26].

A second large-scale study evaluated progression-free survival and cardiac safety in patients receiving pegylated liposomal doxorubicin or conventional doxorubicin as a first-line therapy for MBC [27]. In that prospective study conducted by Wigler and colleagues, 509 patients with no prior history of heart disease received 1-hour infusions of either pegylated liposomal doxorubicin, 50 mg/m2 once every 4 weeks, or conventional doxorubicin, 60 mg/m2 once every 3 weeks. Cardiac safety was measured using MUGA scans to assess LVEF at baseline and throughout the study. Patients were also monitored for signs and symptoms of CHF. Cardiotoxicity was defined as a decrease in LVEF >=20% from baseline, when the resting LVEF remained in the normal range, or a decrease >=10%, when the LVEF decreased below the lower limit of normal for that particular institution. Both treatment groups were well matched with respect to baseline cardiac risk factors. In total, 48% of patients treated with pegylated liposomal doxorubicin and 47% of patients treated with conventional doxorubicin had at least one cardiac risk factor. The groups were also well matched with respect to prior adjuvant conventional anthracycline therapy: 15% and 16% of the pegylated liposomal doxorubicin and conventional doxorubicin groups, respectively, had histories of conventional anthracycline treatment.

Although progression-free survival was similar for both treatment groups (for a detailed discussion of efficacy, see [28]), the incidence of cardiac toxicity was significantly lower with pegylated liposomal doxorubicin (p = 0.001) (Table 1Go). Only 10 patients who received pegylated liposomal doxorubicin developed LVEF-defined cardiotoxicity, compared with 48 patients who received conventional doxorubicin, suggesting that the use of pegylated liposomal doxorubicin translates to a nearly fivefold lower incidence of cardiac events. In addition, no patients treated with pegylated liposomal doxorubicin developed cardiotoxicity with signs and symptoms of CHF, compared with 10 patients treated with conventional doxorubicin. Among patients who received pegylated liposomal doxorubicin, cumulative doses that exceeded 450 mg/m2 were not associated with a significant decrease in LVEF from baseline (Fig. 2Go) [27].


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  		Table 1. Incidence of cardiotoxicity: pegylated liposomal doxorubicin versus conventional doxorubicin [27]
 


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  		Figure 2. Median percentage change in LVEF based on cumulative anthracycline dose. Among patients receiving pegylated liposomal doxorubicin, cumulative doses exceeding 450 mg/m2 were not associated with a significant decrease in LVEF [27].

 
The risk for developing a cardiac event was significantly lower in patients treated with pegylated liposomal doxorubicin than in patients treated with conventional doxorubicin (p < 0.001, HR = 3.16). Among all treated patients, at cumulative doses of >500-550 mg/m2, the risk for developing a cardiac event was 11% with pegylated liposomal doxorubicin, compared with a 40% risk in the conventional doxorubicin group. In groups of patients with high risks for developing cardiotoxicity, the risk of developing a cardiac event was significantly lower for patients treated with pegylated liposomal doxorubicin than for those treated with the conventional formulation (Table 2Go). As an example, in the subgroup that received prior adjuvant conventional anthracycline treatment, the risk of developing cardiotoxicity was approximately seven times higher with conventional doxorubicin than with pegylated liposomal doxorubicin [27].


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  		Table 2. Lower cardiotoxicity of pegylated liposomal doxorubicin in high-risk patients [27]
 
Based on these results, pegylated liposomal doxorubicin appears to be associated with a significantly better cardiac safety profile than conventional doxorubicin, with comparable efficacy when used as a first-line treatment for MBC. Moreover, pegylated liposomal doxorubicin therapy resulted in a significantly lower risk for cardiotoxicity in patients with cardiac risk factors present at baseline, particularly in those who had received prior adjuvant anthracycline treatment.

Taken together with the results of Safra and colleagues [26], it is apparent that cumulative doses of pegylated liposomal doxorubicin >500 mg/m2 are associated with a significantly lower risk of cardiotoxicity than conventional doxorubicin. Thus, pegylated liposomal doxorubicin may offer the clinical benefit of allowing patients to receive higher cumulative doses (compared with conventional doxorubicin) over a longer period of time, ultimately resulting in greater drug exposure. For example, in a histologic assessment of patients with advanced malignancies who received a median pegylated liposomal doxorubicin dose of 708 mg/m2, minimal cardiotoxicity was observed (median endomyocardial biopsy score [Billingham scale] = 0.75) [29]. Likewise, data from a series of patients with AIDS-related Kaposi’s sarcoma suggest that some patients may tolerate cumulative pegylated liposomal doxorubicin doses up to 2,360 mg/m2 (given over a 5-year period) with little or no decrease in cardiac function, although these findings require confirmation in controlled clinical trials [30].

Further study is also warranted to determine the feasibility of combining pegylated liposomal doxorubicin with other treatment modalities, such as the taxanes, trastuzumab, and chest irradiation. Although not yet proven, it is hoped that the ability to administer prolonged liposomal anthracycline therapy (either alone or in combination with other agents) will benefit patients by further extending both progression-free and overall survival rates.


   MUGA SCAN RECOMMENDATIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Liposomal Anthracyclines
 MUGA Scan Recommendations
Round-table Discussion
 Conclusions
 References
 
Baseline MUGA scans should be performed on all patients treated with pegylated liposomal doxorubicin. Because there are no safety data available for patients with preexisting heart disease, patients with LVEFs <50% at baseline should not be considered appropriate candidates for liposomal anthracycline therapy. Repeat MUGA scans should be performed after the cumulative dose reaches 400 mg/m2, and again at every 100- to 120-mg/m2 cumulative dose increase thereafter. In patients who have received prior anthracycline treatment, MUGA scans should be performed more frequently, after every 200-mg/m2 dose increment. Regardless of prior anthracycline use, treatment should be stopped immediately if clinical signs of cardiotoxicity appear. If cardiac decompensation is suspected, a complete cardiac evaluation—including MUGA scan—is warranted before the decision is made to continue treatment.


   ROUND-TABLE DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Liposomal Anthracyclines
 MUGA Scan Recommendations
 Round-table Discussion
Conclusions
 References
 
Our round table of experts discussed the implications of these cardiac safety studies, specifically those studies with pegylated liposomal doxorubicin, which generated several points that deserve additional consideration. For example, discussion focused on the question of whether previous anthracycline exposure in the adjuvant setting should limit cumulative doses of pegylated liposomal doxorubicin. While results demonstrate significantly less cardiotoxicity with pegylated liposomal doxorubicin than conventional doxorubicin in the metastatic setting, one cannot say conclusively that it is not a cardiotoxic drug. We do not know enough about the subclinical and long-term toxicities of pegylated liposomal doxorubicin or other liposomal anthracyclines; therefore, this needs to be examined thoroughly before we can make any definitive conclusions about the long-term cardiac safety of these agents.

Unfortunately, determining the long-term cardiac effects of liposomal anthracyclines is challenging, because patients who receive high cumulative doses of these drugs (i.e., in the metastatic setting) rarely live long enough to provide long-term safety data. Round table participants agreed that the decision to give relatively high doses of pegylated liposomal doxorubicin to patients who had received substantial doses of conventional doxorubicin in the adjuvant setting (i.e., cumulative dose up to 360 mg/m2) depends on the specific situation. If a patient experiences recurrent disease, participants agreed that high doses of pegylated liposomal doxorubicin would be a valid option because long-term survival in those patients is unlikely. However, in patients who may have received adjuvant conventional doxorubicin in the past but now may benefit from additional adjuvant therapy (perhaps disease was found in the other breast), participants said that they would be more likely to be conservative when dosing pegylated liposomal doxorubicin, since the subclinical and long-term cardiac effects of this drug have not been established.


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Liposomal Anthracyclines
 MUGA Scan Recommendations
 Round-table Discussion
 Conclusions
References
 
Despite their excellent antitumor activity in MBC, the clinical use of conventional anthracyclines is limited by their associated toxicities, particularly cardiotoxicity. In fact, results from a recent retrospective analysis of three phase III trials suggest that cardiotoxicity associated with conventional anthracycline combinations occurs more frequently and at lower cumulative doses (5% CHF at a cumulative dose of 400 mg/m2 of conventional doxorubicin) than previously reported in the literature [3]. In an effort to improve the therapeutic index of anthracyclines, several liposomal anthracycline formulations have been developed and studied in patients with MBC and other malignancies. More studies are needed to define the cardiac safety of liposomal daunorubicin. Liposomal doxorubicin and pegylated liposomal doxorubicin have demonstrated improved cardiac safety profiles compared with conventional doxorubicin. Pegylated liposomal doxorubicin has been studied the most extensively, and results show similar efficacy to conventional doxorubicin in patients with MBC, with a significantly lower risk for cardiotoxicity.

Some oncologists may not be aware of these data and, therefore, may not realize the magnitude of difference in cardiac safety between liposomal anthracyclines (particularly pegylated liposomal doxorubicin) and conventional anthracyclines. While we do not yet know the long-term cardiac safety implications associated with these liposomal formulations, it can be concluded that liposomal doxorubicin and pegylated liposomal doxorubicin demonstrate significantly less cardiotoxicity than conventional doxorubicin in patients with MBC. These results may translate into a clinical benefit for patients with higher risks for anthracycline-induced cardiotoxicity.


   FOOTNOTES
Top
 Learning Objectives
 Abstract
 Introduction
 Liposomal Anthracyclines
 MUGA Scan Recommendations
 Round-table Discussion
 Conclusions
 References
 
This material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Reprints{at}AlphamedPress.com


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Liposomal Anthracyclines
 MUGA Scan Recommendations
 Round-table Discussion
 Conclusions
 References
 

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Received July 7, 2003; accepted for publication August 13, 2003.




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