This report was reviewed for medical and scientific accuracy by Malgorzata E. Wojtowicz, MD, Assistant Professor of Medicine, Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Editorial

Tamar Safra, MD, Medical Oncologist, Chief Physician Oncology Division, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

The cytotoxic anthracycline doxorubicin is highly efficacious and is widely used in clinical practice to treat a variety of tumor types. However, its clinical utility is restricted by cumulative dose-limiting cardiac toxicity. At least 7.5% of patients receiving a cumulative doxorubicin dose of ≥550 mg/m² experience clinical cardiomyopathy.¹ To avoid this potentially life-threatening toxicity, an empirical dose limit of 500 mg/m² has been suggested as a strategy to minimize the risk of cardiomyopathy.²

Liposomal formulations have been developed to increase the therapeutic index of anthracyclines—specifically to reduce cardiac toxicity and allow the use of higher cumulative doses. Data presented at the 38th Annual Meeting of the American Society of Clinical Oncology held May 18-21, 2002 in Orlando, Florida, provided evidence of the comparable efficacy and improved cardiac safety of two forms of liposomal doxorubicin, one of which was compared to conventional doxorubicin. Wigler and colleagues presented the results of a multicenter, randomized phase III trial comparing pegylated liposomal doxorubicin (Doxil®-in U.S., Caelyx®-international) to conventional doxorubicin administered to 509 women with metastatic breast cancer.³ In this study, pegylated liposomal doxorubicin was associated with similar efficacy (progression-free survival and overall survival) and significantly less cardiac toxicity than conventional doxorubicin. Only 2 patients treated with pegylated liposomal doxorubicin manifested clinical signs and symptoms of congestive heart failure (no decrease in left ventricular ejection fraction (LVEF) percentage) compared to ten patients in the doxorubicin treatment arm. This improved cardiac safety profile extended to patients typically considered at high risk for cardiac toxicity, including patients ≥55 years of age, those with a history of adjuvant anthracycline therapy, or those with cardiac risk factors. Most notably, patients with a history of adjuvant anthracycline therapy treated with conventional doxorubicin were more than 7 times more likely to develop cardiac toxicity than patients treated with pegylated liposomal doxorubicin. This finding, in particular, suggests that cardiac toxicity can be minimized by use of pegylated liposomal doxorubicin in the place of conventional doxorubicin in high-risk patients, particularly those with a history of adjuvant anthracycline therapy.

Data presented by Theodoulou and colleagues suggest that substitution of liposomal doxorubicin (TLC D99, Myocet™) for conventional doxorubicin can also reduce the risk for cardiac toxicity in HER2-positive metastatic breast cancer patients requiring a combination of anthracycline and trastuzumab regimens.⁴ Of the 39 patients treated with combination liposomal doxorubicin and trastuzumab (Herceptin®) therapy for a median of 6 cycles (median cumulative doxorubicin dose, 360 mg/m²), only 2 patients experienced cardiac toxicity (reversible in both cases). Although this was a noncomparative study, these findings are noteworthy considering the known cardiotoxicity of conventional doxorubicin and trastuzumab in combination.⁵ These promising results warrant additional large-scale studies designed to confirm the improved cardiac safety of liposomal doxorubicin and trastuzumab combination regimens.

Liposomal Anthracyclines: Reducing the Risk and Incidence of Cardiac Toxicity

Liposomal encapsulation has been reported to reduce the risk of cardiac toxicity, the cumulative dose-limiting toxicity of doxorubicin, presumably by altering the pharmacokinetics of the drug. Pegylated liposomal doxorubicin, one of 3 liposomal anthracyclines, exhibits a longer half-life⁶ (approximately 55 hours) and smaller volume of distribution⁶ (approximately equal to plasma volume) than conventional doxorubicin.⁷ Pegylated liposomal doxorubicin consists of small (~100 nanometer) rigid liposomes, onto which a polymeric coat of polyethylene glycol has been grafted. These pegylated liposomes display inhibited interaction with plasma proteins and mononuclear phagocytes resulting in lower peak plasma levels and preferential delivery to tissues with increased microvascular permeability. These properties are likely to contribute to the reduced incidence of dose-limiting toxicities observed in studies of pegylated liposomal doxorubicin. In contrast, liposome-encapsulated doxorubicin (Myocet™) consists of moderately sized (~190 nanometer) liposomes and provides a limited degree of prolonged circulation as compared with conventional doxorubicin.

Published reports indicate a relatively low incidence of cardiotoxicity among patients treated with "high" doses of pegylated liposomal doxorubicin (≥500 mg/m²). A retrospective analysis of patients administered cumulative doses of ≥500 mg/m² (N = 41) in phase I and phase II trials of pegylated liposomal doxorubicin suggested that the risk of cardiomyopathy is less with pegylated liposomal doxorubicin than with conventional doxorubicin.⁸ In these studies, none of the 41 patients treated with doses ≥500 mg/m² experienced clinical signs and symptoms of congestive heart failure, and a decline of ≥10% of LVEF was observed in only 5 of 41 patients undergoing post-treatment multiple-gated acquisition (MUGA) scans. Prior anthracycline exposure could be a significant contributor to cardiac toxicity, as a decline of ≥10% LVEF was observed in 3 of 7 patients with prior doxorubicin, while a similar reduction of cardiac function was observed in only 2 of 34 patients with no prior doxorubicin exposure (P = .028).

The improved cardiac safety profile of pegylated liposomal doxorubicin compared to conventional doxorubicin is further supported by the results of a comparative study in which myocardial biopsies from 10 patients with AIDS-related Kaposi's sarcoma, treated with cumulative doses of pegylated liposomal doxorubicin of 440-840 mg/m², were compared to controls who had received similar cumulative doses of conventional doxorubicin (174-671 mg/m²).⁹ Biopsy scores were significantly lower among patients treated with pegylated liposomal doxorubicin than among patients treated with similar cumulative doses of conventional doxorubicin (median Billingham scores of 0.3 and 3.0, respectively; P = .002).

Cardiac Safety of Pegylated Liposomal Doxorubicin versus Conventional Doxorubicin

Emerging data further support the improved cardiac safety profile of pegylated liposomal doxorubicin compared to conventional doxorubicin. Wigler and colleagues evaluated the comparative efficacy and cardiac safety of pegylated liposomal doxorubicin and conventional doxorubicin in a phase III randomized, multicenter trial.³ Five-hundred nine patients with metastatic breast cancer participated in the trial, 15% of whom had a history of adjuvant anthracycline therapy. Patients were either treated with pegylated liposomal doxorubicin 50 mg/m² intravenously over 60 minutes every 4 weeks, or conventional doxorubicin 60 mg/m² intravenously over 60 minutes every 3 weeks.

Efficacy evaluations were performed every 12 weeks and assessments of cardiac function were performed at baseline, after 300 mg/m² cumulative anthracycline exposure and after every additional 100 mg/m² of pegylated liposomal doxorubicin or 120 mg/m² of conventional doxorubicin. Cardiotoxicity was defined as clinical signs and symptoms of congestive heart failure or a decrease from baseline LVEF of ≥20 points if resting LVEF remained within the institution's normal range, or ≥10 points if resting LVEF fell below the institution's lower limit of normal.

Pegylated liposomal doxorubicin and conventional doxorubicin were shown to have comparable efficacy as illustrated by similar progression free survival (hazard ratio 1.00; 95% Confidence Interval (CI), 0.82-1.22) and overall survival (hazard ratio 0.94; 95% CI, 0.74-1.19) in both treatment groups. However, as anticipated, pegylated liposomal doxorubicin was associated with significantly lower risk of cardiac toxicity (hazard ratio 3.16; 95% CI, 1.58-6.31; P<.001) (Figure 1). Only 10 of 254 patients treated with pegylated liposomal doxorubicin developed cardiac toxicity as manifested by changes in LVEF—none of whom exhibited clinical signs or symptoms of congestive heart failure (CHF). In contrast, 48 of 255 patients treated with conventional doxorubicin developed cardiac toxicity as manifested by changes in LVEF (hazard ratio 3.2, P = .0006), and 10 of these individuals exhibited clinical signs and symptoms of congestive heart failure. Two patients in each of the treatment groups exhibited clinical signs or symptoms of CHF without an altered LVEF. Importantly, and in contrast with conventional doxorubicin, the risk of cardiac toxicity with pegylated liposomal doxorubicin did not increase with cumulative doses >450 mg/m². The comparative risk for cardiac toxicity among patients treated with cumulative doses greater than 500-550 mg/m² was 11% for pegylated liposomal doxorubicin and 40% for conventional doxorubicin.

Furthermore, the risk of cardiotoxicity with pegylated liposomal doxorubicin remained low even among high-risk patients such as those ≥55 years of age, those with a history of prior adjuvant therapy with conventional doxorubicin, and those with cardiac risk factors (Table 1). Importantly, the risk for cardiac toxicity among patients with prior anthracycline exposure was greater (hazard ratio 7.27; 95% CI, 0.93-56.80) among patients treated with conventional doxorubicin than with pegylated liposomal doxorubicin in the trial.

Is it Possible to Safely Combine Liposomal Anthracyclines and Trastuzumab?

Combination therapy with cytotoxic anthracyclines and trastuzumab has been suggested as one for improving survival among patients with HER2-positive metastatic breast cancer. However, concerns about the cardiotoxicity of such a combination (both agents possess an inherent risk of cardiotoxicity) have limited its clinical utility. Slamon and colleagues (2001) reported significant clinical benefits of the addition of trastuzumab to anthracycline therapy (anthracycline/cyclophosphamide/trastuzumab, n = 143; anthracycline/cyclophosphamide, n = 138) including longer time to disease progression (7.8 months vs 6.1 months, P<.001), longer duration of response (7.2 months vs 5.6 months, P<.001), and improved overall survival (26.8 months vs 21.4 months, P = .16).⁵ However, the addition of trastuzumab to anthracycline/cyclophosphamide therapy was associated with an increased risk of cardiotoxicity, with heart failure reported in 27% of patients receiving anthracycline/cyclophosphamide/trastuzumab therapy (compared to 8% of patients receiving anthracycline/cyclophosphamide alone).

Recent data presented by Theodoulou and colleagues suggest an improved cardiac safety profile can be achieved in anthracycline and trastuzumab combination regimens by substituting liposomal doxorubicin for conventional doxorubicin.⁴ In their phase I/II study, 39 patients with HER2-positive metastatic breast cancer were treated with liposomal doxorubicin 60 mg/m² intravenously every 3 weeks and trastuzumab 4 mg/kg intravenously (Week 1) and 2 mg/kg intravenously weekly thereafter. Seventeen patients (46%) had a history of prior chemotherapy for metastatic breast cancer, 15 patients (38%) had a history of prior doxorubicin therapy (median cumulative dose, 240 mg/m²), and 11 patients (28%) had a history of trastuzumab therapy.

Patients were treated for a median of 6 cycles (range, 1-11) and received median cumulative doses of doxorubicin of 360 mg/m² (range, 60-660 mg/m²). Only 2 patients were reported to have cardiotoxicity, which was reversible. One patient developed NYHA Class III/IV heart failure and an asymptomatic decline in LVEF was observed in a second patient. Both patients had a history of prior doxorubicin therapy.

The outcomes of additional research into the combination of liposomal doxorubicin and trastuzumab are anticipated. The comparative cardiac safety of combination pegylated liposomal doxorubicin and docetaxel with or without trastuzumab in metastatic breast cancer (if HER2-positive/negative) are currently being investigated in an ECOG trial (E-3198).¹⁰ The objective of the study is to determine the safety and feasibility of pegylated liposomal doxorubicin in combination with docetaxel with or without trastuzumab (pegylated liposomal doxorubicin 30 mg/m² plus docetaxel 60 mg/m² every 3 weeks with or without trastuzumab 4 mg/kg in Week 1 and 2 mg/kg weekly thereafter). Interim results should be presented in 2003.

References

1. von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91:710-717.
2. Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA. A clinicopathologic analysis of Adriamycin cardiotoxicity. Cancer. 1973;32:302-314.
3. Wigler N, Inbar M, O'Brien M, et al. Reduced cardiac toxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin (Caelyx/Doxil) vs. doxorubicin for first-line treatment of metastatic breast cancer. Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 177.
4. Theodoulou M, Campos SM, Batist G, et al. TLC D99 and Herceptin is safe in advanced breast cancer: final cardiac safety and efficacy analysis. Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 216.
5. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Eng J Med. 2001;344:783-792.
6. Lyass O, Uziely B, Ben-Yosef R, et al. Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer. 2000;89:1037-1047.
7. Adriamycin [package insert]. Pharmacia Corporation. Available at http://www.pnu.com/products/pdf/Adriamyc.pdf. Accessed September 24, 2002.
8. Safra T, Muggia F, Jeffers S, et al. Pegylated liposomal doxorubicin (Doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m². Ann Oncol. 2000;11:1029-1033.
9. Berry G, Billingham M, Alderman E, et al. The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi's sarcoma patients treated with pegylated liposomal doxorubicin. Ann Oncol. 1998;9:711-716.
10. Phase II study of doxorubicin HCl liposome and docetaxel with or without trastuzumab (Herceptin) in women with metastatic breast cancer. Eastern Cooperative Oncology Group. National Cancer Institute Protocol IDS E-3198. Available at http://www.cancer.gov/clinical_trials. Accessed October 15, 2002.

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Disclosure

Tamar Safra, MD
Consultant-Schering-Plough; Speakers Bureau-Ortho Biotech Products L.P., Schering-Plough

Malgorzata E. Wojtowicz, MD
Has no significant relationships to disclose.

This report contains information on commercial products that are unlabeled for use or investigational uses of products not yet approved. Pegylated liposomal doxorubicin is not approved by the US FDA for the treatment of metastatic breast cancer. Liposome-encapsulated doxorubicin is not approved for use in the US.

This report is supported by an educational grant from Ortho Biotech Products, L.P., Bridgewater, New Jersey

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Oncology Express Report™ includes discussion of treatment and indications outside of current approved labeling. This Oncology Express Report™ was made possible through an educational grant from Ortho Biotech Products, L.P., Bridgewater, New Jersey.

© 2002 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education