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Published on 6 June 2008

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Reduced cardiotoxic profile of Myocet (nonpegylated liposomal doxorubicin)

teaser

Liposomal encapsulation helps minimise side-effects of conventional doxorubicin by improving tumour specificity. This review discusses use of encapsulated doxorubicin citrate (Myocet®) in breast cancer

Mohamed Shehata*
MBBCh MD DM Oncology

Oncology Research Fellow

Abhik Mukherjee*
MBBS DMRT MSc PhD

Oncology Research Fellow

Ravi Sharma
MBBS MRCP FRCR

Locum Consultant Oncologist

Stephen Chan*
MBBS FRCP FRCR MD

Consultant Oncologist

*Nottingham University Hospitals NHS Trust

†Hull and East Yorkshire Hospitals NHS Trust

UK

Doxorubicin (DOX) is an established drug for treating breast cancer but cardiotoxicity limits its clinical utility. When combined with other cytotoxic agents or radiation therapy, DOX-associated cardiac events may occur more frequently and at lower cumulative doses.[1] Drug delivery carriers such as liposomal encapsulations enhance both drug selectivity and antitumour efficacy. Drummond and colleagues outline certain advantages of liposome-encapsulated anthracyclines. This formulation reduces the volume of distribution (Vd) and clearance (CL) and prolongs half-life (t½), resulting in prolonged release within the tumour environment. The limited conversion to aglycones or secondary alcohol metabolites confers increased drug stability. The drug selectively accumulates in tumours or in organs containing macrophages such as those of the reticuloendothelial system (liver and spleen) while sparing healthy tissues such as the heart that have a normal endothelial barrier. This forms the scientific rationale for reduced cardiac toxicity for these agents.[2]

There are two liposomal doxorubicin formulations currently in clinical use: liposomal encapsulated doxorubicin citrate (Myocet/D-99/LEDC), and pegylated (STEALTH) liposomal doxorubicin (Doxil®/Caelyx®; PLD). This review examines the reduced cardiotoxic profile of nonpegylated liposomal doxorubicin (Myocet) vs traditional and pegylated formulations of doxorubicin in breast cancer.

Phase I studies
Different dose levels and schedules of Myocet were tested in phase I trials either alone or in combination with other chemotherapeutic agents (see Table 1).

Using a single-dose-weekly/three-weekly regimen, the maximum tolerated dose (MTD) was 37.5 mg/m2 and 90 mg/m2 respectively. Myelosuppression was the main dose-limiting toxicity (DLT).[3–5] In a combination study with docetaxel in MBC (metastatic breast cancer), the MTD was 50 mg/m2 of Myocet in combination with  25 mg/m2 of weekly docetaxel. Serious cardiac events occurred in 14% of patients. Myocet, in combination with weekly docetaxel, at the doses and schedule administered in this trial, was not recommended for future phase II testing.[6] For the combination of Myocet with docetaxel and gemcitabine the MTD was 60, 75 and 350 mg/m2 respectively and the DLTs were stomatitis, diarrhoea and infection. The only grade (G) 3/4 toxicity observed was neutropenia (20%).[7]

Phase II studies
Several phase II studies have been conducted for Myocet in MBC as well as LAPC (locally advanced primary breast cancer), either as monotherapy or in combination (Table 2). The response rate (RR) ranged from 65% to 80% with clinical complete response (CR) between 5% and 27%. The most common toxicities were haematological (G3–4 neutropenia).[7,9−14]

Recently, a phase II study (GEICAM 2003-03)[15] examined three-weekly Myocet (M)/docetaxel (T)/pegfilgrastim (N) in combination with weekly trastuzumab (H) as primary treatment in HER2-positive early breast cancer (EBC) patients (II–IIIa). M 50 mg/m2 and T 60 mg/m2 were given on day one and N on day two every three weeks for six cycles; H (4 mg/kg loading dose, then 2 mg/kg/week) was given intravenously for 17 weeks. In an intermediate analysis of 26 patients, objective clinical RR was 96.2% (CI: 88.2–100) with 16 (64%) CR and nine (36%) partial response (PR). Eight patients (30.8%; 13.1–48.5) achieved a pathological CR in the breast. Only four patients (15.4%) experienced asymptomatic and reversible cardiac left-ventricular-function reduction (G1). This is an early indication that Myocet may be combined with trastuzumab with minimal increase in cardiac toxicity in EBC treatment.

A phase I–II escalation trial currently investigated the first-line treatment of HER-2/neu-positive ABC patients with Myocet, docetaxel and trastuzumab in three to six patients/cohort. The treatment schedule was: M 50 mg/m2 (or 60, depending on dose level assignment) on day one, T 30 mg/m2 on day two and nine, H 4 mg/kg on day two followed by weekly dose of 2 mg/kg, every three weeks. Four patients were allocated to dose level 50/30 (M/T) and three patients to dose level 60/30. At dose level 60/30 febrile neutropenia (DLT) occurred in two patients. One event of tachycardia (G1) at MTD recovered completely without treatment. LVEF values were unmodified. The MTD was defined at M 50 mg/m2 in combination with T 30 mg/m2.[8]

[[HPE38_14-16_Tbl1]]

Phase III studies
Phase III trials (see Table 2) were conducted to compare Myocet with DOX as monotherapy or in combination. There was no difference in RR but a significant reduction in the risk of cardiac toxicity was reported. For example, in first-line treatment of MBC the RRs for both monotherapy treatment arms were 26%. Cardiac events that led to patient withdrawal from the study were more than twice as frequent in DOX-treated patients as Myocet-treated patients (29% vs 13%, p = 0.0001). The probability of the first onset of a cardiac event was related to the lifetime cumulative dose (CD) of DOX or Myocet, and the risk of onset of cardiotoxicity at the same CD was much higher with DOX treatment than Myocet (hazard ratio: HR = 3.56; p = 0.0001).[16]

In the multicentre phase III trial in MBC comparing the combination of Myocet and cyclophosphamide (MC) with the doxorubicin and cyclophosphamide (AC) combination, a CR or PR was observed in 43% of patients in both treatment groups. The RRs were comparable among DOX-naive patients: 42% in the MC-treated group vs 45% in the AC-treated group. In the DOX pretreated subset (10%), the objective RR was 50% for the MC group compared with 20% in the AC group. Protocol-defined cardiotoxicity was evident in 6% of the patients treated with MC versus 21% treated with AC (p = 0.0001). All five cases of congestive heart failure (CHF) occurred in the AC arm (p = 0.02), and occurred after cumulative lifetime doses ranging from 360 to 480 mg/m2. The median cumulative lifetime dose of doxorubicin at the first occurrence of protocol-defined cardiac toxicity was greater than 2,220 mg/m2 for the MC arm vs 480 mg/m2 for the AC arm with an HR of 4.8.[17]

A retrospective analysis[18] based on pooled data from the aforementioned2 phase III trials addressed the issue of cardiotoxicity with Myocet/DOX following previous exposure to adjuvant anthracyclines. Sixty-eight patients were included in this analysis: 39 and 29 patients from the studies by Harris et al16 and Batist et al17 respectively, had received prior adjuvant anthracycline treatment. Of the 29 patients in the latter study,17 14 received MC and 15 received AC; of the 32 patients in the former study,16 18 received M and 21 received A. Hence, 32 patients received M-containing regimens and 36 A-containing regimens.

The groups were well balanced in terms of demographic characteristics (median age 54 years). ORRs were 31% and 11% for M-treated patients and A-treated patients, respectively (p = 0.04, odds ratio = 4.0). Median time to progression was 4.5 vs 3.4 months (p = 0.66, HR = 1.14), median time to treatment failure was 4.2 vs 2.1 months (p = 0.01, HR = 2.06) and median survival time was 16 vs 15 months (p = 0.71, HR = 1.12). Cardiac events occurred in 22% of M-treated patients (one CHF) vs 39% of A-treated patients (three CHFs) (p = 0.001). Median lifetime dose at onset of cardiotoxicity was 780 mg/m2 for M versus 580 mg/m2 for A (p = 0.001, HR = 4.8). This retrospective analysis shows that treatment with Myocet significantly reduced the risk of cardiotoxicity in patients with MBC who had received prior adjuvant doxorubicin.

This analysis validates the therapeutic option of including Myocet in the treatment of MBC patients who have had prior adjuvant anthracycline exposure.

While the above studies support lower cardiac toxicities of Myocet versus DOX, there are no studies directly comparing the cardiac safety of Myocet and PLD, the pegylated liposomal doxorubicin preparation. The cardiac safety of PLD in comparison with DOX has also been confirmed. The risk for developing a cardiac event was significantly lower in breast cancer patients treated with PLD than in patients treated with DOX (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 PLD, compared with a 40% risk in the DOX group.[19]

On comparing epirubicin–cyclophosphamide vs Myocet–cyclophosphamide as first-line therapy for MBC, a phase III trial reported that the combination containing Myocet had a trend for higher RR (46% vs 39%, p = 0.42) and longer median survival time (18.3 vs 16 months, p = 0.504). The median time to disease progression was significantly longer in the Myocet arm as compared with the epirubicin arm (7.7 vs 5.6, p = 0.02). The liposomal combination arm showed higher neutropenia and stomatitis/mucositis rates compared with epirubicin and cyclophosphamide (EC). Cardiac toxicity was low in both treatment groups: at comparative cumulative doses, nine patients in the liposomal combination and eight patients in the EC arm developed asymptomatic LVEF reductions. Thus Myocet appears to be an acceptable substitute for epi¬rubicin as first-line treatment for MBC.[20]

[[HPE38_14-16_Tbl2]]

Conclusions and future perspectives
There are several theoretical advantages of using Myocet. These include prolonged half-life, increased drug stability and selective accumulation in tumour, which reduce adverse effects on the heart. The clinical trials in LAPC and MBC which compared DOX with Myocet at the same dose have shown similar efficacy and a toxicity profile in favour of Myocet. Myocet has a potential advantage in use in combination with trastuzumab as it has been shown to overcome the problem of increased cardiac toxicity encountered when DOX is administered concurrently with trastuzumab in breast cancer. The data, however, need further validation. Several other biological agents with impressive efficacy for treating HER2 overexpressed breast cancer that are orally administered and also have low cardiac toxicity are in development (eg the receptor tyrosine kinase, inhibitors, such as lapatinib). In addition, the long-term safety issues of Myocet should be carefully evaluated before its routine application for the curative treatment of early-stage disease. ■

References
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8. J Clin Oncol 2006;24 Suppl 18: Abstract 10744.
9. J Clin Oncol 2005;23 Suppl 16: Abstract 798.
10. J Clin Oncol 2005;23 Suppl 16: Abstract 753.
11. J Clin Oncol 1999;17:1425-34.
12. J Clin Oncol 2006;24 Suppl 18: Abstract 10659.
13. J Clin Oncol 2006;24 Suppl 18: Abstract 10651.
14. Ann Oncol 2005;16:1624-31.
15. GEICAM 2003-03 study. San Antonio Breast Cancer Conference, 2007.
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19. Proc Am Soc Clin Oncol 2002;21: Abstract 177.
20. Ann Oncol 4;15:1527-34.
21. J Clin Oncol 99;17:1435.



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