Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Myocet (liposome-encapsulated doxorubicin

citrate): a new approach in breast cancer therapy
Gerald Batist, Jeremy Barton, Philip Chaikin, Christine Swenson & Lauri
Welles
To cite this article: Gerald Batist, Jeremy Barton, Philip Chaikin, Christine Swenson &
Lauri Welles (2002) Myocet (liposome-encapsulated doxorubicin citrate): a new approach
in breast cancer therapy, Expert Opinion on Pharmacotherapy, 3:12, 1739-1751, DOI:
10.1517/14656566.3.12.1739
To link to this article: http://dx.doi.org/10.1517/14656566.3.12.1739

Published online: 25 Feb 2005.

Submit your article to this journal

Article views: 159

View related articles

Citing articles: 4 View citing articles

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ieop20
Download by: [University of Liverpool]

Date: 15 March 2016, At: 10:25

Drug Evaluation

Myocet (liposome-encapsulated
doxorubicin citrate): a new
approach in breast cancer therapy
1. Introduction
2. Chemistry
3. Preclinical pharmacology

Gerald Batist, Jeremy Barton, Philip Chaikin, Christine Swenson & Lauri
Welles
Jewish General Hospital, McGill University, 3755 Cote St Catherine, Montreal, PQ, H3T 1E2
Canada

4. Phase III evaluation programme

5. Clinical efficacy
6. Safety and tolerability

Downloaded by [University of Liverpool] at 10:25 15 March 2016

7. Expert opinion
8. Conclusion

Doxorubicin, either as a single agent or in combination regimens, is considered to be one of the most active chemotherapeutic agents in the treatment
of metastatic breast cancer. However, its clinical utility is limited by a cumulative, dose-dependent cardiac myopathy that can lead to potentially fatal congestive heart failure. Considerable research has gone into improving the
therapeutic index of doxorubicin-based regimens. A new liposomal formulation of doxorubicin (Myocet, Elan Pharmaceuticals) has a significantly
improved therapeutic index compared with conventional doxorubicin. The
development of Myocet, a less cardiotoxic, better tolerated and equally efficacious doxorubicin, extends the therapeutic options in the overall management of breast cancer.
Keywords: anthracyclines, chemotherapy, liposome-encapsulated doxorubicin, metastatic breast
cancer, oncology
Expert Opin. Pharmacother. (2002) 3(12):1739-1751
1. Introduction

Ashley Publications
www.ashley-pub.com

Breast cancer is one of the most prevalent cancers among women, and represents
20 25% of all female cancers. Patients with metastatic breast cancer are essentially
regarded as incurable; the median survival from the manifestation of metastases is
around 2 years [1,2]. However, a proportion of patients remains alive and progression-free for prolonged periods after the first course of treatment with doxorubicinbased systemic chemotherapy regimens [3,4]. Improved therapies, with convincing
tumour response and minimal toxicity, may help achieve the important therapeutic
goals of increasing this fraction of long-term disease-free survivors and improving
quality of life.
Because of the importance of doxorubicin in the treatment of breast cancer, considerable research has been undertaken to improve the therapeutic index of doxorubicin, especially by reducing the associated cardiac toxicity. Doxorubicin, either as a
single agent or in combination regimens, is widely recognised as the gold-standard
anthracycline for the treatment of breast cancer [5]. However, the clinical utility of
this highly efficacious therapy is limited acutely by bone marrow suppression (the
dominant early toxicity that can limit dose intensity) and chronically by cardiotoxicity. In common with other members of the anthracycline family, doxorubicin is
associated with a cumulative dose-dependent cardiomyopathy that can lead to
potentially fatal congestive heart failure (CHF). The mechanism of anthracyclineinduced cardiotoxicity involves the formation of metabolic free radicals that cause
lipid peroxidation [6-9]. The resulting injury is initially subclinical, but continued
treatment cycles result in progressive myocyte damage leading to cumulative dosedependent cardiac dysfunction. This can manifest throughout therapy, months or
even years after the final anthracycline dose [10]. Patients who have received prior
mediastinal irradiation [11] or prior adjuvant anthracycline therapy, in addition to
2002 Ashley Publications Ltd ISSN 1465-6566

1739

Myocet (liposome-encapsulated doxorubicin citrate)

OH

OH
OH

HO

O
O
NH2
OH

Downloaded by [University of Liverpool] at 10:25 15 March 2016

Figure 1. The structure of doxorubicin. Note the axial hydroxyl

group on the sugar motif.

elderly patients [12] and those patients with a history of cardiac

disease [13], are all at increased risk for doxorubicin-induced
cardiac toxicity. In general, 450 mg/m2 is regarded as the maximum safe dose of doxorubicin [11-13]. The implication of
this dose ceiling is that after typical adjuvant therapy using
regimens with a cumulative doxorubicin dose of 240 mg/m2,
only three or four further cycles with doxorubicin 60 mg/m2
can be given for retreatment in the metastatic setting. This
cap on dosing restricts the ability to give continuous cycles of
doxorubicin treatment to patients with metastatic disease who
are responding to the drug.
One strategy designed to overcome the cardiotoxicity of
the anthracyclines, leading to the ability to deliver higher
cumulative doses, is the administration of a cardioprotective
agent. Dexrazoxane is a derivative of EDTA and acts as an
intracellular chelating agent. When the agent is administered
prior to doxorubicin, the incidence of CHF is reduced and
the pharmacokinetics of doxorubicin are unaltered. However,
patients receiving dexrazoxane in combination with doxorubicin may experience an increase in myelosuppression and
other non-cardiac toxicities [14]. Furthermore, in one clinical
trial, a reduced objective response rate was observed in
patients whose initial six cycles of therapy consisted of doxorubicin and dexrazoxane versus doxorubicin alone [15].
Though differences in antitumour efficacy were not observed
in other comparative studies [16], concerns remain that the
cardioprotection offered via this strategy may be at the
expense of both greater haematological toxicity and reduced
anthracycline efficacy. Because of this concern about possible
tumour protection, the 1999 American Society of Clinical
Oncology guidelines do not recommend that dexrazoxane be
used in patients until they have received at least 300 mg/m2
doxorubicin [17], even though it is recognised that injury to
the myocardium begins with the first dose.
Other strategies for reducing the cardiotoxicity associated
with doxorubicin have included amendments to scheduling.
Administration of doxorubicin as a continuous infusion over
96 h was reported to cause less cardiotoxicity, although its
safety and efficacy have not been established in the treatment
of breast cancer [18]. This schedule is also not widely
accepted since it requires a central venous catheter, which
1740

increases the risk of complications such as thrombosis,

extravasation and infection, and a pump, which is inconvenient for the patient.
Epirubicin, an analogue of doxorubicin, appears to be less
cardiotoxic than doxorubicin on a mg/mg basis [19]. However,
recent studies suggest that significantly higher doses of epirubicin in the region of 1.5 times the doxorubicin dose are
necessary for comparable efficacy and, consequently, the cardiac-sparing advantage may be reduced [20].
An important development in the efforts to reduce anthracycline-associated cardiotoxicity was to encapsulate the watersoluble drug within a phospholipid membrane. This liposomal formulation is designed to minimise exposure of
healthy tissues to the cytotoxic agent while retaining or
enhancing the antitumour efficacy of the original anthracycline. Several companies have developed liposomal formulations of anthracyclines, including liposomal daunorubicin,
pegylated liposomal doxorubicin and liposomal doxorubicin
citrate [21]. This review will focus on liposomal doxorubicin
citrate (Myocet, Elan Pharmaceuticals), which is approved
in Europe and Canada for use in patients with metastatic
breast cancer.
The rationale behind the design of Myocet is that intravenously injected liposomes do not readily exit the circulation
through the tight capillary junctions found in healthy tissues
such as the heart and gastrointestinal tract but there is no
impediment to their efflux through damaged vasculature
found in inflamed sites and in tumours [22]. Therefore,
Myocet should preferentially direct doxorubicin away from
sites of potential toxicity but deliver doxorubicin effectively to
tumours. The resulting improvement in the therapeutic index
of doxorubicin makes Myocet an important addition to the
treatment options in the management of breast cancer.
2. Chemistry

Doxorubicin, a member of the rhodomycin group of antibiotics, was originally isolated from filtrates of Streptomyces species
[23]. The compound consists of a flat anthraquinone conjugated ring system linked to an amino sugar via a glycosidic
bond [24] (Figure 1). Epirubicin, an analogue from the same
rhodomycin group, is the 4-epimer of doxorubicin: the only
structural difference between the two compounds is the configuration of the hydroxyl group on the sugar [25].
Both these anthracyclines exert antitumour effects via a
number of mechanisms where maximum activity is seen in the
S-phase of the cell cycle [26]; these are described in Section 3.1.
Liposomes, the mimetics of biological membranes, act as
carriers of drugs; they improve solubility and stability and
prevent the rapid degradation of the encapsulated drug.
They also alter the pharmacokinetics of the carried drug.
Specific or systemic toxicities are potentially lowered and
the efficacy of the conventional agent may be increased. An
increased therapeutic index is achieved by engineering liposomes to persist in the circulation and limiting the

Expert Opin. Pharmacother. (2002) 3(12)

Batist, Barton, Chaikin, Swenson & Welles

pH4
DOX-H+

pH7.4
DOX

Citrate buffer

DOX

DOX-H+

Carbonate buffer

Downloaded by [University of Liverpool] at 10:25 15 March 2016

Figure 2. Doxorubicin accumulation into liposomes is driven

by the establishment of a pH gradient. Reproduced with
permission from [28].

Figure 3. Cryo-electron microscopy image of Myocet

liposomes with bundles of entrapped doxorubicin as
indicated by the arrows. Reproduced with permission from [31].

DOX: Doxorubicin; DOX-H+: Protonated doxorubicin.

availability of encapsulated drug in normal tissues. This

enables accumulation of the drug at sites of infection,
inflammation or neoplasia due to the leaky vasculature
present in these areas [27].
The Liposome Company, Inc. (now Elan Pharmaceuticals) developed a novel strategy that significantly advanced
encapsulation technology of ionisable compounds, eventually leading to the development of Myocet [28]. This strategy
involved the establishment of a pH gradient, whereby a neutral environment was created outside relatively small liposomes (150 nm) and an acidic environment was created
within the liposome. Doxorubicin accumulation into the
liposomes is driven by this pH gradient, as the complexing
of doxorubicin with citrate anion removes it from solution
and enables greater accumulation into the vesicle interior
(Figure 2). Upon loading, the final doxorubicin to lipid
molar ratio is 0.27. Doxorubicin is loaded into the liposomes with an encapsulation efficiency of > 95%, which far
exceeds that achieved via passive encapsulation [29,30]. In
addition, the rate by which doxorubicin leaks from the pHloaded liposomes is reduced as a consequence of doxorubicin
complex formation with citrate anion [31]. Such slow leakage
keeps the doxorubicin encapsulated and is also an important
consideration in the event of extravasation injury.
Within Myocet liposomes, the entrapped doxorubicin
monomers, as a consequence of their planar ring structure and
complex formation with citrate, stack efficiently to form
fibres. These fibres are aligned in a variety of structures that
form bundles with straight, curved and even circular
geometries, as has been shown by cryo-electron microscopy
imaging (Figure 3) [32].
These features of liposome encapsulation of doxorubicin,
afforded by the novel loading technique, enable accumulation
of the drug in tumour tissue through the leaky vessels that
supply them. Furthermore, higher levels of phospholipases
have been demonstrated in tumours [33], which could lead to
the preferential release of doxorubicin from liposomes in these
areas compared with normal tissues.

3. Preclinical pharmacology
3.1 Pharmacodynamics
Several mechanisms are responsible for the antitumour activity of doxorubicin. These include, first, intercalation (of the
conjugated ring system) of the chromophore between DNA
strands and the binding of the amino sugar with the DNA
backbone. As a result, DNA topoisomerase II function is disrupted, leading to DNA strand breakage and cell death [34-37].
Second, damage to DNA and the cell membrane is induced
via reactive oxygen species including hydroxyl radicals and
alkylating free radicals [37-39]. Finally, disruption of calcium
and sodium channels and intracellular electron transport is
believed to contribute to the overall activity of doxorubicin
and anthracycline compounds in general [40,41].
3.2 Pharmacokinetics
The pharmacokinetics of doxorubicin after the administration
of Myocet differ markedly from those after the administration
of conventional doxorubicin.
Doxorubicin undergoes extensive hepatic metabolism with
doxorubicinol as the major, active metabolite [42]. In comparison with the pharmacokinetics of conventional doxorubicin,
the mean clearance of total doxorubicin after Myocet administration was about 9-fold lower, the volume of distribution
was 25-fold lower, and the area under the curve (AUC) was
about 20-fold greater. The terminal half-life of doxorubicin
after Myocet administration was 16 h, versus 43 h with conventional doxorubicin. It has been estimated that at least 85%
of the circulating doxorubicin in patients is liposome-encapsulated [43]. The mean urinary excretion of doxorubicin and
doxorubicinol after Myocet or conventional doxorubicin was
similar [43]. However, peak plasma concentrations of doxorubicinol, as demonstrated in patients with metastatic breast
cancer receiving either Myocet or conventional doxorubicin
in combination with cyclophosphamide (CPA), occurred later
and were marginally lower with the Myocet-containing regimen, although the total AUC values were not different [44]. It

Expert Opin. Pharmacother. (2002) 3(12)

1741

Myocet (liposome-encapsulated doxorubicin citrate)

Table 1. Phase III programme regimens used in the evaluation of Myocet.

Study

Regimen

Schedule

Criteria for discontinuing therapy

1*

Myocet 60 mg/m2 and CPA 600 mg/m2 Every 3 weeks until disease progression Disease progression or unacceptable
versus conventional doxorubicin
or unacceptable toxicity
toxicity (including cardiac toxicity), non60 mg/m2 and CPA 600 mg/m2
compliance or patient/physician request

2*

Myocet 75 mg/m2 versus conventional

doxorubicin 75 mg/m2

Myocet 75 mg/m2 and CPA 600 mg/m2 Every 3 weeks for up to eight cycles or
versus epirubicin 75 mg/m2 and
until disease progression or
CPA 600 mg/m2
unacceptable toxicity

Every 3 weeks until disease progression As above

or unacceptable toxicity
As above

Downloaded by [University of Liverpool] at 10:25 15 March 2016

*Patients were allowed to have received prior adjuvant anthracycline therapy ( 300 mg/m2). Patients were not allowed to have received prior anthracycline therapy.
CPA: Cyclophosphamide.

has been suggested that doxorubicinol may contribute to doxorubicin-mediated cardiotoxicity [45-47]; consequently, avoidance or reduction of high peak plasma concentrations of both
doxorubicin and doxorubicinol is desirable.
The increased presence in the circulation and lower peak
plasma concentrations of total doxorubicin directly relate to
maximisation of drug therapeutic index as demonstrated by
tissue distribution studies. The AUC of radioactivity (representing doxorubicin and/or doxorubicinol) in myocardial tissues of dogs receiving Myocet was 67% of that observed in
conventional doxorubicin-treated animals [48]. Myocet is less
cardiotoxic compared with the same cumulative dose of conventional doxorubicin, as demonstrated in two comparative
preclinical studies [49,50]. In addition to reduced myocardial
toxicity, the incidence of several other doxorubicin-mediated
adverse events was reduced. Compared with Myocet-treated
dogs, dogs treated with conventional doxorubicin were five
times more likely to experience vomiting and diarrhoea [49].
Alopecia and gastrointestinal bleeding were observed after
conventional doxorubicin but not with Myocet. Again, these
results reflect the different tissue distribution of doxorubicin
achieved via liposome encapsulation. Myocet is unable to exit
the circulation readily at sites of healthy tissue that does not
exhibit the type of leaky vasculature found at tumour sites.
Consequently, healthy tissue is exposed to lower levels of doxorubicin after administration of Myocet, which translates into
a reduced adverse event profile.
At equivalent doses, the antitumour activity of Myocet is at
least equivalent to that observed with conventional doxorubicin as demonstrated in murine tumour models [51]. Further
studies in human breast tumour models have shown that doxorubicin is more persistent and pervasive with equivalent efficacy in inhibiting tumour growth after administration as
Myocet, compared with conventional doxorubicin [52,53].
4. Phase

III evaluation programme

Following the demonstration in early clinical studies of promising antitumour activity with improved safety, particularly
reduced cardiotoxicity, Myocet was evaluated in three randomised, Phase III clinical studies [54-56].
1742

The primary objective of the pivotal study (study 1) [54] was

to determine if the incidence of cardiotoxicity was significantly less with the combination of Myocet and CPA (MC)
compared with conventional doxorubicin and CPA (AC) in
patients with metastatic breast cancer. Cardiac tolerability of
Myocet (M) given as a single agent compared with conventional doxorubicin (A) was also the primary study end point
in study 2 [55]. Both of these studies evaluated the antitumour
efficacy as a coprimary end point of Myocet compared with
conventional doxorubicin. The main objective of the final
study (study 3) [56] was to assess the antitumour efficacy of
MC compared with epirubicin/CPA (EC) in the treatment of
metastatic breast cancer. The three study regimens are
described in Table 1.
5. Clinical

efficacy

5.1 Efficacy end points

Efficacy was determined in the three studies by the calculation
of objective tumour response rates. These were defined as the
proportion of patients who attained a complete (CR) and partial (PR) response of at least 6 weeks duration. In all studies,
duration of response and measures of progression-free survival
(time to progression), time to treatment failure, and overall
survival were recorded.
5.2 Efficacy results
The antitumour efficacy results obtained from the Phase III
programme are summarised in Table 2. In study 1 [54], an
overall response rate (CR + PR) of 43% was observed in
patients in both treatment groups. Among patients who were
doxorubicin-naive, the responses were comparable: 42% in
the MC-treated group versus 45% in the AC-treated group.
In the small subset of patients who had received prior doxorubicin, 50% of the MC patients achieved an objective
response, compared with 20% of the AC patients. Overall,
statistical analyses to indicate non-inferiority in response rate
demonstrated that it was highly unlikely (p = 0.0026) that the
MC regimen was less efficacious than the AC combination
regimen. No differences were observed between the two treatment regimens in terms of other efficacy end points; duration

Expert Opin. Pharmacother. (2002) 3(12)

Batist, Barton, Chaikin, Swenson & Welles

Table 2. Summary of antitumour efficacy and cardiotoxicity results from the Phase III programme for Myocet.
Study 1 [54]

Study 3 [56]

MC

AC

MC

EC

142

155

108

116

80

80

Antitumour efficacy
Response rate (%)

43

43

26

26

46

39

Progression-free survival
Patients with progression (%)

77

81

89

83

71

79

Median time to progression (months)

5.1

5.5

2.9

3.2

7.7

5.6

Treatment failure
Patients with failure (%)

80

87

91

93

75

84

Median time to failure (months)

4.6

4.4

2.8

2.8

5.7

4.4

Duration of response
Median duration of response (months)

9.6

9.1

7.2

6.4

10.0

7.7

Overall survival
Patients dead (%)

52

57

76

67

58

61

19.0

16.0

15.7

21.2

18.3

16.0

21

17

37

12

10

No. patients

Downloaded by [University of Liverpool] at 10:25 15 March 2016

Study 2 [55]

Median duration of survival (months)

Cardiotoxicity
Occurrence of cardiotoxicity (%)
Cases of CHF

Median lifetime doxorubicin dose at first cardiotoxic event (mg/m2)

> 2220

480

785

533

Median time to onset of first cardiotoxic event (months)

> 22.0

10.0

9.8

6.9

Patients with cardiac biopsy grade 3.0 (%)

Regimens consist of: A: Doxorubicin; AC: Doxorubicin and CPA; EC: Epirubicin and CPA; M: Myocet; MC: Myocet and CPA.
CHF: Congestive heart failure; CPA: Cyclophosphamide.

of response, time to treatment failure, progression-free survival and overall survival were comparable (Table 2).
In study 2 [55], equivalent response rates of 26% were
observed in both the Myocet and conventional doxorubicin
treatment groups. As in study 1, there were no statistically significant differences between the groups regarding duration of
response, time to treatment failure, progression-free survival
and overall survival (Table 2). There was a non-significant
trend in survival in favour of the doxorubicin group. This is
most likely explained by an imbalance in prognostic factors
between the two groups, favouring those patients treated with
conventional doxorubicin.
The results from study 3 [56] showed tumour response rates
of 46% with MC compared with 39% for EC (Table 2).
Although the response was higher with MC, the difference
was not statistically significant, as in studies 1 and 2. Noninferiority tests for overall response rate showed that MC is
highly unlikely to be less efficacious than the EC regimen
(p = 0.0019). Secondary efficacy variables demonstrated
superiority of the MC regimen. Patients treated with MC
had significantly longer duration of response (p = 0.005),
time to treatment failure (p = 0.007) and progression-free
survival (p = 0.02), compared with EC-treated patients

(Table 2). No statistically significant difference in overall survival was observed.

The results from the Phase III programme for Myocet
clearly demonstrate that the efficacy of doxorubicin therapy,
in combination with cyclophosphamide or as a single agent, is
not compromised by encapsulation of the active agent within
liposomes. Furthermore, in comparison with epirubicin and
cyclophosphamide, the Myocet combination regimen is significantly superior in various efficacy variables.
6. Safety

and tolerability

6.1 Cardiotoxicity end points and adverse event

measures
The primary safety end point in studies 1 and 2 was reduction
in cardiotoxicity [55,56]. The time to the first cardiotoxic event
was also recorded. Cardiotoxicity was defined as a decrease in
resting left ventricular ejection fraction (LVEF) of 20 units
from baseline to a final value of 50%, a decrease of
10 units to a final value of < 50%, or clinical evidence of
CHF. These LVEF reductions could be asymptomatic but
would still be considered representative of cardiotoxicity in
each protocol. Endomyocardial biopsies were also performed

Expert Opin. Pharmacother. (2002) 3(12)

1743

Myocet (liposome-encapsulated doxorubicin citrate)

1.0

Myocet/CPA

Proportion of patients without cardiac event

Downloaded by [University of Liverpool] at 10:25 15 March 2016

Doxorubicin/CPA
p = 0.0001

0.8

0.6

0.4

0.2

0.0
0

200

400

600

800

1000

Lifetime cumulative dose to a cardiac event (mg/m2)

Figure 4. Cardiotoxicity (left ventricular ejection fraction or congestive heart failure) observed in study 1 as measured by
lifetime cumulative dose of doxorubicin. Median dose to the first cardiotoxic event (Myocet + CPA versus doxorubicin + CPA):
> 2220 versus 480 mg/m2. Reproduced with permission from [54].
CPA: Cyclophosphamide.

in a small number of patients in study 2; biopsies were discontinued after an interim analysis demonstrated a statistically
significant reduction in cardiac toxicity with Myocet.
Study-drug-mediated adverse events were also measured
and graded for severity.
6.2 Cardiotoxicity results
In study 1 [54], 6% of patients treated with MC developed protocol-defined cardiotoxicity compared with 21% of patients
treated with AC (p = 0.0001; Table 2). Five cases of CHF were
reported, all in the AC arm of this study, following cumulative
lifetime doses of doxorubicin of 360 480 mg/m2. By KaplanMeier analysis, the estimated median cumulative lifetime
dose of doxorubicin at the first occurrence of cardiac toxicity
was > 2220 mg/m2 for the MC arm, versus 480 mg/m 2 for the
AC arm (Figure 4). This difference was highly statistically significant (p = 0.0001), consistent with a reduction in cardiac risk
associated with Myocet compared with the conventional drug.
Similarly, the time to onset of cardiotoxicity when measured from the start of protocol therapy was significantly

1744

longer in the MC arm: in excess of 22 months for MC versus

10 months for AC (p = 0.0003; Table 2) [54].
The single-agent comparative study (study 2) [55] demonstrated an equally impressive reduction in cardiotoxicity. Only
17% of patients who were administered Myocet developed cardiotoxicity, compared with 37% of patients treated with conventional doxorubicin (Table 2). A total of 11 cases of CHF were
observed, 9 of which occurred on the conventional doxorubicin
arm, while 2 occurred with Myocet. In addition, the development of CHF occurred at significantly higher doses of Myocet
than with conventional doxorubicin (p = 0.0001). As in study 1,
a significantly higher lifetime cumulative dose was achieved in
Myocet-treated patients compared with conventional doxorubicin-treated patients before the occurrence of the first cardiotoxic event (785 versus 533 mg/m2, respectively; p = 0.0001;
Figure 5). In addition, the time to this first event was significantly longer with Myocet compared with conventional doxorubicin (9.8 versus 6.9 months, respectively; p = 0.0007).
In study 3, the incidence of cardiotoxicity was low, and
comparable between Myocet and epirubicin (12 versus 10%,

Expert Opin. Pharmacother. (2002) 3(12)

Batist, Barton, Chaikin, Swenson & Welles

1.0

Myocet

Proportion of patients without cardiac event

Downloaded by [University of Liverpool] at 10:25 15 March 2016

Doxorubicin
p = 0.0001

0.8

0.6

0.4

0.2

0.0
0

200

400

600

800

1000

1200

Lifetime cumulative dose to a cardiac event (mg/m2)

Figure 5. Cardiotoxicity (left ventricular ejection fraction, cardiac biopsy or congestive heart failure) observed in study 2 as
measured by lifetime dose of doxorubicin. Median dose to the first cardiotoxic event (Myocet versus doxorubicin):
785 versus 533 mg/m2. Reproduced with permission from [55].

respectively), both administered in combination with CPA.

No prior anthracyclines were permitted on this study and lifetime cumulative anthracycline doses of the study drugs were
capped at 600 mg/m2. The cardiotoxicity observed was
asymptomatic in all cases and occurred at cumulative doses of
100 600 mg/m2. No CHF was observed with either regimen. Epirubicin is often used in the management of metastatic breast cancer since it is associated with less
cardiotoxicity than conventional doxorubicin [57,58]. The
results from this comparative study in combination with CPA
demonstrate that Myocet is associated with equivalently low
cardiac toxicity compared with epirubicin and with superior
efficacy at the doses studied. Thus, Myocet may represent not
only a better alternative to conventional doxorubicin in the
management of breast cancer, but also a superior treatment in
comparison with epirubicin-containing regimens.
6.3 Adverse events
With comparable drug exposure, there were no new or unexpected adverse events in any of the patients receiving

Myocet-containing regimens in the Phase III programme and

there was no increase in incidence or severity of adverse
events known to be associated with doxorubicin. All of the
treatments were generally well-tolerated, but at least one
adverse event related to drug administration was experienced
by all participating patients. The most common adverse
events were haematological toxicities such as neutropenia and
anaemia and gastrointestinal toxicities such as stomatitis and
mucositis (Table 3).
In study 1, there was a significant reduction in incidence of
all grades of stomatitis (p = 0.008) and, consistent with this,
there was a reduction in the incidence of diarrhoea (although
not statistically significant; p = 0.08). The incidence of
grade 4 neutropenia was significantly reduced in the
MC-treated patients (p = 0.017). With the single-agent dosing regimen in study 2 [55], there was no difference in haematological toxicity, including grade 4 neutropenia, between the
two treatment groups. However, the incidence of diarrhoea
(p = 0.01) and overall infection (p = 0.001) was significantly
reduced for the Myocet-treated patients. Reduction in the

Expert Opin. Pharmacother. (2002) 3(12)

1745

Myocet (liposome-encapsulated doxorubicin citrate)

Table 3. Adverse events in the Phase III studies in patients with metastatic breast cancer.
Patients (%)
Study 1 [54]
Toxicity
Haematological toxicity
Anaemia (haemoglobin < 80 g/l)

Downloaded by [University of Liverpool] at 10:25 15 March 2016

Thrombocytopenia (platelets < 20 x

109/l)

Study 2 [55]

Study 3 [56]

MC

AC

MC

EC

23

27

22

26

25

14

13

10

Neutropenia
ANC < 0.5 x 109/l
ANC < 0.5 x 109/l for 7 days
ANC < 0.5 x 109/l with fever 38C, i.v. antibiotics and/or hospitalisation

61
1
9

75
5
13

50
0
11

58
0
9

87
26
5

67
31
1

Other toxicity
Grade 3 nausea/vomiting
Grade 3 stomatitis/mucositis
Grade 3 diarrhoea
Grade 3 asthenia/fatigue
Grade 3 cutaneous
Grade 2 alopecia
Injection-site toxicity (all grades)

13
4
3
6
0
91
5

16
7
8
5
1
95
8

13
9
1
14
1
84
15

24
14
4
19
1
88
18

21
7
1
0
0
82
1

19
0
1
1
1
77
10

Regimens consist of: A: Doxorubicin; AC: Doxorubicin and CPA; EC: Epirubicin and CPA; M: Myocet; MC: Myocet and CPA.
ANC: Absolute neutrophil count; CPA: Cyclophosphamide.

incidence of stomatitis was of borderline significance in

favour of Myocet (p = 0.051)
In study 3 [56], stomatitis/mucositis and grade 4 neutropenia (but not prolonged neutropenia) were more common in
patients receiving the MC regimen, while the EC regimen was
associated with a higher incidence of injection site toxicity.
The development of skin toxicity was rare in all studies. No
patients developed grade 3 palmarplantar erythrodysesthesia
(PPE) with any of the treatment regimens. The skin toxicity
results for Myocet in the Phase III programme are of particular relevance when a comparison is made with another liposomal formulation of doxorubicin. Pegylated liposomal
doxorubicin (Caelyx, Schering-Plough) has been established as an effective treatment in AIDS-related Kaposis sarcoma [59,60] and refractory ovarian cancer and was recently
approved in Europe for the treatment of metastatic breast cancer [61-63]. A Phase III comparison with doxorubicin [63]
showed non-inferior efficacy for the primary end point of
progression-free survival at a reduced dose intensity
(50 mg/m2 i.v. every 4 weeks versus doxorubicin 60 mg/m2
i.v. every 3 weeks); grade 3 PPE affected 17% of patients
treated with pegylated liposomal doxorubicin. In general, the
most common adverse effects appear to be PPE and mucositis/stomatitis, which have been shown to complicate up to
25% of treatment cycles and may be dose-limiting [62].
7. Expert

opinion

Considerable research has gone into reducing the cardiac toxicity of doxorubicin. Improving the therapeutic index of doxorubicin, one of the most useful cytotoxic agents in oncology,
1746

is a worthwhile treatment goal. The ability to treat responding

patients for longer periods of time with improved safety, or to
offer an alternative sequential regimen, may result in improvements in quality of life, prolonged time to disease progression
and, theoretically, increased overall survival in patients with
metastatic disease.
The preclinical and clinical data for Myocet demonstrate
an improved therapeutic index compared with conventional
doxorubicin.
Results from comparative Phase III trials showed that, in
combination with CPA at doses of 60 mg/m2 and as single
agent therapy at doses of 75 mg/m2, Myocet and conventional
doxorubicin exhibited comparable antitumour activity.
Equivalent response rates were observed in studies 1 and 2,
with no statistically significant differences in duration of
response, progression-free survival, time to treatment failure
and overall survival.
In comparison with the EC regimen, MC demonstrated
superior antitumour efficacy at the doses administered for several variables. At the study doses, the Myocet-containing regimen was significantly superior in terms of progression-free
survival, time to treatment failure and duration of response.
For the treatment of metastatic breast cancer in the UK and
Canada, epirubicin is the most frequently used anthracycline,
either as a single agent or in combination regimens, at recommended doses of 50 100 mg/m2 [64]. Data suggest that epirubicin may be less effective than conventional doxorubicin
at mg/mg equivalent doses [65] and therefore the dose of epirubicin is often increased. However, increasing the doses of
epirubicin may cause proportionately greater toxicity, including, potentially, greater cardiac toxicity [66]. The results

Expert Opin. Pharmacother. (2002) 3(12)

Batist, Barton, Chaikin, Swenson & Welles

Table 4. Implications of potency, cardiotoxicity and number of treatment cycles during a lifetime of treatment in
breast cancer for doxorubicin, epirubicin and Myocet.

Recommended lifetime maximum dose (mg/m2)

Adjuvant setting
Dose per cycle (mg/m2)
Total dose (4 cycles;
Dose remaining

mg/m2)

(mg/m2)

Metastatic setting
Dose per cycle (mg/m2)

Downloaded by [University of Liverpool] at 10:25 15 March 2016

Number of cycles

described in study 3 demonstrated that, dose-for-dose, the

liposomal formulation of doxorubicin showed superior antitumour activity and suggest that Myocet may be a reasonable
replacement for this alternative anthracycline.
Equivalent antitumour efficacy of Myocet compared with
conventional doxorubicin is accompanied by a significantly
superior cardiotoxicity profile. Encapsulation of doxorubicin
in liposomes has the potential to significantly decrease cumulative, clinically relevant cardiotoxicity. Therefore, by using
Myocet, higher lifetime doses of doxorubicin could be
achieved in patients before the incidence of any cardiac event.
For the MC regimen, the estimated median cumulative lifetime dose of doxorubicin at the first occurrence of protocoldefined cardiotoxicity was estimated by KaplanMeier analysis to be > 2220 mg/m2 with Myocet, versus 480 mg/m2 for
the AC arm. However, one must keep in mind that the MC
curve was somewhat skewed by one patient who received a
Myocet dose of > 800 mg/m2. Equivalent figures in the singleagent study were 785 mg/m2 for Myocet and 533 mg/m2 for
conventional doxorubicin.
Doxorubicin-induced cardiac toxicity begins with the first
dose of therapy and continued treatment can result in CHF
[10], which may be life-threatening or fatal. The ability to
administer more treatment cycles and higher cumulative doses
of doxorubicin could be clinically beneficial in the management of breast cancer, and the ability to maintain planned
dose intensity has been shown to correlate with response and
may also influence time to disease progression and, ultimately,
overall survival of patients with metastatic disease.
It is generally recommended that the lifetime dose of doxorubicin be 450 mg/m2 and for epirubicin this ceiling is
900 mg/m2 (a value determined in anthracycline-naive
patients). Using the combined database of 542 patients
treated with Myocet (at starting doses < 100 mg/m2, 16% of
whom had received prior adjuvant doxorubicin
300 mg/m2), the probability of developing CHF is 5% at
750 mg/m2 [Elan: Data on file]. Therefore, it is recommended that caution should be exercised at higher doses, with
evaluation of left ventricular function before each administration of Myocet once a patient exceeds a cumulative lifetime

Doxorubicin

Epirubicin

Myocet

450

900

750

60

90

60

240

360

240

210

540

510

60

90

60

doxorubicin dose of 550 mg/m2. The implications of potency,

cardiotoxicity and number of treatment cycles that can be
administered during a lifetime of treatment with conventional
doxorubicin, epirubicin or Myocet are illustrated in Table 4.
For patients who receive four cycles of anthracycline chemotherapy in the adjuvant setting and later relapse, the
increased cumulative lifetime dose possible with Myocet therapy could present a therapeutic advantage. In the metastatic
setting, two more cycles of Myocet could be administered
compared with epirubicin and five more compared with doxorubicin. This cumulative lifetime dose of 750 mg/m2 could
consist of both Myocet and conventional doxorubicin
( 300 mg/m2, as per the Myocet clinical trial patient database), or could be Myocet exclusively. Ultimately, the ability
to deliver an increased number of cycles could result in
improved quality of life by delaying relapse.
In a subgroup of patients in the Phase III programme who
had received prior doxorubicin (240 mg/m2), a threefold
higher tumour response rate (p = 0.04) was observed after
Myocet treatment compared with conventional doxorubicin
[67,68]. Time to treatment failure was also significantly longer
and cardiotoxicity was reduced in the Myocet-treated patients.
The safety and efficacy results suggest that this new liposomal
formulation may permit patients who are at increased risk of
cardiotoxicity to receive anthracycline therapy. Such patients
may include those who have received prior radiation that
encompassed the heart (e.g., mediastinal irradiation) or prior
adjuvant anthracycline therapy, as well as the elderly and
patients with a history of cardiac disease. Clinical trials need to
be carried out in these patient populations to obtain a better
understanding of the safety of Myocet in these settings.
Although anthracycline and CPA combination regimens are
the most commonly used chemotherapy treatments for metastatic breast cancer, combination regimens of an anthracycline
with newer chemotherapeutic agents, such as paclitaxel, have
been associated with high tumour response rates and are now
frequently used for the treatment of metastatic breast cancer
[69,70]. However, in some studies, improved tumour response
was observed at the expense of unacceptably increased cardiotoxicity. In one trial, 50% of patients experienced changes in

Expert Opin. Pharmacother. (2002) 3(12)

1747

Downloaded by [University of Liverpool] at 10:25 15 March 2016

Myocet (liposome-encapsulated doxorubicin citrate)

LVEF and 20% of patients developed CHF [70]. This substantially worsened cardiotoxicity is likely explained by decreased
elimination of doxorubicin or doxorubicinol, leading to higher
peak plasma concentrations, as a consequence of pharmacokinetic interactions between the two agents [71,72]. Myocet, with
its improved cardiotoxicity profile, may be a better partner for
paclitaxel than conventional doxorubicin. In a current Phase I
study, the Myocet and paclitaxel combination was well-tolerated and active in 19 patients with metastatic breast cancer.
The overall response rate was 62% (8% CR, 54% PR); one
patient had an asymptomatic decline in LVEF on treatment.
Similarly, Myocet may be of benefit in combination with
trastuzumab, a monoclonal antibody directed against the
human growth receptor, HER2. In the 25 30% of patients
with tumours overexpressing HER2, a combination of conventional doxorubicin, CPA and trastuzumab was associated
with higher tumour response rates and longer survival times
than were seen with paclitaxel and trastuzumab (although it
should be noted that the two trastuzumab-containing regimens were not directly compared); both trastuzumab-containing regimens had greater efficacy than standard
chemotherapy regimens [73]. However, the impressive tumour
response rates in the conventional doxorubicin, CPA and trastuzumab arm came at the expense of increased cardiotoxicity;
approximately 28% of patients developed New York Heart
Association class III IV cardiotoxicity (i.e., symptomatic
cardiotoxicity) [73,74]. A recent Phase I/II study in patients
with advanced breast cancer showed that the combination of
Myocet and trastuzumab was active and well-tolerated. Of the
37 patients studied, two developed cardiotoxicity. However,
both patients had received prior doxorubicin therapy and
both recovered cardiac function following study treatment.
The combination achieved an overall response rate of 59%
(3% CR, 56% PR) [75]. Because of the important antitumour
activity of trastuzumab combined with an anthracycline and
CPA, the use of Myocet as the anthracycline of choice appears
to be a useful strategy to prevent or reduce the cardiotoxicity
associated with this treatment regimen [76].
In addition to the potential applications for Myocet in
combination with new agents for metastatic breast cancer, the
use of Myocet in the treatment of childhood cancers and lymphoma also appears promising. In paediatric oncology, there is
a significant need for therapies that prevent or decrease the
incidence of late complications that are a consequence of conventional doxorubicin-based therapy. In adult oncology,

1748

non-Hodgkins lymphoma (NHL) is one of the few cancers

with an increasing incidence, especially in patients who are
elderly or immunosuppressed (such as AIDS patients or those
on immunosuppressive therapy). As a result of the superior
safety profile demonstrated by Myocet compared with conventional doxorubicin and Myocets altered pharmacokinetics
and biodistribution compared with the conventional drug,
trials are ongoing to assess the effectiveness of Myocet in both
the paediatric and NHL patient populations [77-79]. Two studies, one in patients with newly diagnosed aggressive NHL [77]
and one in patients with AIDS-related NHL [78], have evaluated the COMP regimen, where Myocet replaces doxorubicin
in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone). COMP achieved CR rates of 63 and
81% in each of the two studies [77,78], respectively, and cardiotoxicity was not reported in either study.
8. Conclusion

Anthracycline and cyclophosphamide combinations remain

one of the most commonly used treatments for metastatic
breast cancer. The improved therapeutic index of Myocet suggests that it may be a better alternative in this regimen. Furthermore, by using Myocet in the metastatic setting and
perhaps, in the future, as adjuvant treatment for primary
breast cancer, an increased number of cycles may be given
within the cardiotoxicity risk threshold, thereby potentially
improving quality of life by delaying relapse.
Myocet, a non-pegylated liposome-encapsulated doxorubicin, is an effective and well-tolerated treatment for metastatic
breast cancer. Data from the Phase III programme for Myocet
demonstrate that substitution of Myocet for conventional doxorubicin can significantly reduce the cumulative cardiotoxicity
associated with this anthracycline in both combination and
single-agent dosing regimens. Myocet is also more efficacious
than intermediate-dose epirubicin. Indeed, the above data support the use of Myocet in place of conventional doxorubicin or
epirubicin for the treatment of metastatic breast cancer. Moreover, the ability to raise the cardiotoxicity ceiling compared
with conventional doxorubicin, without compromising antitumour activity, suggests that studies of Myocet for the adjuvant
treatment of primary breast cancer may be warranted. The
data also suggest a promising role for Myocet in combination
with newer agents for breast cancer, as well as for the treatment
of lymphomas or paediatric cancers.

Expert Opin. Pharmacother. (2002) 3(12)

Batist, Barton, Chaikin, Swenson & Welles

Bibliography
1.

2.

Downloaded by [University of Liverpool] at 10:25 15 March 2016

3.

CLARK GM, SLEDGE GW Jr,

OSBORNE CK, MCGUIRE WL: Survival
from first recurrence: relative importance of
prognostic factors in 1,015 breast cancer
patients. J. Clin. Oncol. (1987) 5:55-61.
MICK R, BEGG CB, ANTMAN KH,
KORZUN AH, FREI E 3rd: Diverse
prognosis in metastatic breast cancer: who
should be offered alternative initial
therapies? Breast Cancer Res. Treat. (1989)
13:33-38.
GREENBERG PA, HORTOBAGYI GN,
SMITH TL, ZIEGLER LD, FRYE DK,
BUZDAR AU: Long-term follow-up of
patients with complete remission following
combination chemotherapy for metastatic
breast cancer. J. Clin. Oncol. (1996)
14:2197-2205.

4.

SLEDGE GW Jr: Should we dream the

impossible dream? The meaning of longterm survival in metastatic breast cancer.
J. Clin. Oncol. (1996) 14:2191-2193.

5.

VERRILL M: Anthracyclines in breast

cancer: therapy and issues of toxicity. The
Breast (2001) Suppl. 2:8-15.
Concise review of toxicity considerations
when using anthracyclines for breast
cancer patients.

6.

7.

8.

9.

10.

11.

12.

DOROSHOW JH: Effect of anthracycline

antibiotics on oxygen radical formation in
rat heart. Cancer Res. (1983) 43:460-472.
RAJAGOPALAN S, POLITI PM, SINHA
BK, MYERS CE: Adriamycin-induced free
radical formation in the perfused rat heart:
implications for cardiotoxicity. Cancer Res.
(1988) 48:4766-4769.
JACKSON JA, REEVES JP, MUNTZ KH
et al.: Evaluation of free radical effects and
catecholamine alterations in adriamycin
cardiotoxicity. Am. J. Pathol. (1984)
117:140-153.
MYERS CE, MCGUIRE WP, LISS RH,
IFRIM I, GROTZINGER K,
YOUNG RC: Adriamycin: the role of lipid
peroxidation in cardiac toxicity and tumor
response. Science (1977) 197:165-167.
BILLINGHAM ME, MASON JW,
BRISTOW MR, DANIELS JR:
Anthracycline cardiomyopathy monitored
by morphologic changes. Cancer Treat. Rep.
(1978) 62:865-872.
PRAGA C, BERETTA G, VIGO PL et al.:
Adriamycin cardiotoxicity: a survey of 1273
patients. Cancer Treat. Rep. (1979)
63:827-834.
VON HOFF DD, LAYARD MW, BASA P

13.

14.

et al.: Risk factors for doxorubicin-induced

congestive heart failure. Ann. Intern. Med.
(1979) 91:710-717.
Landmark paper showing dose-dependent
doxorubicin-associated cardiotoxicity from
US cancer co-operative group patient
database.
BRISTOW MR: Anthracycline
cardiotoxicity. In: Drug-Induced Heart
Disease. Bristow MR (Ed.), Elsevier, New
York, NY, USA (1980):191-215.
Anthracycline cardiotoxicity from the
cardiologists perspective.
HOCHSTER H, LIEBES L, WADLER S
et al.: Pharmacokinetics of the
cardioprotector ADR-529 (ICRF-187) in
escalating doses combined with fixed-dose
doxorubicin. J. Natl. Cancer Inst. (1992)
84:1725-1730.

15.

SWAIN SM, WHALEY FS, GERBER MC

et al.: Cardioprotection with dexrazoxane
for doxorubicin-containing therapy in
advanced breast cancer. J. Clin. Oncol.
(1997) 15:1318-1332.

16.

SEYMOUR L, BRAMWELL V, MORAN

LA: Use of dexrazoxane as a
cardioprotectant in patients receiving
doxorubicin or epirubicin chemotherapy for
the treatment of cancer. Cancer Prev. Control
(1999) 3:145-159.

17.

18.

19.

20.

21.

HENSLEY ML, SCHUCHTER LM,

LINDLEY C et al.: American Society of
Clinical Oncology clinical practice
guidelines for the use of chemotherapy and
radiotherapy protectants. J. Clin. Oncol.
(1999) 17:3333-3355.
LEGHA SS, BENJAMIN RS, MACKAY B
et al.: Reduction of doxorubicin
cardiotoxicity by prolonged continuous
intravenous infusion. Ann. Intern. Med.
(1982) 96:133-139.
Important study showing that reducing
peak plasma levels of doxorubicin
significantly reduces cardiotoxic effects.
RYBERG M, NIELSEN D,
SKOVSGAARD T, HANSEN J, JENSEN
BV, DOMBERNOWSKY P: Epirubicin
cardiotoxicity: an analysis of 469 patients
with metastatic breast cancer. J. Clin. Oncol.
(1998) 16:3502-3508.
LAUNCHBURY AP, HABBOUBI N:
Epirubicin and doxorubicin: a comparison
of their characteristics, therapeutic activity
and toxicity. Cancer Treat. Rev. (1993)
19:197-228.
SPARANO JA, WINER EP: Liposomal
anthracyclines for breast cancer. Semin.
Oncol. (2001) 28:(4, Suppl. 12):32-40.
Expert Opin. Pharmacother. (2002) 3(12)

Comprehensive review of development and

efficacy of liposomal anthracyclines for
breast cancer.

22.

TARDI PG, BOMAN NL, CULLIS PR:

Liposomal doxorubicin. J. Drug Target.
(1996) 4:129-140.
Not all liposomes are the same review of
optimal features for a liposomal drug
formulation.

23.

WOODRUFF HB, WAKSMAN SA: The

actinomycin historical background. Ann.
NY. Acad. Sci. (1960) 89:287 (Abstract).

24.

MYERS CE: Antitumor antibiotics I,

anthracyclines. In: Cancer Chemotherapy.
Poinedo HM (Ed.), Excerpta Medica,
Amsterdam, The Netherlands
(1979):56-73.

25.

SMITH IC, HUTCHEON AW,

HEYS SD: Current and potential
chemotherapeutic agents used for induction
chemotherapy in the treatment of breast
cancer. Curr. Pharm. Des. (2000)
6:327-343.

26.

HILL BT, WHELAN RD: A comparison of

the lethal and kinetic effects of doxorubicin
and 4-epi-doxorubicin in vitro. Tumori
(1982) 68:29-37.

27.

BROWN JM, GIACCIA AJ: The unique

physiology of solid tumors: opportunities
(and problems) for cancer therapy. Cancer
Res. (1998) 58:1408-1416.

28.

SWENSON CE, PERKINS WR,

ROBERTS P, JANOFF AS: Liposome
technology and the development of
Myocet (liposomal doxorubicin citrate).
The Breast (2001) Suppl. 2:1-7.
Concise introduction to liposomal
technology; useful review of preclinical
pharmacology of Myocet (note that
figure 4 is labelled incorrectly; doxorubicin
and Myocet are reversed)

29.

MADDEN TD, HARRIGAN PR, TAI LC

et al.: The accumulation of drugs within
large unilamellar vesicles exhibiting a proton
gradient: a survey. Chem. Phys. Lipids
(1990) 53:37-46.

30.

MAYER LD, TAI LCL, KO DS et al.:

Influence of vesicle size, lipid composition,
and drug-to-lipid ratio on the biological
activity of liposomal doxorubicin in mice.
Cancer Res. (1989) 49:5922-5930.

31.

LI X, CABRAL-LILLY D, JANOFF AS,

PERKINS WR: Complexation of
internalized doxorubicin into fibre bundles
affects its release rate from liposomes.
J. Liposome Res. (2000) 10:15-27.

32.

LI X, HIRSH DJ, CABRAL-LILLY D et al.:

1749

Myocet (liposome-encapsulated doxorubicin citrate)

encapsulated doxorubicin (TLC-D99;

Myocet). Proc. Ann. Meet. Am. Soc. Clin.
Oncol. (2001) 20:(Abstract 463).

Doxorubicin physical state in solution and

inside liposomes loaded via a pH gradient.
Biochim. Biophys. Acta (1998) 1415:23-40.
33.

UCHIDA N, OKAMURA S,
NAGAMACHI Y, YAMSHITA S:
Increased phospholipase D activity in
human breast cancer. J. Cancer Res. Clin.
Oncol. (1997) 123:280-285.

34.

DI MARCO A, ZUNINO F,
SILVESTRINI R, GAMBARUCCI C,
GAMBETTA RA: Interaction of some
daunomycin derivatives with
deoxyribonucleic acid and their biological
activity. Biochem. Pharmacol. (1971)
20:1323-1328.

Downloaded by [University of Liverpool] at 10:25 15 March 2016

35.

36.

37.

38.

39.

45.

46.

PIGRAM WJ, FULLER W, HAMILTON

LD: Stereochemistry of intercalation:
interaction of daunorubicin with DNA.
Nat. New Biol. (1972) 235:17-19.
LIU LF, ROWE TC, YANG L, TEWEY
KM, CHENG GL: Cleavage of DNA by
mammalian topoisomerase II. J. Biol. Chem.
(1983) 258:15365-15370.
TEWEY KM, ROWE TC, YANG L,
HALLIGAN BD, LIU LF: Adriamycininduced DNA damage mediated by
mammalian DNA topoisomerase II. Science
(1984) 226:466-468.
BACHUR NR, GORDON SL, GEE MV,
KON H: NADPH cytochrome P450
reductase activation of quinone anticancer
agents to free radicals. Proc. Natl. Acad.
Sci. USA (1979) 76:954-957.
BERALDO H, GARNIER-SUILLEROT
A, TOSI L, LAVELLE F: Iron(III)adriamycin and iron(III)-daunorubicin
complexes: physicochemical characteristics,
interaction with DNA, and antitumor
activity. Biochemistry (1985) 24:284-289.

40.

MURPHREE SA, CUNNINGHAM LS,

HWANG KM, SARTORELLI AC: Effect
of adriamycin on surface properties of
sarcoma 180 ascites cells. Biochem.
Pharmacol. (1976) 25:1227-1231.

41.

OLSON RD, BOERTH RC, GERBER JG,

NIES AS: Mechanism of adriamycin
cardiotoxicity: evidence for oxidative stress.
Life Sci. (1981) 29:1393-1401.

42.

MROSS K, MAESSEN P, VAN DER

VIJGH WJ, GALL H, BOVEN E,
PINEDO HM: Pharmacokinetics and
metabolism of epidoxorubicin and
doxorubicin in humans. J. Clin. Oncol.
(1988) 6:517-526.

43.

44.

NIEMANN B, MROSS K, DREVS J,

UNGER C, BHAMRA R, SWENSON C:
The pharmacokinetic profile of liposome-

1750

47.

48.

49.

MARTY M: Liposomal doxorubicin

(Myocet) and conventional
anthracyclines: a comparison. The Breast
(2001) Suppl. 2:28-33.
Reviews key findings from Phase III
development programme of Myocet.
STEWART DJ, GREWAAL D,
GREEN RM et al.: Concentrations of
doxorubicin and its metabolites in human
autopsy heart and other tissues. Anticancer
Res. (1993) 13:1945-1952.
DEL TACCA M, DANESI R, DUCCI M,
BERNARDINI C, ROMANINI A: Might
adriamycinol contribute to adriamycininduced cardiotoxicity? Pharmacol. Res.
Commun. (1985) 17:1073-1084.
OLSON RD, MUSHLIN PS, BRENNER
DE et al.: Doxorubicin cardiotoxicity may
be caused by its metabolite doxorubicinol.
Proc. Natl. Acad. Sci. USA (1988)
85:3585-3589.
POTCHOIBA MJ, WEST M,
SMOLAREK TA et al.: Tissue distribution
of doxorubicin in the free and liposomal
forms in male beagles. Proc. Ann. Meet. Am.
Soc. Cancer Res. (1996) 37:(Abstract 2675).
KANTER PM, BULLARD GA,
GINSBERG RA et al.: Comparison of the
cardiotoxic effects of liposomal doxorubicin
(TLC D-99) versus free doxorubicin in
beagle dogs. In vivo (1993) 7:17-26.

50.

THE LIPOSOME COMPANY: Data on

file. D-99 intravenous toxicity study in
beagle dogs. (1996) Study no. 93-974-01.

51.

OSTRO MJ: Liposomes from the bench

to the marketplace: doxorubicin liposomes
as an example. In: Liposomes in the Therapy
of Infectious Diseases and Cancer. LopezBerestein G, Fidler IJ (Eds), Alan R Liss,
Inc., New York, NY, USA (1989):155-163.

52.

ROBERTS P, MASTERS G, JANOFF A,

AHMAD I, MAYHEW E: Distribution of
doxorubicin fluorescence in a human breast
carcinoma (MCF7) grown on SCID mice
after treatment with Evacet or free
doxorubicin. 21st San Antonio Breast Cancer
Symposium (1998) San Antonio, TX, USA.

53.

54.

ROBERTS P, JANOFF AS, MAYHEW E:

Doxorubicin fluorescence in a human breast
carcinoma (MX-1) after treatment with
liposome-associated or free doxorubicin.
Proc. Ann. Meet. Am. Soc. Cancer Res.
(2000) 41:(Abstract 3327).
BATIST G, RAMAKRISHNAN G,
Expert Opin. Pharmacother. (2002) 3(12)

55.

SEKHAR RAO C et al.: Reduced

cardiotoxicity and preserved antitumour
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. (2001) 19:1444-1454.
Phase III trial results showing reduced
cardiotoxicity and equivalent efficacy with
Myocet plus CPA versus doxorubicin
plus CPA.
HARRIS L, BATIST G, BELT R et al.:
Liposome-encapsulated doxorubicin
compared with conventional doxorubicin in
a randomized multicenter trial as first-line
therapy of metastatic breast carcinoma.
Cancer (2002) 94:25-36.
Phase III trial results showing reduced
cardiotoxicity and equivalent efficacy of
Myocet versus conventional doxorubicin.

56.

CHAN S, DAVIDSON N, JUOZAITYTE

E et al.: Liposome-encapsulated
doxorubicin (Myocet) and
cyclophosphamide is superior to epirubicin
and cyclophosphamide in first-line therapy
of metastatic breast cancer. Eur. J. Cancer
(2001) 37(Suppl. 5):28.

57.

HORTOBAGYI GN, YAP HY, KAU SW

et al.: A comparative study of doxorubicin
and epirubicin in patients with metastatic
breast cancer. Am. J. Clin. Oncol. (1989)
12:57-62.

58.

JAIN KK, CASPER ES, GELLER NL et al.:

A prospective randomized comparison of
epirubicin and doxorubicin in patients with
advanced breast cancer. J. Clin. Oncol.
(1985) 3:818-826.

59.

NORTHFELT DW, DEZUBE BJ,

THOMMES JA et al.: Pegylated-liposomal
doxorubicin versus doxorubicin, bleomycin,
and vincristine in the treatment of AIDSrelated Kaposis sarcoma: results of a
randomized Phase III clinical trial. J. Clin.
Oncol. (1998) 16:2445-2451.

60.

STEWART S, JABLONOWSKI H,
GOEBEL FD et al.: Randomized
comparative trial of pegylated liposomal
doxorubicin versus bleomycin and
vincristine in the treatment of AIDS-related
Kaposis sarcoma. J. Clin. Oncol. (1998)
16:683-691.

61.

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.

62.

RANSON MR, CARMICHAEL J,

Batist, Barton, Chaikin, Swenson & Welles

OBYRNE K, STEWART S, HOWELL A:

Treatment of advanced breast cancer with
sterically stabilized liposomal doxorubicin:
results of a multicenter Phase II trial.
J. Clin. Oncol. (1997) 15:3185-3191.
63.

Downloaded by [University of Liverpool] at 10:25 15 March 2016

64.

65.

66.

67.

68.

WIGLER N, INBAR M, OBRIEN M

et al.: Reduced cardiac toxicity and
comparable efficacy in a Phase III trial of
pegylated liposomal doxorubicin
(Caelyx/Doxil) versus doxorubicin for firstline treatment of metastatic breast cancer.
Proc. Ann. Meet. Am. Soc. Clin. Oncol.
(2002); 21:45a (Abstract 177).
ORMROD D, HOLM K, GOA K,
SPENCER C: Epirubicin: a review of its
efficacy as adjuvant therapy and in the
treatment of metastatic disease in breast
cancer. Drugs Aging (1999) 15:389-416.
BONTENBAL M, ANDERSSON M,
WILDIERS J et al.: Doxorubicin versus
epirubicin, report of a second-line
randomized Phase II/III study in advanced
breast cancer. EORTC Breast Cancer
Cooperative Group. Br. J. Cancer (1998)
77:2257-2263.
MICHELOTTI A, VENTURINI M,
TIBALDI C et al.: Single agent epirubicin
as first line chemotherapy for metastatic
breast cancer patients. Breast Cancer Res.
Treat. (2000) 59:133-139.
BATIST G, HARRIS, L, AZARNIA N,
LEE L: Improved therapeutic index of TLC
D-99 (liposome-encapsulated doxorubicin)
compared to free doxorubicin in first-line
treatment of metastatic breast cancer in
patients who had received prior adjuvant
doxorubicin. Proc. Ann. Meet. Am. Soc. Clin.
Oncol. (2000) 19:(Abstract 405).
WINER E, BATIST G, BELT R,
GUTHEIL J, PARK Y, WELLS L: Reduced
cardiotoxicity of liposome-encapsulated
doxorubicin (TLC D-99) compared to free
doxorubicin in first-line therapy of
metastatic breast cancer in patients at
increased risk for anthracyclines-induced
cardiac toxicity. Proc. Ann. Meet. Am. Soc.
Clin. Oncol. (2000) 19:(Abstract 323).

GIANNI L, MUNZONE E, CAPRI G

et al.: Paclitaxel by 3-hour infusion in
combination with bolus doxorubicin in
women with untreated metastatic breast
cancer: high antitumor efficacy and cardiac
effects in a dose finding and sequencefinding study. J. Clin. Oncol. (1995)
13:2688-2699.

76.

70.

GEHL J, BOESGAARD M, PAASKE T,

VITTRUP JENSEN B,
DOMBERNOWSKY P: Combined
doxorubicin and paclitaxel in advanced
breast cancer: effective and cardiotoxic.
Ann. Oncol. (1996) 7:687-693.

77.

71.

HOLMES FA, MADDEN T, NEWMAN

RA et al.: Sequence-dependent alteration of
doxorubicin pharmacokinetics by paclitaxel
in a Phase I study of paclitaxel and
doxorubicin in patients with metastatic
breast cancer. J. Clin. Oncol. (1996)
14:2713-2721.

LEVINE AM, TULPULE A, ESPINA BM

et al.: A Phase I/II trial of liposomal
doxorubicin (TLC D-99, Myocet) with
cyclophosphamide, vincristine, and
prednisone in newly diagnosed aggressive
non-Hodgkins lymphoma (NHL).
Proc. Ann. Meet. Am. Soc. Clin. Oncol.
(2002) 21:284a (Abstract 1133).

78.

TULPULE A, ESPINA BM,

DHARMAPALA D et al.: Treatment of
newly diagnosed AIDS-related lymphomas
with liposomal doxorubicin (TLC-D99,
Myocet) combined with cyclophosphamide,
vincristine, and prednisone: results of a
Phase I/II trial. Proc. Ann. Meet. Am. Soc.
Clin. Oncol. (2002) 21:284a
(Abstract 1135).

79.

LOWE ES, ADAMSON PC,

WIDEMANN BC et al.: Phase I trial and
pharmacokinetic study of liposomal
doxorubicin (TLC-D99, MyocetTM) in
children with refractory solid tumors. Proc.
Ann. Meet. Am. Soc. Clin. Oncol. (2002)
21:109a (Abstract 434).

69.

72.

73.

GIANNI L, VIGANO L, LOCATELLI A

et al.: Human pharmacokinetic
characterization and in vitro study of the
interaction between doxorubicin and
paclitaxel in patients with breast cancer.
J. Clin. Oncol. (1997) 15:1906-1915.
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. Engl. J. Med. (2001)
344:783-792.
Landmark trial shows rare survival
improvements with targeted therapy in
women with metastatic breast cancer (and
emerging cardiotoxicity risk).

74.

FELDMAN AM, LORELL BH, REIS SE:

Trastuzumab in the treatment of metastatic
breast cancer: anticancer therapy versus
cardiotoxicity. Circulation (2000)
102:272-274.

75.

THEODOULOU M, CAMPOS SM,

BATIST G et al.: TLC D99 (D, Myocet)
and Herceptin (H) is safe in advanced breast
cancer (ABC): final cardiac safety and
efficacy analysis. Proc. Ann. Meet. Am. Soc.
Clin. Oncol. (2002) 21:55a (Abstract 216).

Expert Opin. Pharmacother. (2002) 3(12)

SEIDMAN A, HUDIS C, PIERRI MK

et al.: Cardiac dysfunction in the
trastuzumab clinical trials experience.
J. Clin. Oncol. (2002): 20:1215-1221.
Antitumour activity of trastuzumab with
anthracyclines and CPA warrants research
into strategies to prevent or treat associated
cardiac dysfunction.

Affiliation
Gerald Batist MD1, Jeremy Barton MD2, Philip
Chaikin Pharm. D, MD3, Christine Swenson
PhD 3, & Lauri Welles MD3
Author for correspondence
1Jewish General Hospital, McGill University,
3755 Cote St Catherine, Montreal, PQ, H3T
1E2 Canada
Tel: +1 514 340 7915; Fax: +1 514 340 7916
E-mail: gbatist@onc.jgh.mcgill.ca
2Elan Pharma Ltd, Abel Smith House, Gunnels
Wood Road, Stevenage, Herts, SG1 2FG, UK
3Elan Pharmaceuticals Inc., One Research Way,
Princeton, NJ 08540, USA

1751