Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer

S. Chan1,*, N. Davidson2, E. Juozaityte3, F. Erdkamp4, A. Pluzanska5, N. Azarnia6 and L. W. Lee6 On behalf of the Myocet Study Group{dagger}

1 City Hospital, Nottingham; 2 North Middlesex Hospital, London, UK; 3 Kaunas Medical Academy, Kaunas, Lithuania; 4 Maasland Hospital, Sittard, the Netherlands; 5 Lodz Chemotherapy Clinic, Lodz, Poland; 6 Elan Pharmaceuticals, Princeton, NJ, USA

* Correspondence to: Dr Stephen Chan, Department of Clinical Oncology, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. Tel: +44-115-969-1169; Fax: +44-163-683-0070; Email: ytschan{at}innotts.co.uk


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective: To ascertain the efficacy and tolerability of non-pegylated liposomal doxorubicin (MyocetTM) and epirubicin combined with cyclophosphamide in the first-line treatment of patients with metastatic breast cancer.

Methods: One hundred and sixty anthracycline-naïve metastatic breast cancer patients were randomised to receive Myocet (M; 75 mg/m2) or epirubicin (E; 75 mg/m2) in combination with cyclophosphamide (C; 600 mg/m2), every 3 weeks for up to eight cycles.

Outcome measures: Response (overall response = complete + partial response rates), time to disease progression, overall survival and cardiac function (left ventricular ejection fraction).

Results: Overall response rates were 46% and 39% for MC and EC treatment, respectively (P=0.42). MC was superior to EC with respect to median time to treatment failure (5.7 versus 4.4 months; P=0.01) and median time to disease progression (7.7 versus 5.6 months; P=0.02). Median survival times were 18.3 and 16.0 months for MC and EC, respectively (P=0.504). Unsurprisingly, given an equimolar comparison, neutropenia and stomatitis/mucositis were significantly more common in patients who received MC. However, there was less injection site toxicity with MC. Both treatments showed a low incidence of cardiotoxicity.

Conclusion: Myocet appears to be an acceptable alternative to epirubicin as a first-line treatment for patients with metastatic breast cancer because it combines the dose–effect reliability of doxorubicin with the level of safety provided by epirubicin.

Key words: cyclophosphamide, epirubicin, liposomal doxorubicin, metastatic breast cancer, MyocetTM, phase III study


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Unlike most other incurable malignancies, metastatic breast cancer is relatively responsive to chemotherapy and the natural history is relatively prolonged, with up to half of patients living for 2 years and 10% surviving for 10 years [1Go]. Doxorubicin is one of the most active chemotherapeutic agents for the treatment of metastatic breast cancer, although its use is limited by a cumulative dose-dependent cardiotoxicity that can lead to congestive heart failure (CHF) [2Go–6Go]. As myocardial injury occurs cumulatively from the first dose [7Go], the use of less cardiotoxic anthracycline formulations could prevent both early and late cardiac damage. Early injury may be subclinical but could render the myocardium vulnerable to future cardiac dysfunction.

Epirubicin, a stereoisomer of doxorubicin, is a more recently developed anthracycline that is used increasingly in the treatment of breast cancer. The clinically effective dose of epirubicin is generally in the range 75–90 mg/m2, while the corresponding range for doxorubicin is 60–75 mg/m2 [8Go], giving a dose ratio required to achieve equal efficacy of up to 1:1.5 [9Go–11Go]. It has been estimated that epirubicin is about 75% as myelotoxic and 50% as cardiotoxic at equimolar doxorubicin doses [12Go].

MyocetTM (Elan Pharmaceuticals, Princeton, NJ, USA) is a non-pegylated liposomal formulation of doxorubicin. It has significantly less cardiotoxicity than doxorubicin in metastatic breast cancer and similar anti-tumour efficacy at equimolar doses [13Go, 14Go].

The purpose of this study was to compare the efficacy of these two newer anthracyclines, in combination with cyclophosphamide, as first-line therapy for patients with metastatic breast cancer. When planning the study, the choice of dose of epirubicin and Myocet was based on the following rationale. For Myocet, phase I/II development had shown that it was equipotent with doxorubicin at equimolar doses and that dose escalation was feasible with haematological growth factor support [15Go–17Go]. The uncertainty regarding the equipotent doses of epirubicin and doxorubicin was also taken into consideration [9Go–11Go], and a comparison for the present study of equimolar doses was favoured. A dose of 75 mg/m2 was chosen for epirubicin because it lay within the licensed dose range of 60–90 mg/m2 [18Go] and for doxorubicin (as Myocet), 75 mg/m2 would probably elicit the pharmacodynamic effects necessary to appraise this drug's tolerability properly; early-phase studies with single-agent Myocet showed a maximum tolerated dose of 90 mg/m2 [19Go].

Objectives
The primary objective was to assess the efficacy (response rate) of Myocet in combination with cyclophosphamide (MC) compared with that of epirubicin in combination with cyclophosphamide (EC) in the treatment of patients with metastatic breast cancer. The secondary objective was to assess the myelotoxicity, cardiotoxicity and gastrointestinal toxicity of MC compared with EC.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
The study enrolled patients with metastatic breast cancer who had not previously received any cytotoxic chemotherapy for their metastatic disease, and who had not received any previous anthracycline therapy.

Eligibility criteria included: age ≥18 years; histologically or cytologically proven breast carcinoma with measurable metastatic disease; an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2; life expectancy of ≥3 months; adequate bone marrow, liver and renal functions; and a resting left ventricular ejection fraction (LVEF) ≥50%. Women of childbearing potential were eligible if using reliable contraception.

Patients were ineligible if: they had metastases to bone only (usually not measurable) or brain (because of short life expectancy); they had received previous anthracyclines or had other cytotoxic chemotherapy for metastatic disease; or they had received adjuvant chemotherapy within the past 6 months. Patients with previous radiation >3500 cGy to the mediastinal area or to >50% of the bone marrow were excluded. Patients with a history of significant cardiac problems were excluded for safety reasons. Pregnant or lactating women were ineligible.

The trial was approved by the Ethics Committee at each participating centre. All patients gave written informed consent.

Treatment
Patients were stratified according to the country of the treatment centre and randomised to receive Myocet 75 mg/m2 plus cyclophosphamide 600 mg/m2 (MC), or epirubicin 75 mg/m2 plus cyclophosphamide 600 mg/m2 (EC). The dose of Myocet represents the doxorubicin content delivered via liposome. Cyclophosphamide was administered intravenously (i.v.) over 15 min, followed by Myocet or epirubicin as a 1-h i.v. infusion. Treatment was repeated every 3 weeks for up to eight cycles, or until disease progression or significant toxicity requiring drug discontinuation.

Criteria for G-CSF use and dose reduction
Granulocyte colony-stimulating factor (G-CSF) use was allowed as needed for shortening the severity and duration of neutropenia, based on the results of full blood counts performed 4 days after dosing and twice a week. G-CSF was administered daily if the absolute neutrophil count (ANC) was ≤1.0 x 109/l, and was continued until the ANC was ≥5.0 x 109/l for two successive days. G-CSF was discontinued at least 2 days before the start of the next chemotherapy cycle. Doses were reduced (Myocet or epirubicin by 15 mg/m2 and cyclophosphamide by 150 mg/m2) for a platelet nadir <50 x 109/l or ANC nadir <0.5 x 109/l on two consecutive counts, onset of grade 4 mucositis, or onset of grade 3–4 vomiting despite antiemetics. Following a dose-reduced cycle, doses could be increased by the same amount provided the platelet nadir was ≥75 x 109/l, the ANC nadir was ≥0.5 x 109/l, and there was no other grade 3 or 4 toxicity. If these criteria were not met, the patient continued with a further dose-reduced cycle. Dose escalation was not allowed.

Study conduct
The scheme of assessments is outlined in Table 1. LVEF was determined by two-dimensional M-mode echocardiography.


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Table 1. Schedule of study assessments

 
Patients were withdrawn from the study for disease progression, unacceptable toxicity, non-compliance with the protocol, patient's request or investigator's discretion. Patients were withdrawn for cardiac toxicity, defined as a decrease in resting LVEF of ≥20 units from baseline to a final value of ≥50%, or a decrease of ≥10 units from baseline to <50%, or clinical evidence of CHF.

Outcome measures
The primary efficacy variable was the proportion of patients who attained a complete or partial response (CR or PR, respectively). CR was defined as the disappearance of all evidence of disease for ≥6 weeks. Partial response (PR) was defined as a ≥50% decrease in the sum of the products of the two longest perpendicular diameters of all measured lesions for ≥6 weeks, with no evidence of progressive disease. Stable disease (SD) was defined as no significant change in measurable and non-measurable disease. Progressive disease (PD) was defined as a ≥25% increase in the product of the two longest perpendicular diameters of any measurable lesion or in the estimated size of non-measurable disease, the appearance of a new lesion, or the reappearance of old lesions.

The duration of response for patients with a CR or PR was measured from the time a CR or PR was first detected to the first evidence of PD or death.

The time to treatment failure (TTF) was the time from day 1 of treatment to discontinuation of treatment for an adverse event, lack of efficacy or patient intolerance, onset of cardiac toxicity, first evidence of PD, or death.

Time to progression (TTP) was the time from day 1 of treatment to the first evidence of PD or death. Patients who discontinued study drug treatment were followed for information on time to disease progression and survival. Thus, removal from treatment did not censor these observations. Surgical removal of the remaining measurable lesion or hormonal therapy off-study was considered to be a censored event, and the use of other systemic chemotherapy and/or radiation was considered to be a failure event in the analyses of time to disease progression, TTF and duration of response.

Overall survival was defined as the time from day 1 of treatment to death.

The time-to-event variables were also expressed as hazard ratios (HRs), indicating the overall risk of experiencing an event in one group relative to the other (here, a hazard ratio >1 suggests that the result favours MC-treated patients).

All toxicities were graded according to National Cancer Institute Common Toxicity Criteria.

Analysis of study results
Between May 1996 and August 1997, 160 women with metastatic breast cancer were randomised into this study by 41 investigators in Europe, as opposed to 278 patients as originally planned. The study was closed to further accrual in August 1997 as a result of changes within the overall Myocet clinical development programme. The closure was unrelated to the present study design, conduct or results. At the time of closure, no knowledge of the study results was available to investigators or sponsors. These results are from the first and only analysis performed on this study, and the original statistical plan was unchanged. This report is based on data collected from patients with follow-up at February 1999 (n=160), when all patients were off-study.

All randomised patients were assessed for efficacy. All treated patients were evaluated for safety, including cardiac toxicity.

A 50% response rate was expected for EC in previously untreated metastatic breast cancer. The efficacy objective was to rule out the possibility that the true response rate to MC therapy in this patient population was 15% less than the true response rate to EC. A sample size of 139 patients per treatment group was considered sufficient to achieve that objective with a 5% alpha value and 80% power. With a sample size of 80 patients per group and a one-sided 5% significance level, there was a 59% power to reject the null hypothesis of non-inferiority. However, the lack of power does not affect the validity of a statistically significant difference between treatments, if detected.

Pretreatment characteristics, efficacy and safety variables for the treatment groups were compared using Fisher's exact test for binary variables and Wilcoxon rank-sum test for continuous and ordered variables.

Distribution of time-to-event variables was estimated using the Kaplan–Meier product-limit method, and compared using the log-rank {chi}2 test. The Cox proportional-hazards model was used to estimate the hazard ratio. Two-sided confidence limits for hazard ratios and medians of all time-to-event variables were estimated.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient disposition
Pretreatment characteristics were balanced between the two treatment groups (Table 2). Four patients randomised to MC did not receive treatment: two developed brain metastases before the first dose, one already had chemotherapy for advanced disease, and one could not be treated because the delivery of drug supplies was delayed. Two patients randomised to EC did not receive treatment: one had a baseline LVEF of 48% and the other was erroneously given conventional doxorubicin. These patients were included in the efficacy analyses, but excluded from safety analyses.


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Table 2. Patient characteristics

 
Efficacy
The objective response rate (CR + PR) for all randomised patients was 46% in the MC-treated group and 39% in the EC-treated group (P=0.42) (Table 3). The P-value for non-inferiority was 0.002, thus ruling out the possibility that MC was inferior to EC.


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Table 3. Response rates and time-to-event variables

 
Response was observed at all major sites of disease for both drugs. Median time to onset of response was 42 days in both groups.

TTF (Figure 1A) was significantly longer for patients randomised to MC than for EC-treated patients (5.7 versus 4.4 months; P=0.007). The HR of 1.54 [95% confidence interval (CI) 1.14–2.35] significantly favoured MC.



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Figure 1. Kaplan–Meier curves for time-to-event variables in patients receiving Myocet 75 mg/m2 and cyclophosphamide 600 mg/m2 (MC), or epirubicin 75 mg/m2 and cyclophosphamide 600 mg/m2 (EC). (A) Time to treatment failure. (B) Time to disease progression. (C) Overall survival.

 
TTP (Figure 1B) was also significantly longer with MC than with EC treatment, at 7.7 and 5.6 months, respectively (P=0.022). The hazard ratio of 1.52 (95% CI 1.06–2.20) was significant in favour of MC.

Median overall survival (18.3 and 16.0 months with MC and EC, respectively) and the HR (1.15) were numerically in favour of the MC-treated group, but the log-rank test result was not statistically significant (P=0.504) (Figure 1C).

Haematological toxicity
Neutropenia was the most frequent and severe toxicity (Table 4). Grade 4 neutropenia occurred in 87% of MC-treated patients and 67% of the EC-treated group (P=0.004). However, the frequency of prolonged grade 4 neutropenia (26% and 31% of MC and EC patients, respectively) did not differ significantly between the two groups.


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Table 4. Adverse events

 
Dose reduction was more frequent in the MC-treated patients, occurring in 20% (11% of cycles) of the MC-treated patients and in 6% (3% of cycles) of the EC-treated patients. The most frequent reason for dose reduction was myelosuppression, although relatively few cycles were dose-reduced for neutropenia: 4% of MC cycles and 1% of EC cycles. Dose delays were infrequent and the overall median cycle was 21 days. Dose intensities were comparable (20 and 24 mg/m2/week for M and E, respectively); relative dose intensity was 91% for MC and 96% for EC.

In the MC group, 45 out of 76 patients (39% of cycles) received G-CSF as specified by the protocol, compared with 27 of 76 (29% of cycles) in the EC group.

Non-haematological toxicity
In terms of gastrointestinal toxicity, significantly more patients in the MC group had grade 3 stomatitis/mucositis (7% versus none; P=0.03). The incidence of nausea/vomiting and diarrhoea was similar in the two groups. Among other grade 3/4 non-haematological toxicities, the frequency of injection-site toxicity (all grades) was lower in the MC group (1% versus 10%; P=0.03). No palmar-plantar erythrodysesthesia (hand–foot syndrome) was reported.

There was no major difference in the incidence of abnormal serum chemistry variables between the treatment groups, nor any clinically important trends.

Cardiotoxicity
Cardiotoxicity was low in both treatment groups: nine patients on MC and eight on EC had asymptomatic LVEF reductions at comparable cumulative doses (Table 5). For MC there were two cases at 100–299 mg/m2, four at 300–399 mg/m2 and three at 500–599 mg/m2; for EC there was one case at 200–299 mg/m2, four at 300–399 mg/m2 and three at 400–499 mg/m2. There was no clinical evidence of CHF in any patient.


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Table 5. Number of patients with a decrease in LVEF (either by ≥20 points from baseline or 10 points from baseline to a final value <50%) by lifetime cumulative dose

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This is the first randomised controlled trial comparing MC and EC as first-line therapy for patients with metastatic breast cancer. In the present study, MC achieved a higher objective response rate than EC (46% versus 39%), but the difference did not reach statistical significance. Interestingly, with a median follow-up of 21 months, median duration of response, TTP and TTF were significantly longer in patients treated with MC.

Both Myocet and epirubicin had relatively low cardiotoxicity at the planned maximum cumulative dose of 600 mg/m2 [13Go, 14Go, 20Go, 21Go]. Cardiotoxicity was low in both treatment groups and no clinical CHF was observed in any patient, including the 41 patients who received the 600 mg/m2 cumulative dose of either Myocet or epirubicin. This compares well with doxorubicin. In an early analysis of 4018 patients, the incidence of doxorubicin-associated CHF was 7% at a cumulative dose of 550 mg/m2 [22Go]. For patients who survive over a period of years, late cardiotoxicity is likely to add considerably to this figure [23Go].

There were more episodes of grade 4 neutropenia with MC, but no difference between groups in the incidence of prolonged or febrile grade 4 neutropenia. In retrospect, perhaps Myocet and epirubicin should have been compared at equipotent doses to gauge their relative efficacy better. However, as described previously, the uncertainty surrounding the equipotent dose ratio of epirubicin and doxorubicin led to equimolar doses being chosen, given that the optimal dose of epirubicin remains unclear.

On the other hand, studies comparing equal milligram doses of Myocet and doxorubicin, either as single agents [13Go] or in combination with cyclophosphamide [14Go], have shown identical overall response rates and similar survival outcomes. A recent overview analysis by a Canadian group of trials comparing doxorubicin and epirubicin concluded that epirubicin at equivalent or slightly higher doses (x1.3–1.5) is as efficacious as doxorubicin and less toxic. Escalated doses of epirubicin may improve efficacy over lower doses, at least in terms of response rate, but at the expense of increased acute haematological toxicity [24Go].

Myocet received European approval for use in patients with metastatic breast cancer at a dose of 60 mg/m2 in combination with cyclophosphamide, on the basis of phase III data [14Go] showing equivalent efficacy and a marked reduction in cardiotoxicity compared with doxorubicin 60 mg/m2 plus cyclophosphamide. In recent studies, doxorubicin has usually been given at a dose of 60 mg/m2 in combination with cyclophosphamide [25Go], and a dose of 60 or 75 mg/m2 as monotherapy for metastatic breast cancer [26Go, 27Go]. The 75 mg/m2 dose of Myocet in the MC regimen was associated with a high incidence of neutropenia, confirming that the 60 mg/m2 dose is a more appropriate choice when given in combination with cyclophosphamide.

The difference observed here between MC and EC in terms of haematological toxicity follows the pattern that would be expected in a comparison of doxorubicin and epirubicin, given the estimate of epirubicin having 75% of the myelotoxicity of doxorubicin [8Go, 12Go]. At doses of epirubicin higher than that employed in this study, a parallel increase in haematological toxicity of epirubicin might be expected.

Unsurprisingly, our results suggest that at equimolar doses, in combination with cyclophosphamide, Myocet has modest but significant advantages over epirubicin for some efficacy end points and a non-significant trend towards improvement in others. Additional comparative studies of Myocet and epirubicin in other combination regimens and doses are worth considering. Myocet appears to be an acceptable alternative to epirubicin when considering less cardiotoxic options to conventional doxorubicin for first-line treatment of patients with metastatic breast cancer. Given the well established correlation between dose and therapeutic effect for doxorubicin, and in light of the uncertainty surrounding the optimal therapeutic dose of epirubicin, Myocet offers clinicians the opportunity to make clinical use of a drug that combines the dose/effect reliability of doxorubicin with the level of safety provided by epirubicin.


    Acknowledgements
 
The following investigators and institutions participated in the study. Belgium: M. Beauduin (Hopital de Jolimont, Haine-Saint-Paul), Y. Humblet (Hopital Universitaire Saint Luc, Brussels), J. Lemmens (Medisch Instituut Sint Augustinus, Wilrijk), R. Mathijs (Algemeen Ziekenhuis Middelheim, Antwerp), M. M. Rauis (Hopital Brugmann, Brussels); Bulgaria: I. Chernozemsky (National Oncology Centre, Sofia); Germany: T. Bauknecht (Universitatsfrauenklinik Freiburg, Freiburg), W. Eiermann (Frauenklinik vom Rotenkreuz, Munich), H. Gerhartz (Stadt Kliniken Duisburg, Duisburg), J. Hartlapp (Stadt Kliniken Osnabruck, Osnabruck), H.-G. Meerpohl (Saint Vincentius Hospital, Karlsruhe), A. Scharl (Universitatsklinik Koln, Cologne); Hungary: M. Csepreghy (Uzsoki Hospital, Budapest), M. Dank (Semmelweis University Clinic, Budapest), J. Erfan (Jozsa Andras Hospital, Nyiregyhaza), E. Juhos and I. Szakolczai (National Institute of Oncology, Budapest), G. Laszlo (Municipal Hospital, Veszprem), M. Osváth (County Hospital, Tatabanya), L. Perenyi (Municipal Hospital, Szeged), E. Szekely (Peterfy Sandor Teaching Hospital, Budapest), M. Wenczl (Markusovzsky Teaching Hospital, Szombathely); Lithuania: S. Bruzas (Lithuanian Oncology Centre, Vilnius), R. Jurgutis (Klaipeda Oncology Centre, Klaipeda); Poland: P. Koralewski (Wojewodzki Szpital Specjalistyczny, Krakow); the Netherlands: A. van Bochove (Ziekenhuis De Heel, Zaandam), J. Croles (Willem Alexander Ziekenhuis, Hertogenbosch), J. J. Mol (Ziekenhuis Rijnstate, Arnhem), D. van Toorn (Lukas Ziekenhuis, Apeldoorn); UK: R. C. F. Leonard (Western General Hospital, Edinburgh), P. Hardman (South Cleveland General Hospital, Cleveland), T. Iveson (Salisbury District Hospital, Salisbury), E. Murray (Pilgrim Hospital, Boston), A. L. Stewart (Christie Hospital, Manchester), J. Stewart (Northampton General Hospital, Northampton). This study was supported by a grant from Elan Pharmaceuticals, Princeton, NJ, USA, and was presented in part at the 7th Nottingham International Breast Conference, UK, in 2001.


    Notes
 
{dagger} Participants are listed in the Acknowledgements. Back

Received for publication April 16, 2003. Revision received June 3, 2004. Accepted for publication June 15, 2004.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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