1 Kent Cancer Center, Maidstone, UK; 2 Ichilov Hospital, Tel Aviv, Israel; 3 Oncologia Medica I Ist., Genova, Italy; 4 Frauenklinik der Ruprecht-Karls-Universitat Vosstrasse, Heidelberg, Germany; 5 Oncologia Medica & Ematologie, Istituto Clinico Humanitas, Rozzano (MI), Italy;6 Shaare Zedek Medical Center, Jerusalem, Israel; 7 Maastricht University Medical Center, Maastricht, The Netherlands; 8 Oncology Clinic, Poznan, Poland; 9 Newcastle Mater Misericordiae Hospital, Waratah, Australia; 10 Hospital Dipreca, Santiago, Chile; 11 Schering-Plough Research Institute, Kenilworth, NJ, USA
Received 26 June 2003; revised 16 October 2003; accepted 16 December 2003
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ABSTRACT |
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This study was designed to demonstrate that efficacy [progression-free survival (PFS)] of CAELYXTM [pegylated liposomal doxorubicin HCl (PLD)] is non-inferior to doxorubicin with significantly less cardiotoxicity in first-line treatment of women with metastatic breast cancer (MBC).
Patients and methods:
Women (n = 509) with MBC and normal cardiac function were randomized to receive either PLD 50 mg/m2 (every 4 weeks) or doxorubicin 60 mg/m2 (every 3 weeks). Cardiac event rates were based on reductions in left ventricular ejection fraction as a function of cumulative anthracycline dose.
Results:
PLD and doxorubicin were comparable with respect to PFS [6.9 versus 7.8 months, respectively; hazard ratio (HR) = 1.00; 95% confidence interval (CI) 0.821.22]. Subgroup results were consistent. Overall risk of cardiotoxicity was significantly higher with doxorubicin than PLD (HR = 3.16; 95%CI 1.586.31; P <0.001). Overall survival was similar (21 and 22 months for PLD and doxorubicin, respectively; HR = 0.94; 95%CI 0.741.19). Alopecia (overall, 66% versus 20%; pronounced, 54% versus 7%), nausea (53% versus 37%), vomiting (31% versus 19%) and neutropenia (10% versus 4%) were more often associated with doxorubicin than PLD. Palmar-plantar erythrodysesthesia (48% versus 2%), stomatitis (22% versus 15%) and mucositis (23% versus 13%) were more often associated with PLD than doxorubicin.
Conclusions:
In first-line therapy for MBC, PLD provides comparable efficacy to doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.
Key words: cardiotoxicity, pegylated liposomal doxorubicin
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Introduction |
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The clinical usefulness of doxorubicin, the most widely used anthracycline, is limited by toxicity that may preclude adequate dosing and rechallenge on relapse, or lead to drug resistance. High cumulative doses of doxorubicin increase the probability of cardiotoxicity while individual doses are often limited by myelosuppression. Alopecia, severe acute nausea and vomiting, and mucositis are additional adverse effects of doxorubicin that may limit therapy. Doxorubicin analogs such as epirubicin are also associated with cardiotoxicity, alopecia, nausea and vomiting. An anthracycline formulation with comparable efficacy and improved safety would increase the drugs therapeutic index and enhance its overall clinical benefit.
Pegylated liposomal doxorubicin (PLD; CAELYXTM, Schering-Plough Corp., Kenilworth, NJ, USA/DOXIL", ALZA, Mountain View, CA, USA) is doxorubicin confined in liposomes that have been sterically stabilized by grafting polyethylene glycol onto the surface (Stealth Liposome"). PLD has a circulation half-life of approximately 73.9 h, whereas doxorubicin has a half-life of <10 min [Schering-Plough Research Institute (Kenilworth, NJ, USA), unpublished data]. Prolonged circulation facilitates greater uptake of PLD liposomes by tumor tissue. PLD accumulates selectively in metastatic breast carcinoma tissue, resulting in 10-fold higher intracellular drug concentrations compared with adjacent normal tissue [5]. Pegylated liposomal encapsulation also reduces plasma levels of free doxorubicin and may reduce drug delivery to normal tissue, which may reduce toxicity.
The dosage of PLD selected for this study was based upon the results of phase I and II studies in patients with solid tumors, including breast cancer, and upon a phase III ovarian cancer trial. The results of these trials indicated that a dosage of 50 mg/m2 every 4 weeks is clinically active and well tolerated [6, 7]. In patients with MBC treated with PLD doses of 4560 mg/m2 every 3 to 4 weeks, a response rate of 31% has been reported [8].
The present study was designed as a noninferiority trial to assess treatment efficacy, measured by progression-free survival (PFS), and to assess whether PLD has a superior cardiac safety profile as compared with doxorubicin in first-line therapy for women with MBC.
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Patients and methods |
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Patient status was reviewed every 3 weeks (doxorubicin arm) or 4 weeks (CAELYXTM arm) while on study treatment with assessment of physical signs, performance status, adverse events, complete blood count and serum chemistry. After disease progression, patients were followed up at least every 3 months for assessment of subsequent treatment and survival. Patients who discontinued study treatment prior to disease progression had tumor assessments every 12 weeks until progression was documented, and then were followed as above.
The study was conducted in accordance with International Conference on Harmonization Good Clinical Practice guidelines. An informed consent document and protocol were reviewed and approved by the appropriate local ethics or review boards prior to study initiation.
Study population
Female patients 18 years of
age with World Health Organization (WHO) performance status
2 and
measurable or evaluable, stages IIIB or IV MBC [9] were eligible for enrollment. Patients
with measurable disease had tumors with clearly defined margins, as defined
by any of the following: plain X-ray with at least one diameter
1.0 cm
(excluding bone lesions); computed tomography (CT), magnetic resonance
imaging (MRI) or other imaging scan with both diameters
1.0 cm;
palpation with both diameters
2.0 cm; or unidimensionally measurable
disease
1.0 cm. Patients with evaluable disease had tumors with margins
not clearly defined on CT, MRI or X-ray, or with both diameters
1.0 cm, or had palpable masses with either diameter <2.0 cm, or bone
metastases. Prior hormonal or adjuvant anthracycline therapy was permitted
with a cumulative doxorubicin (or doxorubicin-equivalent) dose of
300
mg/m2, and an adjuvant chemotherapy-free interval of >12
months. Normal hematological, hepatic, renal and cardiac [left
ventricular ejection fraction (LVEF) within normal limits] function
was required. Patients with elevated bilirubin concentration and/or
elevated alanine aminotransferase/aspartate aminotransferase were eligible
for inclusion if reduced liver function was secondary to liver metastases.
Bisphosphonate use at the time of study entry was permitted.
Patients who had received prior chemotherapy for metastatic disease, radiation less than 3 weeks before treatment initiation or had symptomatic central nervous system metastasis, uncontrolled systemic infection or were unable to give informed consent were not eligible for participation. Patients were excluded if they had a history of ischemic heart disease or arrhythmia requiring treatment, clinically significant valvular disease or LVEF below the range of normal (less than the lower limit of normal for the institution).
Patient stratification
Patients were
prospectively stratified based on three criteria to balance major
prognostic risk factors between treatment groups:
Cardiac risk factors were defined
as prior mediastinal irradiation, age 65 years, history of heart
disease (previous myocardial infarction, arrhythmia or angina, not
requiring treatment) or had hypertension, or diabetes requiring medical
treatment.
Clinical assessments
Primary objectives
were to test whether efficacy (PFS) of PLD was statistically non-inferior
to doxorubicin and whether significantly less cardiotoxicity was observed
with PLD. Tumor evaluations were performed every 12 weeks until disease
progression. PFS was measured from the date of randomization to the date of
disease progression, death (within 4 months of last tumor evaluation
indicating no progression) or last tumor assessment (censored), whichever
was the earliest. Multigated blood-pool imaging (MUGA) scans were performed
to measure LVEF before onset of treatment, after 300 mg/m2
cumulative anthracycline exposure, and after every additional 100
mg/m2 of PLD and every 120 mg/m2 of doxorubicin.
Secondary objectives were to compare treatment effects on overall survival
(OS), overall response rate, tolerability and health care resource
utilization (defined as the proportion of patients in each treatment group
who received antiemetics, growth factors or transfusions during the study).
OS was measured from the date of randomization to the date of death or last
follow-up (censored). Objective tumor responses were assessed according to
World Health Organization criteria [10] with the exception of progressive
disease. For bidimensionally measurable disease, a 50% increase
in the sum of the products of the longest perpendicular diameters or for
unidimensionally measurable disease, a
50% increase in the sum
of the diameters of all lesions was considered evidence of disease
progression. Furthermore, a
25% increase in the size of any
single lesion, appearance of any new lesions or significant worsening of
evaluable, but nonmeasurable, disease was also considered evidence of
disease progression.
Safety assessments
Safety was
monitored by clinical and selected laboratory evaluations. Certified local
laboratories performed hematology and blood chemistry analyses. Patients
also received a 12-lead electrocardiogram at baseline (within 4 weeks of
initiation of study drug) and at the end of the study. The presence of any
pre-existing signs and symptoms of concomitant illness was noted by the
investigator, as were adverse events that occurred during treatment and/or
follow-up. Data on onset and resolution, severity, frequency, impact on
study treatments, and outcome were recorded for adverse events. Adverse
events were rated by investigators using the National Cancer Institute
(NCI)common toxicity criteria [11]. Alopecia grading was reported as no
loss (grade 0), mild loss (grade 1) or pronounced or total loss (grade 2).
Relationship of an adverse event to treatment was judged by the
investigator to be possibly related, probably related, or
unrelated.
Statistical methodology
Primary
efficacy and all safety analyses were performed on data from all randomized
patients. With enrollment of 500 patients and 390 events (disease
progressions or deaths), the study was designed to test, with at least
80% power and at the 0.025 level of significance (one-sided test),
whether PLD was statistically non-inferior to doxorubicin with respect to
PFS; i.e. PFS for PLD was 80% of that for doxorubicin (lower
boundary of the 95% CI for the hazard ratio [HR] >0.8).
A true HR of 1.06 for doxorubicin relative to PLD was assumed. Having
demonstrated non-inferiority with respect to PFS, differences in cumulative
anthracycline dose at first cardiac event would be analyzed. The study had
80% power at an overall 5% significance level to show
statistical significance (adjusted for one interim analysis) if the HR for
cardiac toxicity was 1.76 or higher.
PFS and cumulative
anthracycline dose at first protocol-specified cardiac event were estimated
for each treatment group using the KaplanMeier method; the
stratified log-rank test was utilized to compare treatment groups. A
protocol-specified cardiac event was defined as a decrease of
20% from baseline if the resting LVEF remained in the normal
range, or a decrease of
10% if the LVEF became abnormal (less
than the institutional lower limit of normal). Patients were also assessed
for signs and symptoms of congestive heart failure. The differential
diagnosis of congestive heart failure (CHF) required the presence of a
constellation of signs and symptoms (such as dyspnea upon exertion,
peripheral edema, orthopnea or tachypnea) requiring treatment specific for
CHF. In addition, the investigators discretion was accepted as the
determination of whether symptoms were specific to CHF rather than disease
progression. Patients who discontinued treatment without experiencing
cardiotoxicity were censored at the cumulative dose received at the time of
discontinuation.
Analyses of cardiotoxicity included comparison of the proportion of patients in each treatment group who developed cardiotoxicity (by protocol-specified cardiac event) at any time during the study, as well as a comparison of the mean percentage change in LVEF from baseline by cumulative anthracycline dose for each treatment group.
OS was estimated for each treatment group using the KaplanMeier method; the stratified log-rank test was utilized to compare treatment groups. The effect of prognostic factors (in addition to treatment) on PFS and OS was examined in supplementary analyses using Coxs Proportional Hazards Model. Overall response to treatment (complete plus partial response) in patients with measurable disease at study entry was tabulated.
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Results |
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Overall, 339 patients (152 PLD and 187 doxorubicin) had electronic MUGA scan data for evaluation of cardiotoxicity (baseline and at least one scan during treatment) and were included in the analysis. Patients in the PLD arm had a median cumulative anthracycline dose of 398 mg/m2 (including prior anthracycline exposure). Patients in the conventional doxorubicin arm had a median cumulative anthracycline dose of 421 mg/m2 (including prior anthracycline exposure). Fifty-eight patients (10 PLD, 48 doxorubicin) met the protocol-defined LVEF criteria for cardiotoxicity during treatment and/or follow-up (Table 3). The risk of developing cardiotoxicity was significantly higher for patients receiving doxorubicin than for those receiving PLD (P <0.001, HR = 3.16 for comparison of cumulative anthracycline dose at the first, protocol-specified, cardiac event). The increase in risk of developing cardiotoxicity on doxorubicin versus PLD was observed in all subgroups analyzed, including those at high risk for developing CHF [12] (Table 4). In the subgroup that received prior adjuvant anthracycline therapy, the risk of developing cardiotoxicity was seven-fold higher with doxorubicin than with PLD. None of the 10 PLD-treated patients who had cardiotoxicity by LVEF criteria developed clinical signs or symptoms of CHF, whereas 10 of 48 doxorubicin-treated patients who had cardiotoxicity by LVEF criteria developed signs or symptoms of CHF. Two patients in each group developed clinical CHF but did not have a corresponding decrease in LVEF.
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Safety
Both drugs were
administered on schedule, at or near the defined dose. The mean cycle
length for PLD was 29.6 days and the mean dose of drug per cycle was 48.3
mg/m2. For doxorubicin, the mean cycle length was 22.3 days and
the mean dose of drug per cycle was 58.0 mg/m2. In both groups,
24% of patients discontinued due to toxicity (adverse event or
cardiac toxicity). Among PLD patients, 56 (22.0%) discontinued due
to an adverse event and six (2.4%) discontinued due to cardiac
toxicity, whereas among doxorubicin patients 24 (9.4%) discontinued
due to an adverse event and 36 (14.1%) discontinued due to cardiac
toxicity. PPE was the most common adverse event associated with PLD
(48%); PPE was reported in five (2%) doxorubicin patients
(Table 6). The
incidence of grade 3 PPE was 17% on PLD and there was no grade 4
(life-threatening) PPE. PPE resulted in treatment discontinuation in
7% of PLD-treated patients.
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Alopecia was markedly less frequent with PLD (20%) than with doxorubicin (66%). Pronounced or total hair loss was reported in 7% of PLD-treated patients compared with 54% of doxorubicin patients.
The incidence of grades 3 and 4 hematological toxicities (anemia, leukopenia, neutropenia and thrombocytopenia) was low in both groups (Table 6). Grades 3 and 4 anemia occurred in 12% of patients in both groups, and grade 4 thrombocytopenia occurred in one doxorubicin-treated patient. The occurrence of grades 3 and 4 leukopenia was higher among doxorubicin-treated patients (9%) than PLD-treated patients (1%). Neutropenia was more commonly reported as an adverse event with doxorubicin (all grades, 10%; grade 3 and 4, 7%) than with PLD (all grades, 4%; grade 3 and 4, 2%). Eight doxorubicin patients compared with two PLD patients developed concomitant fever and neutropenia during the study. The use of blood product support (8.2% versus 5.5%) and hematopoietic growth factor support (8.6% versus 5.1%) were higher on doxorubicin than PLD.
Infusion reactions were more common with PLD than with doxorubicin (13% versus 3%). Allergic reactions (14 PLD versus two doxorubicin) and flushing (7 PLD versus zero doxorubicin) were the most common reactions. The majority were mild to moderate and did not limit treatment; 84% of these patients were successfully rechallenged and tolerated therapy for two to 14 subsequent cycles. Four PLD-treated patients discontinued due to infusion reactions.
There were 30 (PLD, 14; doxorubicin, 16) deaths that occurred during study treatment or within 30 days after patients completed treatment; 50% occurring within the context of disease progression. Adverse events causing death in five patients (two PLD-treated patients and three doxorubicin-treated patients) were considered to be related to treatment. The three patients on conventional doxorubicin died due to neutropenic sepsis. Of the two patients on the PLD arm, one died due to cardiac arrest. This patient had pre-existing bone, liver, lung and pleural involvement. She received two cycles of PLD before being discontinued due to severe dyspnea. The second patient had pre-existing cardiac insufficiency requiring medication, as well as pre-existing liver disease and was therefore not eligible for enrollment (protocol violation). She received a reduced dose of PLD at cycle 1 (12 mg/m2) and died due to cardiac failure within 5 days of receiving the first dose. These PLD patients are those listed as developing signs and symptoms of CHF in Table 3.
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Discussion |
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Previous studies have shown that the
incidence of anthracycline-induced CHF increases in relation to total dose
of drug administered [13], and that the risk of
anthracycline-induced cardiotoxicity is increased for patients 65 years
of age, those who received previous adjuvant anthracycline therapy, and
those with one or more cardiac risk factor [12]. The results of this trial clearly
demonstrated that there was less risk of developing cardiotoxicity with PLD
than with doxorubicin in all subgroups analyzed, including those subgroups
at increased risk of developing a cardiac event.
In the short-term, there was a higher incidence of skin toxicity (PPE) with PLD; but unlike cardiotoxicity, this side-effect is not life threatening, and is reversible and manageable with appropriate supportive care measures. Measures such as advising patients to wear loose-fitting clothing and to avoid exposure to heat and vigorous exercise may minimize PPE. Published reports also suggest that concomitant medication with pyridoxine and/or dexamethasone may alleviate the symptoms of PPE [1416], although this has not been established in randomized trials. More recent phase II studies have reported a significantly lower incidence of grade 3 PPE (<10%) [1719] than that reported in this randomized study, most likely the result of improved awareness among clinicians of this side-effect and improved implementation of supportive care or dosing modification measures.
Patients treated with PLD experienced less alopecia, nausea, vomiting and myelosuppression than those treated with doxorubicin. Pronounced or total hair loss was reported in 54% of patients treated with doxorubicin but in only 7% of patients treated with PLD. Nausea, vomiting and myelosuppression occurred less frequently with PLD even though there was greater use of supportive care including 5-HT3 antagonists, growth factors and transfusions among patients treated with doxorubicin.
The cardiac
safety of PLD demonstrated in this study is supported by a previous
retrospective analysis of cardiac safety among patients treated with PLD
for solid tumors [20]. Among 34
patients who had received doses of PLD from 500 to 1450 mg/m2
(median 654 mg/m2) and who had not received conventional
anthracyclines, the median change in LVEF was 1%. Only two
patients (6%) experienced a drop in LVEF of 10%, and none
of the patients developed clinical congestive heart failure.
PLD should be explored as an alternative to non-anthracycline based adjuvant therapies in elderly women with breast cancer. In addition, the use of PLD in combination with trastuzumab for HER2+ breast cancer might offer an efficacious anthracycline-based regimen without the known associated cardiotoxic morbidity of conventional anthracyclines plus trastuzumab. These avenues should be investigated in clinical trials in the near future.
Doxorubicin analogs, such as epirubicin, demonstrate less cardiac toxicity than doxorubicin on an equimolar basis [21], but as with conventional doxorubicin, the cardiac risk increases with increased cumulative dose [22, 23]. Another option to conventional anthracyclines is TLC-D99, a nonpegylated liposomally encapsulated formulation of doxorubicin [24, 25]. In a randomized phase III trial of TLC-D99 versus conventional doxorubicin for first-line MBC, overall response rates were similar (26%), but there was a trend in favor of doxorubicin with respect to overall survival [24]. In another randomized phase III trial, TLC-D99 in combination with cyclophosphamide provided comparable antitumor efficacy and better cardiac safety as compared with conventional doxorubicin in combination with cyclophosphamide [24, 25]. However, TLC-D99 in combination with cyclophosphamide did not offer a safety advantage with respect to alopecia, nausea, vomiting or myelosuppression.
For patients with MBC who are at increased cardiac risk (the elderly, patients with specific cardiac risk factors, and patients who have been previously treated with anthracyclines) PLD is an important new therapeutic option. In addition, for individual patients with MBC who wish to minimize some of the short-term side-effects of conventional anthracyclines, or who seek the convenience of a once-monthly dosing schedule, PLD is a rational therapeutic choice.
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Acknowledgements |
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FOOTNOTES |
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M. E. R. OBrien and N. Wigler contributed equally to this work
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