Phase II study of pegylated liposomal doxorubicin (Caelyx®) and docetaxel as first-line treatment in metastatic breast cancer

A. Alexopoulos*, M. V. Karamouzis, H. Stavrinides, A. Ardavanis, K. Kandilis, J. Stavrakakis, C. Georganta and G. Rigatos

First Department of Medical Oncology, St Savvas Anticancer-Oncologic Hospital, Athens, Greece

Received 27 November 2003; revised 28 January 2004; accepted 2 February 2004


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

The aim of this study was to determine the activity and safety of pegylated liposomal doxorubicin (PLD; Caelyx®) and docetaxel combination as first-line treatment in patients with metastatic breast cancer (MBC).

Patients and methods:

Forty-four patients with a median age of 63 years were treated with PLD 30 mg/m2 (day 1) and docetaxel 75 mg/m2 (day 2) every 3 weeks for six cycles. Recombinant human Granulocyte Colony-Stimulating Factor (rhG-CSF) could be used in patients with grade ≥3 neutropenia after the first cycle.

Results:

Forty-two of 44 patients were assessable for response. The response rate (RR) was 64.3% (95% confidence interval 49.8% to 78.8%). Six patients (14.3%) achieved complete response (complete disappearance of all measurable and assessable disease lasting at least 4 weeks, no new lesions, no disease-related symptoms), partial response was observed in 21 patients (50%) (≥50% decrease of measureable disease lasting at least 4 weeks, no progression of assessable disease, no new lesions, no disease-related symptoms), eight patients had stable disease and seven patients progressive disease. Median disease-free and overall survival were not reached, but were in excess of 17 months (range 6–17 months). Twenty of the patients had received previous adjuvant chemotherapy (10 with epirubicin-containing regimen with a median cumulative dose of 400 mg/m2). Grade ≥3 neutropenia occurred in 18.4% and neutropenic fever in 9% of patients. Palmar–plantar erythrodysesthesia was observed in four patients. Dose reduction was necessary in seven patients. Two patients discontinued treatment: one due to prolonged grade 3–4 neutropenia and one due to neurotoxicity. No treatment-related deaths occurred.

Conclusions:

The combination of PLD and docetaxel achieved high RRs with acceptable toxicity as first-line treatment in MBC.

Key words: docetaxel, metastatic breast cancer, pegylated liposomal doxorubicin


    Introduction
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Metastatic breast cancer (MBC) is considered incurable with current treatment options and patients with MBC have a median survival of ~2 years [1]. The most active cytotoxic agents include alkylating drugs, antimetabolites, vinca alkaloids, anthracyclines and taxanes. Used as monotherapy, these agents produce objective responses in 20%–80% of patients with MBC [2]. However, complete responses are rare and <20% of these patients maintain such status beyond 5 years [3].

In MBC, anthracyclines are considered among the most active single agents. However, the use of anthracyclines is limited by their acute toxicities and by their potential to cause cumulative cardiac damage. An attempt to improve the therapeutic index of anthracyclines includes drug encapsulation in liposomes [4]. The development of pegylated liposomes resulted in prolonged drug circulation time and better drug distribution into tumor tissue [5]. Two phase I studies with pegylated liposomal doxorubicin [PLD; Caelyx®, Doxil® (Schering-Plough Pharmaceuticals, Kenilworth, NJ and Ortho-Biotech, Raritan, NJ)] initially provided evidence of antitumor activity in breast cancer [6]. In the first reported phase II study of PLD in MBC, an overall response rate of 31% was achieved. Dose-limiting toxicity was grade ≥3 skin toxicity at doses of 60 mg/m2 every 3 weeks. The incidence of this toxicity proved to be dose- and schedule-dependent and it was substantially reduced at doses of 45 mg/m2 every 4 weeks. The mild myelosuppression seen with this regimen favored its use in combination chemotherapy [7].

Docetaxel is a semi-synthetic taxane with marked efficacy in the treatment of various solid tumors. In MBC, docetaxel has shown superiority with regard to tumor response and time to progression when compared with doxorubicin [8], and it is considered one of the most effective antitumor agents currently available for first-line treatment of MBC, with response rates of 40–68% in previously untreated patients [9] and 53–57% in patients with anthracycline-resistant breast cancer [10, 11].

The combined use of docetaxel and anthracyclines was the next rational step [12]. The combination of doxorubicin with docetaxel proved to be a highly effective regimen for MBC in terms of response rates and time to disease progression, with myelotoxicity being the main adverse event [13]. PLD has been proved comparable to doxorubicin in terms of efficacy and toxicity in a non-inferiority design study [14]. A phase I study was conducted recently to evaluate the combination of PLD and docetaxel for the treatment of advanced breast cancer. This study generated encouraging response rates [15].

The objectives of this study were to determine the therapeutic efficacy and to evaluate the safety of the combination of PLD and docetaxel as first-line treatment in MBC.


    Patients and methods
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patient selection
Women 18–75 years of age with histologically confirmed and bidimensionally measurable MBC were eligible for enrolment. Patients receiving previous hormonal or chemotherapy (including anthracycline-based regimens) for adjuvant disease were eligible. However, no previous chemotherapy for metastatic disease was permitted. In addition, patients were required to have: Eastern Cooperative Oncology Group (ECOG) performance status ≤2, no functionally important cardiovascular disease [normal left ventricular ejection fraction (LVEF)], adequate renal (clearance >50 ml/min) and liver (bilirubin level <2 mg/dl) function, adequate bone marrow reserve (absolute white blood cell count >3000/µl and platelet count >100 000/µl), absence of uncontrolled infection, no CNS metastases, and absence of pregnancy. The local Scientific and Ethics Committees approved the protocol. All patients gave written informed consent before study entry, which was performed according to the Declaration of Helsinki.

Treatment schedule and dose modifications
Cycles consisted of PLD 30 mg/m2 on day 1 and docetaxel 75 mg/m2 on day 2, repeated every 3 weeks for a total of six cycles. PLD was dissolved in dextrose saline 5% and was given as intravenous infusion over a period of 1 h. Docetaxel was administered as a 1 h i.v. infusion. Patients also received oral corticosteroids (methylprednisolone 32 mg 12 and 3 h before and 12 h after docetaxel administration, and 64 mg daily on days 2–4) and diphenhydramine hydrochloride (50 mg i.v. 30 min before docetaxel infusion). Anti-emetic therapy consisted of ondasetron and dexamethasone, as clinically indicated. Treatment was discontinued in case of disease progression, intolerable toxicity or patient refusal. Pamidronate and palliative radiotherapy were not allowed until progression.

Dose modifications were permitted for hematological and non-hematological toxicities. rhG-CSF (5 µg/kg/day s.c.) was administered on days 7–12 or until recovery of leukocytes to the patients who experienced grade 3 or 4 neutropenia after the first cycle of chemotherapy. If the neutrophil count on the day of scheduled treatment was <1.5 x 109/l or the platelet count was <100 x 109/l, treatment was postponed for 1 week without dose adjustment. In the case of neutrophil count <0.5 x 109/l lasting for >7 days or complicated with fever, or platelet count <25 x 109/l, the subsequent doses of both drugs were reduced by 25%. With respect to PLD, the dose was to be reduced by 10% in case of palmar–plantar erythrodysesthesia (PPE) if symptoms had resolved after a 1 week delay. If longer delays were required for resolution of PPE, or greater toxicity developed, then a 25% reduction was indicated. Regarding docetaxel, 25% reduction of the previous dose was recommended in case of grade 2 skin reactions and grade 2 neurotoxicity, whereas treatment would be stopped in case of persistent grade 2 skin reactions and grade 3 neurotoxicity. In case of fluid retention, no dose reduction of docetaxel was planned, although treatment with spironolactone 50 mg would be recommended.

Treatment evaluation
The primary efficacy measurement was response rate, assessed using the World Health Organization (WHO) scale. Secondary measures of response included disease-free and overall survival. Toxicity was assessed using the National Cancer Institute common toxicity criteria guidelines.

Initial evaluation included a thorough medical history and physical examination, complete blood count, biochemistry profile and clotting studies. Chest X-ray, computed tomography (CT) scan of the lungs, abdominal ultrasound, bone scintigraphy, ECG and echocardiogram were performed when the patient was entering the study. During treatment, clinical and hematology laboratory evaluations were performed every 3 weeks. If a response was documented with imaging studies after a minimum of two cycles of treatment (6 weeks), re-evaluation was performed every two cycles and at the end of chemotherapy or earlier if there was clinical or other evidence of relapse. LVEF assessment and ECG were also obtained after the completion of chemotherapy for all patients, whilst in anthracycline-pretreated patients, cardiotoxicity evaluation was performed when the total dose of anthracycline was ≥300 mg/m2 (including past therapies), and every 100 mg/m2 thereafter.

Statistical analysis
This was a non-randomized, non-comparative, single-institution, phase II study evaluating the efficacy and toxicity profile of PLD and docetaxel combination in patients with MBC. A response rate of >50% was the cut-off for considering the schedule sufficiently active. The study followed Simon’s two-stage optimal design; the first step consisted of 20 patients. If more than seven responses were observed, accrual was to continue to a total of 40 patients with a 5% rejection error and a power of 90%.

Time-to-event curves were estimated using the Kaplan–Meier method and compared using the long-rank test. Standard response criteria were applied [16]. The duration of complete response (CR), partial response (PR) or stable disease (SD) was calculated from the first confirmation of response until the date of radiologically documented progression, provided that this lasted at least 4 weeks. Survival was calculated from the date of registration to the date of death, irrespective of its cause. Time to disease progression was determined by the interval between the initiation of therapy to the first date that disease progression was objectively documented.


    Results
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Baseline demographics
Forty-four patients with histologically confirmed and bidimensionally measurable MBC were enrolled in the study between January 2002 and February 2003 (Table 1). All patients had an ECOG performance status <2. The median age was 63 years (range 33–78 years). Twenty patients received previous chemotherapy for adjuvant disease, including 10 patients who received a conventional anthracycline-containing regimen.


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Table 1. Patients’ characteristics
 
Drug administration
A total of 226 cycles of chemotherapy were administered, with a median of six cycles per patient (range two to six cycles). The planned dose intensities of PLD and docetaxel were 10 mg/m2/week and 25 mg/m2/week, respectively. The median delivered doses were 50 mg PLD and 130 mg docetaxel, and the relative dose intensities were greater than 94% and 94%, respectively.

Efficacy
Forty-two out of 44 patients were assessed for response. The other two patients experienced a rapid deterioration of their disease soon after the first cycle of chemotherapy. The median follow-up time was 8 months (range 4–17 months). The overall response rate (CR + PR) is estimated to be 64.3% [95% confidence interval (CI) 49.8–78.8%]. At the time of analysis, 13 patients (29.5%) have progressed and six patients (13.6%) have died. The median time to disease progression (Figure 1; range 3–17 months) and the median overall survival of all patients have not been reached, but are in excess of 17 months (Figure 2; range 6–17 months).



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Figure 1. Disease-free survival of the patients enrolled in the study.

 


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Figure 2. Overall survival of the patients enrolled in the study.

 
Six out of 42 patients (14.3%) experienced CR (95% CI 3.7–24.9%), with a median time to disease progression of 12 months (range 6–17 months) and median overall survival of 17 months (range 7–17 months). Partial response was observed in 21 patients (50%; 95% CI 34.9–65.1%), with a median time to disease progression of 17 months (range 5–17 months) and median overall survival of 17 months (range 8–17 months). Eight out of 44 patients (19%; 95% CI 7.2–30.9%) had SD with a median time to disease progression of 17 months (range 3–17 months) and median overall survival of 17 months (range 6–17 months). Seven patients (16.7%; 95% CI 5.4–27.9%) had progressive disease with median overall survival of 12 months (range 6–17 months).

Toxicity and complications
All patients were assessed for toxicity. Hematological toxicity was the most frequently reported adverse event (Table 2). Neutropenia was recorded in 26 patients (59%): grade 1 in 13 patients (29.5%), grade 2 in five patients (11.4%), grade 3 in three patients (7%) and grade 4 in five patients (11.4%). Neutropenic fever that required administration of antibiotics was reported in four patients (9%). Treatment was discontinued in only one patient due to prolonged grade 3–4 neutropenia. Anemia was mild: nine patients (20.5%) experienced grade 1 and five patients (11.4%) grade 2. Thrombocytopenia grade 1 was reported in only two patients (4.5%). In five patients (11.4%), subsequent dose reduction of both chemotherapeutic agents was required due to prolonged myelotoxicity. Eight patients (18.4%) experienced grade 3–4 neutropenia and needed granulocyte colony-stimulating factor (G-CSF). The total number of cycles that were delivered with growth factors was 20 (9%).


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Table 2. Toxicity profile
 
PPE was reported in four patients (9%), of whom one patient required a 10% reduction and one required a 25% reduction in PLD dose. Peripheral neurotoxicity was reported in six patients (13.6%), but only one patient discontinued due to grade 3 neurosensory defects and neuromotor symptoms. Allergic reactions, observed in 10 patients (22.7%), consisted of flushing with onset early during the first PLD infusion. Interruption of PLD with the administration of anti-histamines and corticosteroids led to immediate recovery. The infusion was re-started at a slower rate and no further allergic reactions occurred again with subsequent cycles. Alopecia grade 1–3 was observed in nearly all patients (95%), but only two patients (4.5%) had grade 3. Other non-hematological grade 1 adverse reactions were fatigue in eight patients (18.2%), anorexia in six patients (13.6%), nausea and vomiting in six patients (13.6%), stomatitis in five patients (11.4%) and diarrhea in two patients (4.5%). No patient developed fluid retention syndrome. No toxic death occurred.

Cardiotoxicity
The median cumulative dose of liposomal anthracycline of all patients was 151.5 mg/m2 (range 30–180 mg/m2). Of the 20 patients who had received previous adjuvant chemotherapy, 10 (50%) had received therapy with a conventional anthracycline (epirubicin). The median cumulative doses of free and liposomal anthracycline in these patients were 400 mg/m2 (range 300–420 mg/m2) and 118.5 mg/m2 (range 30–157.5 mg/m2), respectively. All of these patients were closely monitored for cardiac toxicity before, during and after chemotherapy. The mean change in LVEF from baseline of anthracycline-pretreated patients was 4%. Fifteen more patients (including the other 10 who have received adjuvant chemotherapy) experienced a mean change of 3% in baseline LVEF. No patient experienced LVEF decrease <60%.


    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The aim of this study was to evaluate the clinical efficacy and toxicity profile of the docetaxel–PLD combination regimen as first-line treatment in MBC. An initial phase I study involving patients with locally advanced and metastatic breast cancer demonstrated that the response rate of this combination regimen was ~55% [15]. This phase II study confirmed the promising efficacy seen in the phase I trial, with an overall response rate of 64%.

The established anticancer potential of PLD and docetaxel monotherapy in MBC and their limited cross-resistance provided the rationale for combining these drugs in patients with MBC [17]. Both anthracyclines and taxanes are known to have dose–response relationships and some overlapping toxicities, so their combined use should theoretically increase their antineoplastic effect, albeit with a potentially augmented toxicity profile.

To the best of our knowledge, this is the first phase II study reporting on the efficacy and toxicity of the combination of docetaxel and PLD in MBC. The doses of the two drugs used in combination have been evaluated in a recently performed phase I study [15]. Based on previous published phase I studies of PLD with taxanes, we chose the 2-day schedule in order to achieve better clinical outcome and to reduce dose-dependent toxicities [18, 19]. In our study, the overall response rate was 64.3%, with CR in six patients (14.3%) and PR in 21 patients (50%). In order to avoid bias, the short interval of our follow-up and the low percentage of patients enrolled in our study who were previously treated with anthracyclines should be highlighted. The latter might be of great importance since the activity of PLD in anthracycline-resistant patients, a subset of those who are anthracycline-pretreated, is currently under debate [20].

PLD has a distinct toxicity profile compared with conventional doxorubicin. Significant neutropenia, alopecia, and nausea and vomiting are rare, while skin toxicities (mucositis, PPE) are the most prominent adverse events [21]. Although it has been suggested that PLD treatment dose intervals of 3 weeks increase the potential for development of PPE [22], in our study only two patients (4.5%) required modification of PLD dose for this. As has already been noted in the literature, skin toxicity was not seen following the first cycles of treatment, but rather during cycles three to four, implying a cumulative effect of PLD. Grade 3–4 nausea and vomiting, as well as mucositis, were not seen in our study. Noteworthy, however, is that alopecia was documented in virtually all of our patients. Although PLD causes significantly less alopecia than doxorubicin, it is commonly associated with docetaxel.

The hematological toxicity profile observed in our study was moderate and manageable. Neutropenia grade ≥3 was reported in eight patients (18.4%) and neutropenic fever in four patients (9%), but only one patient discontinued treatment due to prolonged myelotoxicity. This might be due to the prophylactic administration of G-CSF.

Combinations of anthracyclines with docetaxel appear to be less cardiotoxic than with paclitaxel [23]. In addition, the safer cardiotoxic profile of PLD compared with conventional doxorubicin is well documented [14, 24]. In our study, cardiac evaluation did not reveal any significant alteration during chemotherapy or follow-up, even in anthracycline-pretreated patients.

In conclusion, the present study indicates that the combination of PLD and docetaxel yields high response rates with a well-tolerated safety profile as first-line treatment in patients with MBC. These encouraging results should be confirmed in further studies. In addition, stratifying patients according to previous anthracycline exposure will be of interest.


    FOOTNOTES
 
* Correspondence to: Dr A. Alexopoulos, 171 Alexandras Street, Athens 11522, Greece. Tel: +30-210-6409381; Fax: +30-210-6420146; E-mail: karam{at}otenet.gr Back


    REFERENCES
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
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