First Department of Medical Oncology, St Savvas Anticancer-Oncologic Hospital, Athens, Greece
Received 27 November 2003; revised 28 January 2004; accepted 2 February 2004
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ABSTRACT |
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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 617 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. Palmarplantar erythrodysesthesia was observed in four patients. Dose reduction was necessary in seven patients. Two patients discontinued treatment: one due to prolonged grade 34 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
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Introduction |
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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 4068% in previously untreated patients [9] and 5357% 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.
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Patients and methods |
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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 24) 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 712 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 palmarplantar 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 Simons 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 KaplanMeier 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.
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Results |
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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 417 months). The overall response rate (CR + PR) is estimated to be 64.3% [95% confidence interval (CI) 49.878.8%]. 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 317 months) and the median overall survival of all patients have not been reached, but are in excess of 17 months (Figure 2; range 617 months).
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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 34 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 34 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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Cardiotoxicity
The median cumulative dose of liposomal anthracycline of all patients was 151.5 mg/m2 (range 30180 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 300420 mg/m2) and 118.5 mg/m2 (range 30157.5 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%.
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Discussion |
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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 doseresponse 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 34 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.
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FOOTNOTES |
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