Department of Surgery, Kansai Rosai Hospital, Hyogo, Japan
Received 17 May 2001; revised 16 August 2001; accepted 5 September 2001.
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Abstract |
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This study was conducted to investigate the efficacy and toxicity of weekly docetaxel administration in patients with metastatic breast cancer.
Patients and methods
Thirty-seven women were treated with 1 h infusions of docetaxel at 40 mg/m2/week after pre-medication with 8 mg dexamethazone. Each cycle consisted of three consecutive weekly treatments followed by a 1 week rest. All patients were assessed for toxicity; five patients were not assessable for clinical response, time to progression (TTP) and overall survival (OS) because of early treatment failure, but they were included in intention-to-treat analysis.
Results
Patients received a median of four cycles (range, 19), with a median dose intensity of 28 mg/m2/week (range 2230) and a median relative dose intensity of 0.95 (range 0.731.0). No patients showed complete response, whereas 14 had partial response, which accounted for 38% of objective response rate [95% confidence interval (CI) 22% to 53%]. In addition, three patients (8%, 95% CI 0% to 17%) had stable disease over 6 months. Clinical responses were achieved at a median of three cycles (range 14 cycles). The median TTP and OS were 5 and 12 months, respectively. The weekly docetaxel regimen was generally well tolerated. About half of the patients experienced grade 1 neutropenia; only 19% had grade 3/4 neutropenia, including one case of grade 4. No febrile neutropenia was observed and fluid retention syndrome was uncommon. Non-hematologic toxicity, however, such as asthenia/fatigue, nail damage, tearing or hearing disorders, was seen with successive treatment cycles.
Conclusions
Weekly docetaxel at 40 mg/m2/week is an active and feasible regimen for patients with metastatic breast cancer.
Key words: breast cancer, chemotherapy, docetaxel, phase II
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Introduction |
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Because palliation is the principal aim of chemotherapy for metastatic breast cancer patients, it is important to determine a regimen that can reduce the toxicity of the chemotherapeutic agent while retaining its clinical activity. Weekly administration of paclitaxel, another taxane-class cytotoxic agent, has a mild myelotoxicity profile compared with conventional every-three-weeks administration schedules, without lessening the efficacy [14]. To date, several phase I studies on weekly docetaxel administration have been reported [15, 16]. However, evaluation of the effects of weekly administration of docetaxel is clinically important. This administration schedule could potentially improve the severity of neutropenia, which is the dose-limiting toxicity of this drug. This conclusion is supported by the results of our pharmacokinetic study [17], which demonstrated that the area under the plasma concentrationtime curve (AUC) for docetaxel correlated with the administered dose of docetaxel, and that the median AUC of weekly docetaxel (40 mg/m2) was about half that of conventional every-three-weeks doses used in Japan, 60 mg/m2, although the dose intensity of a weekly schedule was 1.5-fold higher than that of the conventional schedule [17].
Based on the recommended dose for phase II studies, which ranged from 36 to 40 mg/m2/week, we conducted a phase II clinical trial of weekly docetaxel administration in patients with metastatic breast cancer, at a dose of 40 mg/m2/week. Here we report the results of this phase II trial.
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Subjects and methods |
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Treatment plan
Patients were pre-medicated with dexamethasone 8 mg intravenously, followed by 1 h intravenous infusion of docetaxel 40 mg/m2. Each 4-week cycle consisted of three consecutive weekly course of treatment, followed by a 1 week rest. Complete blood count as well as blood chemistry tests were evaluated prior to each treatment. Patients were assessed weekly for toxicity according to the National Cancer InstituteCommon Toxicity Criteria. When a grade 3 neutropenia was noted before the first infusion of each cycle, initiation of the cycle was delayed. When such a side effect was noted during the cycle, the next infusion was skipped. The dose of docetaxel was reduced by 25% when any of the following was noted: grade
2 fluid retention syndrome; grade
3 for other non-hematological toxicities; or if treatment was delayed or skipped twice in a given patient.
Patients were re-staged after each cycle and the following criteria were used to assess the clinical response: (i) complete response (CR), the disappearance of all signs, symptoms and biochemical changes related to breast cancer for a period of >4 weeks during which no new lesions appeared. (ii) Partial response (PR), a reduction of >50% in the sum of the products of perpendicular diameters of all measured lesions lasting >4 weeks during which no new lesions appeared and no existing lesions increased in size. (iii) Stable disease (SD), a reduction of <50% or an increase of <25% in the sum of the products of two perpendicular diameters of all measured lesions lasting >4 weeks during which no new lesions appeared. (iv) Progressive disease (PD), an increase of >25% in the product of two perpendicular diameters of any measured lesion over the dimensions at study entry, or the appearance of new areas of malignant disease. Treatment of patients who showed response or stable disease was continued for six to nine cycles.
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Data analysis |
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The response rate (P1) of weekly docetaxel was considered as 40%, and the threshold response rate (P0) as 20%. The number of patients required for this phase II study under binomial distribution was calculated to be 35 (one-side alpha = 0.05 and beta = 0.20).
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Results |
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The therapeutic outcome of weekly docetaxel is shown in Table 2. Patients received a median of four cycles (range 19), with a median cumulative dose of 560 mg/m2 (range 1201080 mg/m2). The projected dose intensity was 30 mg/m2/week, and the median received dose intensity of 28 mg/m2/week (range 2230 mg/m2/week), with a median relative dose intensity of 0.95 (range 0.731.0). Eight patients required delay/skip of treatment at a median of first infusion of four cycles, including six for neutropenia, one for fatigue/asthenia and another for surgery for a bone fracture. Four patients required a 25% dose reduction, including three for recurrent neutropenia and one for leg edema.
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Discussion |
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While retaining the above efficacy, with our weekly regimen neutropenia, which is the dose-limiting toxicity of conventional every-three-weeks regimen, was mild. Based on our prior pharmacokinetic assessment of weekly docetaxel, we determined that the AUC for docetaxel was a predictor of the percent decrease in neutrophil counts. The median values of AUC for docetaxel 40 mg/m2 (present weekly dose) and for docetaxel 60 mg/m2 (conventional Japanese every-three-weeks dose) s, 2.313.57), respectively [17]. The median AUC for our weekly dose is about half that of the every-three-weeks regimen at 60 mg/m2. Consequently, only 19% of the patients showed grade 3/4 neutropenia, including one case of grade 4.
During the preparation of this manuscript, Burstein et al. [18] reported the results of their phase II study on weekly docetaxel in advanced breast cancer, using a dose of 40 mg/m2/week. The efficacy and neutropenia profile in these two studies was similar, but the incidence of fluid retention syndrome was rather different. It was reported that, among patients receiving a cumulative dose of docetaxel 600 mg/m2, the proportion that developed fluid retention was 40%, and approached 60% at 800 mg/m2. In comparison, it was significantly less frequent in our series. Fluid retention was not observed in any patient who received less than 800 mg/m2, and in 29% of patients who received more than 800 mg/m2, although the dose of dexamethazone pre-medication used by Burstein et al. [18] (24 mg orally) was larger than ours (8 mg intravenously). One possible explanation for this discrepancy is the different populations of these two studies. The incidence of fluid retention with every-three-weeks regimen in a Japanese population (21%) [7] was less than that of a Western population (64%) [19]. Yet this explanation does not seem convincing, because the standard dose for the every-three-weeks regimen is different (60 mg/m2 versus 100 mg/m2). In this regard, the incidence of edema reported by Löffler et al. [16] in their phase I study on weekly docetaxel (8%) is similar to ours (5%). Further studies are required to determine the severity of fluid retention syndrome with a weekly docetaxel regimen.
The unexpected side effects experienced in our study were hearing disorders, as well as tearing/conjunctivitis, which occurred in 1 of 6 and 1 of 8 patients, respectively. Mild tearing/conjunctivitis was observed in 2952% of patients in previous phase I/II studies of weekly docetaxel [18, 20]. Furthermore, nail changes, asthenia/fatigue and taste disturbance were relatively common. The incidence of non-hematological toxicity increased with successive administration of treatment cycles.
Based on the likely improved toxicity profile with retained efficacy, our results indicate that weekly docetaxel at a dose of 40 mg/m2 is a feasible and active regimen in treating metastatic breast cancer. Phase III study of weekly versus conventional every-three-weeks regimen should be conducted to compare the survival benefits, toxicity profile and/or the quality of life. Further studies of the weekly regimen in combination with other agents, such as anthracyclines, vinorelbin or herceptin, are also warranted. In particular, significant clinical activity of concurrent use of docetaxel with anthracyclines in every-three-weeks regimens for metastatic breast cancer has already been reported [21, 22]. However, the side effects, in-cluding myelosuppression and febrile neutropenia, are severe. The combination of weekly docetaxel with anthracycline is anticipated to have substantial activity with less serious side effects. A phase I study of weekly docetaxel in combination with epirubicin is currently in progress in our hospital.
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Footnotes |
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Correspondence to: Department of Surgery, Kansai Rosai Hospital, 3-1-69 Inabaso, Amagasaki, Hyogo 660-8511, Japan. Tel: +81-6-6416-1221; Fax: +81-6-6419-1870; E-mail: yuichi-takatsuka@kanrou.net
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