Phase II study of weekly docetaxel in patients with metastatic breast cancer

T. Aihara, Y. Kim,+ and Y. Takatsuka,§

Department of Surgery, Kansai Rosai Hospital, Hyogo, Japan

Received 17 May 2001; revised 16 August 2001; accepted 5 September 2001.


    Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
Background

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, 1–9), with a median dose intensity of 28 mg/m2/week (range 22–30) and a median relative dose intensity of 0.95 (range 0.73–1.0). 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 1–4 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


    Introduction
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 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
Metastatic breast cancer remains incurable and difficult to treat. Several cytotoxic agents play important roles in the treatment of such a disease. Anthracycline-containing regimens have been applied as first-line therapy, but such treatment becomes quite difficult once resistance to anthracycline develops. Docetaxel (Taxotere®; Aventis Pharma, Tokyo, Japan), a taxane-class cytotoxic agent derived from Taxus baccata, has been reported to have significant activity in patients with metastatic breast cancer when used as either a first-line or second-line therapy [15]. Moreover, docetaxel has been observed to have clinical activity even in anthracycline-resistant cases [5, 6]; thus, docetaxel has become a key drug in the treatment of metastatic breast cancer. The conventional docetaxel treatment schedule for breast cancer consists of 1 h intravenous infusion of 60–100 mg/m2 dose every 3 weeks. Metastatic breast cancer tumor response has been observed over a range of doses, reported as 44% for 60 mg/m2 dose [7], 33–52% for 75 mg/m2 dose [1, 3, 8] and 23–68% for 100 mg/m2 dose [2, 4, 911]. Under these doses, the dose-limiting toxicity of docetaxel is myelosuppression, which generally accounts for >90% of the incidence of grade 3/4 neutropenia, in a dose-dependent manner [12]. The other severe adverse effect reported to date is fluid retention syndrome, which correlates with the administered cumulative dose of docetaxel [13].

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 concentration–time 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.


    Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
Inclusion criteria
Inclusion criteria included the following: (i) histopathologically proven primary breast cancer, with one or more bi-dimensionally measurable metastatic sites by physical examination and/or radiographic evaluation. (ii) An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. (iii) Absolute neutrophil count >=2000/µl, platelet count >=100 000/µl, bilirubin concentration <= upper limit of normal, aspartate aminotransferase and alanine aminotransferase <2 x the upper limit of normal and creatinine concentration < upper limit of normal. Patients were included even if they had received prior systemic adjuvant therapy and/or therapy for metastatic breast cancer (chemotherapy and/or hormonal therapy) other than either paclitaxel or docetaxel. Informed consent was obtained from all patients.

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 Institute–Common 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.


    Data analysis
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 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
For the analysis of overall response rate, the 95% Pearson–Clopper confidence interval (CI) was calculated. For the analysis of time to progression (TTP) and overall survival (OS), standard Kaplan–Meier estimates were used. TTP was calculated based on the time between the first day of treatment and the date of disease progression. OS was calculated based on the time between the first day of treatment and the time of death by any cause.

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).


    Results
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 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
Patient characteristics and therapeutic outcome
A total of 37 patients were entered into this study. At the time of analysis, all patients but one were off-protocol. Patients characteristics are listed in Table 1. The median age was 53 years. ECOG performance status for all patients except one was 0 or 1. Most patients (92%) had received prior chemotherapy, and 46% of the patients had received anthracycline-containing regimens. About half of the patients had more than two metastatic sites.


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Table 1. Patient characteristics
 
We experienced five cases of early treatment failure, defined as treatment cessation before three cycles without evidence of disease progression. The reasons for these treatment failures were as follows: hypersensitivity reaction (n = 1), surgery for pathological bone fracture (n = 1), acute gastric mucosal lesions (n = 1), pancytopenia (n = 1) and dyspnea (n = 1). These five events occurred within the first cycle, and these patients were subsequently excluded from the study. They were excluded from the assessment of clinical response, TTP and OS, but were included in intention-to-treat analysis. The dose intensity for these patients was not calculated.

The therapeutic outcome of weekly docetaxel is shown in Table 2. Patients received a median of four cycles (range 1–9), with a median cumulative dose of 560 mg/m2 (range 120–1080 mg/m2). The projected dose intensity was 30 mg/m2/week, and the median received dose intensity of 28 mg/m2/week (range 22–30 mg/m2/week), with a median relative dose intensity of 0.95 (range 0.73–1.0). 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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Table 2. Therapeutic outcome of weekly docetaxel
 
Efficacy
The clinical response is summarized in Table 3. No patients showed CR, whereas 14 showed PR, which accounted for 38% of the objective response rate (95% CI 22% to 53%). Among the nine patients who had stable disease, three patients (8%, 95% CI 0% to 17%) continued to be stable over 6 months. Taking these patients into account, 46% (17 of 37) showed clinical benefit. The response rate was similar between patients who received adjuvant therapy only (5 of 14, 36%) and those who received at least one regimen for metastatic disease (9 of 23, 39%). Patients who received prior anthracycline-containing regimens had a rather better clinical response than those who did not (47% versus 30%). Clinical response was seen at all metastatic sites, including the lung and liver. Relatively good responses were observed in the chest wall and lymph nodes, including two CR (22%) at the chest wall. At the time of analysis, 36 patients (97%) were off-protocol and 22 patients (60%) had died. TTP and OS can thus be considered as a mature data set for assessment. The median TTP was 5 months and the median OS was 12 months. Progression and survival curves are shown in Figure 1.


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Table 3. Efficacy of weekly docetaxel
 


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Figure 1. Kaplan–Meier plot of time to progression and overall survival.

 
Toxicity
The investigated toxicities that could be evaluated in all patients are listed in Table 4. Fifty-one percent (19/37) of patients experienced neutropenia and only 19% had grade 3/4 neutropenia, including one grade 4 case. No febrile neutropenia was observed. Mild anemia was noted but no thrombocytopenia. Although the degree of neutropenia was not severe in many cases, it was the most common cause for delay/skip of the treatment (6 of 8), and for dose reduction (3 of 4). All neutropenia-related treatment skips occurred at the third infusion of a cycle, suggesting a possible role of cumulative dose in neutropenia within the treatment cycle. Liver dysfunction was observed in one-third of patients, but was generally mild.


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Table 4. Subset analysis for clinical response
 
None of the patients showed grade 3 or higher non-hematological toxicity. Alopecia was the most common adverse event, which occurred in about two-thirds of patients. Fluid retention syndrome was uncommon, such that only two patients developed grade 2 toxicity: one at four cycles, requiring dose reduction, and one after nine cycles, after completion of treatment. These patients received more than 800 mg/m2 in cumulative dosage. Fatigue/asthenia was observed in 35% (13 of 37) of patients but was generally mild. Gastrointestinal side effects and skin/nail changes were relatively common but mild. Unexpectedly, 16% (6 of 37) of patients complained of a hearing disorder, which occurred at a median of five cycles (range 2–7).


    Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
In the present study, 37 patients with metastatic breast cancer were treated with weekly administration of docetaxel at a dose of 40 mg/m2. Clinical response was observed in 38% of patients by intention-to-treat analysis. A response rate of 38% in a heavily pretreated population was comparable with that of conventional every-three-weeks regimen, which was reported to range from 23% to 68%. The median received dose intensity of our weekly regimen was 28 mg/m2/week, which was greater than the projected dose intensity of every-three-weeks regimen at 60 or 75 mg/m2 (20 or 25 mg/m2/week). Moreover, it was even comparable with the actuarial received dose intens-ity of every-three-weeks regimens at 100 mg/m2 [1, 2, 4]. Similar clinical activity was observed when our weekly regimen was employed as first-line or second-line therapy (response rate, 36% versus 39%). Prior anthracycline exposure did not affect the clinical activity. In addition, a tumor response was seen in all involved sites. Of equal or greater interest than response rates is the time to progression. The median TTP for every-three-weeks regimen has been reported to range from 3 to 9 months [1, 2, 6, 7]. The median TTP of 5 months in our study was within the range of that for every-three-weeks regimen. It can be concluded that the efficacy of weekly docetaxel at 40 mg/m2 is comparable with that of the conventional every-three-weeks regimen.

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, 2.31–3.57), 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 29–52% 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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Table 5. Toxicity profile of weekly docetaxel
 

    Footnotes
 
+ Present address: Department of Surgery II, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Back

§ 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 Back


    References
 Top
 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
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