Japanese Journal of Clinical Oncology 33:371-376 (2003)
© 2003 Foundation for Promotion of Cancer Research
Multicenter Phase II Trial of Weekly Paclitaxel for Advanced or Metastatic Breast Cancer: the Saitama Breast Cancer Clinical Study Group (SBCCSG-01)
1 Department of Surgery I, National Defense Medical College, Tokorozawa, Saitama, 2 Division of Breast Oncology, Saitama Cancer Center, Kitaadachi-gun, Saitama, 3 Saitama Red Cross Hospital, Saitama, 4 Jichi Medical School, Omiya Medical Center, Saitama, 5 Kawaguchi Medical Center, Kawaguchi, Saitama, 6 Saitama Medical School, Iruma-gun, Saitama and 7 Saitama Social Insurance Hospital, Saitama, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: Weekly dosing of paclitaxel has been demonstrated to be a well-tolerated, feasible and effective administration schedule. In this study, we evaluated the efficacy and safety of weekly paclitaxel in Japanese women with advanced or metastatic breast cancer.
Methods: Seventy-four patients were enrolled in the study. Paclitaxel was administered by 1 h intravenous infusion at a dose of 80 mg/m2 every week. Administration was continued for 3 weeks followed by a 1 week rest. A short premedication, consisting of dexamethasone 10 mg, ranitidine 50 mg and diphenylhydramine 50 mg, was given prior to each dose of paclitaxel. Eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0, 1 or 2 and adequate hematological, hepatic and renal function.
Results: Of 74 patients treated and evaluable for toxicities, 70 were evaluable for response. The mean age was 57.7 years. Forty-nine patients (66.2%) had received prior anthracyclines for metastatic diseases. The overall response rate among 74 patients was 40.5%, including 4.1% complete responses and 36.5% partial responses. The median follow-up time was 481 days (range, 24–903 days). The median time to progression was 4.8 months and median overall survival was 15.8 months. The majority of patients tolerated the treatment very well. Although alopecia was observed in most of the patients (93.2%), grade 3 or 4 neutropenia was 10.8% and grade 2 or 3 peripheral neuropathy was 13.5%.
Conclusion: Weekly paclitaxel as a 1 h infusion was active and generally well tolerated in previously treated patients. Further study of weekly paclitaxel in combination therapy is warranted.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It was estimated that 192 200 women in the USA would be newly diagnosed with breast cancer and 40 200 women would die of the disease in 2001 (1). Japanese incidence and mortality rates of breast cancer have been increasing. According to the annual reports of the Japanese Ministry of Health, Labor and Welfare (2), the age-adjusted incidence rate of breast cancer was 38.9 per 100 000 women and the estimated number of women with breast cancer was 29 448 in 1996. The number of breast cancer deaths in women was 9171, which was 7.9% of women diagnosed with all types of malignant tumors in 2000.
The long-term prognosis for women with early-stage disease is generally good owing to current treatment modalities. However, advanced and metastatic breast cancer remains incurable and difficult to treat and few patients will be long-term survivors (3). Anthracycline-containing regimens have been applied as first-line therapy, but such treatment becomes difficult once resistance to anthracycline develops.
Paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) is an effective agent in the treatment of metastatic breast cancer. Overall response rates of 21–62% have been reported in phase II and III trials evaluating paclitaxel at doses of 135–250 mg/m2 administered by either 3 or 24 hour infusion as initial or subsequent therapy to women with metastatic breast cancer (4–15). According to the results from CALGB 9342, the optimal dose and schedule of single-agent paclitaxel for metastatic breast cancer are 175 or 210 mg/m2 in three administered doses (175, 210 and 250 mg/m2) on 3 h infusion schedules (2,6). In Japan, the standard schedule consists of 3 h of intravenous infusion at a dose of 210 mg/m2 every 3 weeks, which has been reported to induce grade 3 neutropenia in 93% of patients (5). This toxicity is generally the most common and other paclitaxel treatment schedules have generated much interest, with very modest toxicities.
Recent reports of weekly administration of paclitaxicel have attracted great clinical interest. 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 paclitaxicel has been reported to have a mild myelotoxicity profile compared with standard every-3-weeks administration schedules, without lessening the efficacy (16). This administration schedule could potentially lessen the severity of neutropenia, which is the dose-limiting toxicity of this drug.
Authors of studies in which paclitaxel was administered weekly by 1 h infusion at doses ranging from 80 to 100 mg/m2 have reported overall response rates of 50–68% (16–22). Based on these recommended doses for phase II studies, we conducted a phase II clinical trial of weekly paclitaxel administration in patients with metastatic breast cancer, at a dose of 80 mg/m2/week. Here we report the results of this phase II trial.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility Criteria
The Saitama Breast Cancer Clinical Study Group (SBCCSG-01) was open for patient accrual from March 2000 to June 2001. Eligibility criteria included histologically confirmed advanced or metastatic breast cancer. Patients were required to have at least one two-dimensionally measurable indicator lesion that had not been irradiated. Patients were required to be
18 and 
75 years of age, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, have adequate bone marrow, renal and liver function (absolute granulocyte count 2000/µl, platelets 100 000/µl, serum creatinine and total bilirubin 1.5 times the upper normal limit and AST or ALT 2 times the upper normal limit) and have no history of peripheral neuropathy grade 2 evaluated using National Cancer Institute Common Toxicity Criteria (NCI-CTC) Version 2.0 (23). Before treatment began, all patients provided informed consent according to institution review board guidelines.
Treatment Plan
Patients were pretreated with diphenhydramine 50 mg intravenously (i.v.), ranitidine 50 mg i.v. and dexamethasone 20 mg i.v. 30 min before paclitaxel infusion. If no hypersensitivity reactions occurred after the first paclitaxel dose, the dexamethasone dose was reduced to 10 mg. Paclitaxel 80 mg/m2 was administered over 1 h weekly. Each 4 week cycle consisted of three consecutive weekly courses of treatment followed by a 1 week rest. Paclitaxel administration was repeated until there was evidence of progressive disease or unacceptable toxicity, which was defined as follows: serious hematological toxicity (absolute granulocyte count <1000/µl and platelets 50 000/µl) and non-hematological toxicity of grade 3 or more. Complete blood count and blood chemistry tests were evaluated prior to each treatment. Patients were assessed weekly for toxicity according to the NCI-CTC Version 2.0. The dose of paclitaxel was reduced by 10 and 20 mg/m2 when grade 1 and 2 side effects, respectively, except for nausea, vomiting and alopecia, were noted. In the event of serious toxicity, treatment was withheld until recovery.
Study Evaluation
Pretreatment evaluations consisted of a complete medical history and physical examination, which included a complete blood cell count, urinalysis, ECG, chest X-ray, bone scan and computed tomographic scans of the chest and abdomen. At the end of every cycle, patients underwent physical examination, tumor measurements and toxicity evaluations. Patients had a complete blood cell count weekly and tumor markers were examined every cycle. Imaging studies were done to assess objective response every two treatment cycles. Toxic effects were graded according to the NCI-CTC Version 2.0.
Response Criteria
Responses were graded by standard criteria (complete response, partial response, no change and progressive disease) and all responses had to be confirmed by a second measurement after an additional 4 weeks (24). Complete response (CR) was defined as the disappearance of all known disease confirmed by tests at least 4 weeks apart, partial response (PR) was defined as 50% decrease in the lesion and no appearance of new lesions or progression of any lesion confirmed by tests not less than 4 weeks apart and no change (NC) was defined as a <50% decrease in total tumor size or a <25% increase. Progressive disease (PD) was defined as a 25% increase in the size of one or more measurable lesions or the appearance of new lesions.
Statistical Analysis
The primary study end-point was response rate. The secondary end-points included time to progression (TTP), overall survival (OS) and toxicity. The disease progression was assessed every 3 months and the survival was confirmed at every visit. For the analysis of TTP and OS, we analyzed data using the Kaplan–Meier method (25). We calculated TTP from the day of study entry until the day of documented disease progression or death and OS was calculated from the date of study enrollment until death.
The response rate (P1) of weekly paclitaxel was considered to be 35% and the threshold response rate (P0) was 20%. The number of patients required for this phase II study under a binomial distribution was calculated to be 65 (one-sided 
= 0.05 and ß = 0.20) and we used a sample size of 70 in case five patients dropped out.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Characteristics
Between March 2000 and June 2001, 74 patients were enrolled in the study at eight participating institutions. Patients’ characteristics are listed in Table 1. The mean age was 57.7 years (range, 34–75 years). Most patients (96.9%) had an ECOG performance status of 0 or 1. More than half of the patients (54.1%) had two or more metastatic lesions and the majority of patients (89.2%) had received prior chemotherapy, as either adjuvant treatment or therapy for metastatic disease or both. Anthracyclines were administered for metastatic disease in 49 patients (66.2%), among whom 11 patients (14.9%) had received an anthracycline-containing regimen in the adjuvant setting. Four patients (5.4%) were dropped from the protocol because of early treatment failure, defined as treatment cessation before the completion of one cycle. The reasons for treatment failure were grade 3 leukopenia and vomiting in three patients and cancellation of the informed consent in one patient. However, they were included in intention-to-treat analysis as non-evaluable cases (NE). Overall, the median cumulative paclitaxel exposure of 74 patients was 1040 mg/m2 (range, 160–6160 mg/m2). The median number of cycles delivered was 4 (range, 1–26) (Fig. 1) and the mean weekly delivered dose was 56.7 mg/m2 (range, 27.7–65.5 mg/m2). The therapy was delayed or the dose was reduced in 30% of patients, for 11% of them because of toxicity and for 19% of them because of social or other reasons.
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Response
In the 70 assessable patients, there were three complete responses and 27 partial responses, and the overall response rate was 40.5% (95% CI, 29.4–51.7%) in intention-to-treat analysis (Table 2). No change was achieved in 24 patients (34.3%).
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Although the power to detect significant differences in subset analyses was limited owing to the small sample size, the overall responses to paclitaxel therapy were different between patients with and without prior anthracycline exposure. Among patients with various degrees of anthracycline-resistant disease, the overall response was observed in 22.2–37.5% (Table 3). The responses by the metastatic sites are listed in Table 4.
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The median follow-up time was 481 days and ranged from 24 to 903 days. The median time to progression for assessable patients was 4.8 months (range, 0.8–25.8 months) (Fig. 2). The median overall survival was 15.8 months (range, 1.5–30.1 months) (Fig. 3).
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Toxicities
Toxicity data were available for 74 patients who had received at least one dose of paclitaxel. Overall, therapy was generally well tolerated and manageable on an outpatient basis. Patients’ hematological toxicities are listed in Table 5. Grade 3 or 4 neutropenia occurred in eight patients (10.8%). Febrile neutropenia, defined as fever >38.0°C, related possibly or probably to the drug and concomitant with neutropenia (<500 cells/µl) that required intravenously administered antibiotics and/or hospitalization, was observed in only one patient (1.4%). Non-hematological NCI-gradable toxicities possibly or probably related to paclitaxel therapy are listed in Table 6. The most common toxicity was alopecia (93.2%). Neurosensory toxicity was observed in 37 patients (50%), but only one patient (1.4%) experienced grade 3 neurosensory events. No NCI grade 4 non-hematological toxicity was reported.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Metastatic breast cancer is still considered a difficult disease to treat, even though several classes of antineoplastic agents have shown various levels of activity in these patients. Taxanes are the most effective drugs in breast cancer, together with the anthracyclines, but they have several important side effects when given in standard administration schedules. Weekly administration of paclitaxel at 80–100 mg/m2/week is feasible and it has an efficacy level at least comparable to that of the standard 21 day administration of around a 210 mg/m2 dose.
The response rate to a 3 h paclitaxel infusion of 200 mg/m2 every 3 weeks did not differ from the response rate to a weekly 1 h infusion of 67 mg/m2, which is the same dose intensity, in a randomized clinical trial for patients with ovarian cancer treated with prior platinum therapy (26). Seidman et al. reported a 53% response rate in metastatic breast cancer patients to a weekly paclitaxel dose of 91 mg/m2/week with an initial dose of 100 mg/m2 (16). Waintraub et al. also reported a 54% response to weekly paclitaxel at a dose of 90 mg/m2 in patients with prior chemotherapy of anthracycline ± taxane (17). There have been several reports showing a 21–61% response rate to weekly paclitaxel (80–100 mg/m2) in studies of metastatic breast cancer patients with prior chemotherapy (16,21,22,27).
The rationale for weekly administration of paclitaxel, which acts on microtubules to arrest mitosis, is that more frequent delivery of moderate doses may achieve greater efficacy than standard doses every 3 weeks through more sustained exposure of dividing tumor cells to its cytotoxic effects. This dose-dense approach to treatment may inhibit tumor regrowth between cycles and limit the emergence of malignant cell populations resistant to chemotherapy (28). More frequent exposure to paclitaxel may also enhance its apoptotic and antiangiogenic effects. Moreover, weekly therapy also has advantages in terms of improving paclitaxel’s therapeutic index, because of the moderate toxicities. Administration was continued for 3 weeks followed by 1 week of rest, which could reduce the dose intensity of paclitaxel. However, because disease stabilization can be a meaningful outcome of therapy for patients with metastatic breast cancer, this 1 week rest seemed to be important to retain these patients’ quality of life (QOL).
In terms of therapy-related toxicities by weekly paclitaxel administration, Seidman et al. reported grade 3 or more neutropenia in 13% and grade 3 peripheral neuropathy in 24% of patients (16) and Waintraub et al. reported that 31% of patients could not continue therapy owing to peripheral neuropathy but that no patients showed severe hematological adverse events (17). According to our results, toxicities associated with weekly 1 h paclitaxel infusion were tolerable and most were less than grade 2. One patient had grade 3 febrile neutropenia and two patients had grade 4 neutropenia. This trial confirms the tolerability of weekly paclitaxel therapy in Japanese women with advanced or metastatic breast cancer.
Standard premedication is commonly administered prior to treatment with paclitaxel. However, this regimen requires dexamethasone administration beginning 12–14 h prior to paclitaxel administration, which would not be convenient for outpatients. Short premedication including dexamethasone 20 mg, diphenhydramine 50 mg and ranitidine 50 mg has been shown to be safe in terms of hypersensitivity reaction (16,21,22,27,29). There was only one patient with grade 2 allergic reaction in the present study.
Weekly paclitaxel as a 1 h infusion was generally well tolerated in previously treated patients and produced overall response rates of 41%, and especially 22–33% in patients with various degrees of anthracycline-resistant disease. A phase III study of weekly versus a standard every-3-weeks regimen should be conducted to compare the survival benefits, toxicity profile and the QOL of patients receiving weekly paclitaxel, and further study of weekly paclitaxel in combination therapy is also warranted, with medications such as doxorubicin, carboplatin, vinorelbine and trastuzumab.
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FOOTNOTES |
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+ For reprints and all correspondence: Kazuhiko Sato, Department of Surgery I, National Defense Medical College, 3–2 Namiki, Tokorozawa, Saitama 359-8513, Japan. E-mail: sato-k-a{at}mtg.biglobe.ne.jp
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Received May 12, 2003; accepted July 3, 2003
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