Multicenter phase II study of oral capecitabine (Xeloda") in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy

P. Reichardt1,+, G. von Minckwitz2, P. C. Thuss-Patience1, W. Jonat3, H. Kölbl4, F. Jänicke5, D. G. Kieback6,7, W. Kuhn8, A. E Schindler9, S. Mohrmann10, M. Kaufmann2 and H. J. Lück11

1 Robert-Rössle-Klinik, Universitätsklinikum Charité, Humboldt-Universität, Berlin; 2 Universitäts-Frauenklinik, Frankfurt; 3 Universitätsklinikum, Kiel; 4 Martin-Luther-Universität, Halle; 5 Universitätskrankenhaus, Hamburg; 6 Universität-Frauenklinik, Freiburg, Germany; 7 Department of Obstetrics and Gynecology, Maastricht University Medical Center, Maastricht, The Netherlands; 8 Technische Universität, Munich; 9 Universitätsklinikum, Essen; 10 Heinrich-Heine-Universität, Düsseldorf; 11 Medizinische Hochschule, Hanover, Germany

Received 10 February 2003; revised 26 March 2003; accepted 23 April 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Capecitabine is a rationally designed oral, tumor-activated fluoropyrimidine carbamate with high activity in metastatic breast cancer. This multicenter phase II study was designed to evaluate further the efficacy and safety of capecitabine in patients with metastatic breast cancer previously treated with a taxane-containing regimen.

Patients and methods:

All patients had to have documented progression after paclitaxel- or docetaxel-containing chemotherapy. Treatment comprised 3-week cycles of oral capecitabine 1250 mg/m2 twice-daily for 14 days followed by a 7-day rest period.

Results:

One hundred and thirty-six patients were enrolled. Disease stabilization occurred in 63 patients (46%) and the overall response rate was 15% (95% confidence interval 10% to 23%), providing an overall tumor control rate of 62%. Median time to progression was 3.5 months, median duration of response was 7.5 months and median overall survival was 10.1 months. Capecitabine was generally well-tolerated: most treatment-related adverse events were grade 1/2 in intensity; grade 3/4 treatment-related adverse events were hand–foot syndrome (13%), diarrhea (8%), vomiting (4%) and nausea (3%). There were no treatment-related deaths.

Conclusions:

This study confirms that capecitabine achieves a high tumor control rate in heavily pretreated patients with metastatic breast cancer. Due to its favorable safety profile and convenient oral administration, capecitabine can be given as an outpatient therapy. Capecitabine should be considered the reference treatment in this setting based on consistently high efficacy and good tolerability.

Key words: capecitabine, chemotherapy, clinical trial, metastatic breast cancer, phase II, taxane failure


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Breast cancer is one of the most common malignancies affecting women, with 8–11% of all women developing breast cancer at some time during their life [13]. Nearly half of these women will develop metastatic disease, and the average survival time from diagnosis of recurrence for these patients ranges from ~18 to 30 months [4]. The treatment of choice in patients with hormone-resistant, hormone receptor-negative or rapidly disseminating disease is systemic cytotoxic chemotherapy. In recent years, the use of anthracyclines and taxanes has shifted towards application earlier in the course of the disease. Consequently more patients presenting with metastatic disease have been pretreated with anthracyclines and/or taxanes. The subsequent therapy of these patients presents the oncologist with a particular challenge and new therapeutic strategies are required for this growing patient population. The ideal chemotherapeutic agent in this setting would reduce tumor burden and associated symptoms, improve survival and maintain quality of life with minimal toxicity.

Capecitabine (Xeloda"; Hoffmann-La Roche Inc., Nutley, NJ) is a rationally designed oral fluoropyrimidine with high activity in metastatic breast cancer. After administration of capecitabine, 5-fluorouracil (5-FU) is generated preferentially at the tumor site, achieved through exploitation of the significantly higher activity of thymidine phosphorylase in tumor cells compared with normal tissue [5].

Two clinical trials conducted in North America and France have demonstrated that oral capecitabine is a highly effective and well-tolerated treatment for patients with heavily pretreated metastatic breast cancer [6, 7]. In the first of these trials, capecitabine produced an objective response rate of 20% in 162 patients with paclitaxel-pretreated metastatic breast cancer. Median time to disease progression (3 months) and overall survival (12.6 months) were favorable [6]. The second study confirmed the results of the first, with capecitabine achieving an overall response rate of 26%, median time to disease progression of 3.2 months and median overall survival of 12.2 months in 74 patients with paclitaxel- or docetaxel-pretreated metastatic breast cancer [7].

When the present study was initiated, it was already known from the trial by Blum et al. [6] that capecitabine is effective and well-tolerated in patients with paclitaxel-pretreated metastatic breast cancer. However, the first study of Blum et al. was restricted to patients pretreated with paclitaxel and no data were available for patients whose disease had progressed following either paclitaxel or docetaxel therapy. The present multicenter phase II study in patients with paclitaxel- or docetaxel-pretreated metastatic breast cancer was initiated to confirm the efficacy of capecitabine in this setting.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study design
This open-label, multicenter phase II study was designed to evaluate the efficacy and safety of capecitabine in the treatment of patients with metastatic breast cancer relapsing after taxane-containing chemotherapy (either paclitaxel or docetaxel). The primary objective was to determine the overall response rate achieved with an intermittent twice-daily regimen of oral capecitabine. Secondary objectives were to evaluate additional efficacy parameters and the safety profile of capecitabine.

The study was carried out in accordance with the Declaration of Helsinki and International Committee on Harmonization guidelines for good clinical practice. Before initiation, protocol approval was obtained from local ethics committees. Written informed consent was obtained from all patients before screening assessments or enrollment.

Patients received two cycles of oral capecitabine (1250 mg/m2) twice-daily after breakfast and dinner for 14 days, followed by a 7-day rest period. This 3-week treatment course was repeated at least once. In patients experiencing grade 2 or more severe toxicities, the standard capecitabine dose modification scheme, described in detail by Blum et al. [6], was applied. Patients responding [complete response (CR) or partial response (PR)] or with stable disease (SD) at the end of the first 6 weeks were eligible to receive further treatment for up to 18 weeks (six cycles). Patients responding or maintaining SD at the end of this study period could continue treatment for up to 48 weeks. Patients experiencing intolerable toxicity were withdrawn from the study at any time.

Patients and eligibility criteria
The study population comprised female patients, 18–80 years of age, with a histologically confirmed diagnosis of breast cancer and recurrence of disease during or following a taxane-containing chemotherapeutic regimen. A Karnofsky performance status of at least 60% and a life expectancy of at least 3 months were required. A minimum interval of 3 weeks between the last chemotherapy and study enrollment was mandatory. Patients with significant cardiac, liver, gastrointestinal or kidney disease were excluded, as were patients with prior severe and unexplained reaction to fluoropyrimidine therapy, known hypersensitivity to 5-FU, or previous exposure to continuous infusion 5-FU. Cut-off values for laboratory values were as follows: neutrophils >=1.5 x 109/l, platelets >=75 x 109/l, hemoglobin >=9 g/dl, serum bilirubin <2.0 x upper limit of normal, and aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase <2.5 x upper limit of normal. However, in patients with bone or liver metastases, concentrations of AST, ALT and alkaline phosphatase up to 5 x the upper limit of normal were permitted.

Study assessments
All patients underwent routine medical assessment within 2 weeks before treatment start and tumor evaluation using standard radiological methods. All laboratory tests were evaluated within 7 days before treatment start. Expression of HER2, a member of the transmembrane human epidermal growth factor receptor family, which has recently emerged as a prognostic and potentially predictive factor in breast cancer, was not evaluated during this study.

During the treatment period, laboratory tests (hematology and blood chemistry) were performed every 3 weeks. Safety was evaluated in all patients who received at least one dose of capecitabine. Adverse events were assessed at every clinic visit and graded 1–4 according to National Cancer Institute of Canada Common Toxicity Criteria. Hand–foot syndrome was graded 1–3 as defined in previous trials of capecitabine [6, 7].

Evaluation of response
Before the start of capecitabine therapy the indicator lesions were selected and the maximum diameters were recorded. An addition of the sizes of all lesions recorded was performed to estimate tumor burden. Tumor assessments were repeated every 6 weeks thereafter, and at the time of withdrawal from the study.

Tumor responses were evaluated based on World Health Organization criteria [8] and had to be confirmed a minimum of 4 weeks after the response was first observed. Time to response was defined as the interval from treatment start to the date of response for patients who achieved an objective response (CR or PR). For patients achieving a CR, duration of response was defined as the interval from the date CR was first recorded to the date on which progressive disease (PD) was first observed. For patients achieving a PR, duration of response was defined as the period between the first day of treatment and the date of first observation of PD. Time to progression was the interval from treatment start to the date of documented tumor progression, or date of death if the patient died before documentation of disease progression. Survival time was defined as the time from treatment start to the date of death, or to the last date the patient was known to be alive. Survival data were collected every 3 months after patients went off study.

Statistical analysis
The primary objective of this study was to show adequate activity of capecitabine treatment measured by objective response rates. Assuming a type 1 error of 5% and a power of 90%, a sample size of 131 was calculated. This sample size allows for meaningful subgroup analyses. Results are reported with 95% confidence intervals (CIs).

Efficacy analyses were performed on the intention-to-treat (ITT) population. Patients without at least one tumor assessment after start of treatment were considered treatment failures. Safety was evaluated in all patients with documented treatment and at least one further documented visit.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Between March 1999 and December 2000, 136 patients with metastatic breast cancer were enrolled at 10 participating clinical institutions in Germany. All patients were evaluable for clinical response and included in the ITT population.

The demographic and baseline characteristics of all patients are given in Tables 1 and 2. All but two patients received taxanes: approximately half had received prior paclitaxel and half had received prior docetaxel (Table 2). The vast majority of patients had been previously treated with an anthracycline, and half of the patients had received a 5-FU-containing regimen.


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Table 1. Baseline patient and disease characteristics (n = 136)
 

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Table 2. Treatment history (n = 136)
 
A total of 135 patients received at least one dose of capecitabine. One patient stopped treatment during the first cycle, and was excluded from the safety analysis as no safety information was available. In the ITT analysis for efficacy, this patient was considered a treatment failure. A total of 700 treatment cycles were administered, with patients receiving a median of four (range 1–33) cycles. One patient is still receiving treatment (830 mg/m2 twice-daily since cycle 18), and by November 2002 had received 33 cycles of capecitabine.

Capecitabine treatment was initiated at a planned dose of 1250 mg/m2 twice-daily. The starting dose administered ranged from 1010 to 1330 mg twice-daily. Overall, the capecitabine dose was reduced in 39% of patients and in 43% of cycles. Seven percent of patients required further dose reduction. After dose reduction, treatment was well-tolerated, as indicated by the number of cycles administered under these conditions (Table 3).


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Table 3. Summary of dose reductions
 
Efficacy
Overall investigator-assessed response rate in all 136 patients was 15% (95% CI 10% to 23%], consisting of two CRs (1%) and 19 PRs (14%) (Table 4). Sixty-three patients (46%) achieved disease stabilization, giving an overall tumor control rate of 62% (95% CI 53% to 70%). Disease progression occurred in 52 patients (38%) within the first 12 weeks of capecitabine treatment. Interestingly, 18 of 21 responders (86%) had required a dose reduction, most probably due to the fact that patients with a response received treatment over a longer duration and therefore had a higher likelihood of dose reduction. A subgroup of patients with liver metastases (n = 72) demonstrated a higher response rate of 21% (95% CI 12% to 32%) compared with 9% in patients without liver metastases (n = 64; 95% CI 4% to 19%), although the difference did not reach statistical significance (P = 0.095).


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Table 4. Summary of efficacy results with 95% confidence intervals: intention-to-treat (n = 136)
 
Subgroup analysis according to prior taxane therapy was carried out. In the ITT population, a total of 155 taxane-containing therapies were administered to 134 patients. The majority of patients (115; 85%) had received one taxane-containing regimen before enrollment in this trial; 17 patients (13%) and two patients (1%) had received two or three taxane-containing therapies, respectively. The median interval between the last taxane-containing therapy and start of capecitabine treatment was 4.4 months (95% CI 3.3–6.7).

Among the 118 patients receiving their last taxane for metastatic disease, a 32% response rate to taxane therapy was observed: two CRs, 36 PRs, 56 SDs and 22 PDs, with response not known in two patients (Table 5). Following administration of capecitabine, responses were seen in 10 of 78 patients (13%) who had not responded to their last taxane (P = 0.18).


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Table 5. Response to capecitabine according to response to last taxane-containing therapy
 
Patients who had received previous 5-FU therapy (n = 71) showed response rates of 13% (95% CI 6% to 23%), whereas those without 5-FU pretreatment (n = 65) exhibited a response rate of 18% (95% CI 10% to 30%). No significant differences in response rates were found in other subgroups according to previous chemotherapy or radiotherapy (Table 6).


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Table 6. Response to capecitabine according to previous therapy
 
The median duration of response was 7.5 months (95% CI 6.0– 9.2) (Table 4). In most of these patients objective responses were first observed within 6–12 weeks of treatment initiation, but later responses were also seen (median 45 days; range 38–310). At a median follow-up of 10.0 months (range 0.4–31.0), a total of 104 cases of PD or death were documented. Median time to progression was 3.5 months (95% CI 2.8–4.1) (Table 4; Figure 1).



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Figure 1. Time to progression (n = 136).

 
Median overall survival was 10.1 months (95% CI 8.2–11.5) (Table 4) with a significant advantage for responding patients. For patients achieving a CR or PR, median survival was 21.6 months (95% CI 13.8–27.9), for SD 10.6 months (95% CI 8.5–14.3) and for patients with PD as best response 5.5 months (95% CI 2.7–7.5).

Safety
Most treatment-related adverse events were mild (grade 1) or moderate (grade 2) in intensity and were manageable by treatment interruption and, if necessary, dose reduction. The most frequently reported (>=10% of patients) grade 1/2 treatment-related adverse events were hand–foot syndrome (42%), nausea (31%), diarrhea (20%), fatigue (17%), stomatitis (15%), anorexia (13%) and vomiting (12%).

The incidence of grade 3/4 treatment-related adverse events was low: the most frequently reported events were hand–foot syndrome in 13%, diarrhea in 8%, vomiting in 4% and nausea in 3%. No grade 3/4 alopecia was observed. Only six grade 4 adverse events were observed, consisting of one case of stomatitis, one case of diarrhea and four cases of myelosuppression in heavily pretreated patients. No other treatment-related grade 4 adverse events were reported.

Treatment discontinuation due to toxicity occurred in 17% of the patients, and was most frequently secondary to hand–foot syndrome (eight patients) and diarrhea (four patients). Most discontinuations were necessary within 12 weeks after initiation of treatment (median two cycles; range 1–20). The reasons for later discontinuations were hand–foot syndrome (n = 3), diarrhea, general weakness and nausea/vomiting (all n = 1). Six patients required hospitalization for diarrhea (grade 4 in one patient, grade 3 in five), of whom two continued treatment. After continuation of therapy at a reduced dosage, no further grade 3/4 adverse events were observed in these patients. There were no treatment-related deaths during the study.

Changes in blood cell count or laboratory values were recorded as adverse events. The most frequently reported grade 3/4 laboratory adverse events were thrombocytopenia in 2% of patients and leukopenia in 1%.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The results from this open-label phase II study confirm previous findings that oral capecitabine is an effective treatment in patients with heavily pretreated metastatic breast cancer. Disease stabilization was observed in 46% of patients and the overall response rate was 15% (comprising two CRs and 19 PRs), giving an overall tumor control rate of 62%. Median time to progression was 3.5 months, median duration of response was 7.5 months and median overall survival was 10.1 months. These results are similar to those seen in four similar studies assessing capecitabine in this setting. Overall disease control rates of 57–63%, overall response rates of 19–28%, median time to progression of >3 months and overall survival in excess of 12 months have been reported [6, 7, 9, 10].

Capecitabine treatment was well-tolerated in this study and the safety profile was consistent with that seen in previous studies of capecitabine monotherapy in breast cancer [6, 7, 9, 11, 12] or colorectal cancer [13]. The majority of treatment-related adverse events were mild or moderate in intensity and the most frequent adverse event was hand–foot syndrome. This cutaneous condition is characteristic of chronic cytostatic administration, e.g. protracted 5-FU, 96-h vinorelbine or liposomal doxorubicin. In patients treated with capecitabine, this side-effect is reversible and can be managed by treatment interruption and, if necessary, dose reduction. Patients receiving capecitabine must be educated about the need to interrupt treatment if they experience moderate or more severe adverse events, and to seek medical advice if such symptoms occur. The incidence of grade 3/4 treatment-related adverse events was low, and alopecia and myelosuppression were particularly rare.

In patients with anthracycline- and taxane-pretreated metastatic breast cancer, relief of tumor-related symptoms and the maintenance of quality of life are primary goals of treatment. It is important to consider individual patients’ preferences for treatment. Intravenously administered chemotherapeutic agents that have been evaluated in this population include vinorelbine, gemcitabine and combination chemotherapy regimens. Recently, standard doses of vinorelbine were evaluated in 10 patients with advanced breast cancer who had previously been treated with anthracyclines and paclitaxel. No objective responses were observed and neurotoxicity was frequent [14]. In two other studies evaluating vinorelbine [15, 16], an overall response rate of 25%, median overall survival of between 6 and 7.6 months and median time to disease progression of 3.0 months were noted. However, grade 3/4 neutropenia was frequent, occurring in 58% of patients in one study [15] and at grade 4 intensity in 23% of patients in the second study (grade 3 not reported) [16]. In a recent phase II study, gemcitabine failed to produce any objective responses in patients with anthracycline- and taxane-pretreated metastatic breast cancer and it was concluded that it was inactive in this setting [17]. Another approach is the use of polychemotherapy regimens. These regimens may be active but toxicities are usually additive [18].

The convenient oral administration of capecitabine, in combination with its high efficacy and manageable safety profile, make it an attractive agent for use in an outpatient setting. Oral capecitabine avoids the risk of complications associated with intravenous drug administration and allows patients to control their own therapy and achieve a degree of independence. Patients receiving home-based chemotherapy have been found to have a better quality of life than those receiving treatment in hospital [19]. Patients at home are more active, require less analgesia and experience fewer psychosocial or gastrointestinal side-effects.

A considerable body of evidence confirms that capecitabine is a highly active oral chemotherapy. Five studies (including the present trial) in a total of 730 patients with anthracycline- and taxane-pretreated metastatic breast cancer have been reported. Based on the consistently high efficacy and excellent safety profile observed in these trials, oral capecitabine should be considered as the reference treatment for patients with heavily pretreated metastatic breast cancer. Capecitabine monotherapy has gained worldwide approval for the treatment of patients with locally advanced or metastatic breast cancer pretreated with both taxane- (paclitaxel in the USA) and anthracycline-containing chemotherapy. In addition, results from two randomized, phase II studies are promising and indicate that capecitabine monotherapy may also play a role as first- or second-line therapy for breast cancer [11, 12]. Furthermore, a recently reported phase III trial in 511 anthracycline-pretreated patients with metastatic breast cancer has demonstrated that the addition of capecitabine to reduced-dose docetaxel (75 mg/m2) achieves significantly superior efficacy, including overall survival (3-month median survival benefit), compared with standard-dose (100 mg/m2) docetaxel monotherapy [20]. Capecitabine plus docetaxel is the first cytotoxic combination to demonstrate superiority over standard docetaxel therapy, and results of this trial led to regulatory approval in Europe and the USA for the treatment of patients with anthracycline-pretreated metastatic breast cancer. Further phase III trials of capecitabine alone and in combination in the adjuvant and neoadjuvant setting are planned or ongoing.


    Acknowledgements
 
The study was supported by Hoffmann-La Roche AG, Grenzach-Wyhlen, Germany.


    Footnotes
 
+ Correspondence to: Dr P. Reichardt, Robert-Rössle-Klinik, Helios-Klinikum Berlin, Universitätsklinikum Charité, Lindenberger Weg 80, D-13122 Berlin, Germany. Tel: +49-30-9417-1211; Fax: +49-30-9417-1219; E-mail: reichardt{at}rrk-berlin.de Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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