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
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Abstract |
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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 handfoot 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
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Introduction |
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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.
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Patients and methods |
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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, 1880 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 14 according to National Cancer Institute of Canada Common Toxicity Criteria. Handfoot syndrome was graded 13 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.
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Results |
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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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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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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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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 handfoot 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 handfoot 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 handfoot syndrome (eight patients) and diarrhea (four patients). Most discontinuations were necessary within 12 weeks after initiation of treatment (median two cycles; range 120). The reasons for later discontinuations were handfoot 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%.
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Discussion |
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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 handfoot 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.
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Acknowledgements |
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Footnotes |
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References |
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2. Parker SL, Tong T, Bolden S et al. Cancer statistics 1996. CA Cancer J Clin 1996; 65: 527.
3. Black RJ, Bray F, Ferlay J et al. Cancer incidence and mortality in the European Union: cancer registry data and estimates of national incidence for 1998. Eur J Cancer 1997; 33: 10751107.[CrossRef][ISI][Medline]
4. Perez EA. Current management of metastatic breast cancer. Semin Oncol 1990; 26 (Suppl 12): 110.
5. Miwa M, Ura M, Nishida M et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998; 34: 12741281.[CrossRef][ISI][Medline]
6. Blum JL, Jones SE, Buzdar AU et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17: 485493.
7. Blum JL, Dièras V, Lo Russo PM et al. Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast cancer patients. Cancer 2001; 92: 17591768.[CrossRef][ISI][Medline]
8. WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland: World Health Organization 1976.
9. Fumoleau P, Largillier R, Trillet-Lenoir V et al. Capecitabine (Xeloda®) in patients with advanced breast cancer (ABC), previously treated with anthracyclines and taxanes: results of a large phase II study. Proc Am Soc Clin Oncol 2002; 21: 62a (Abstr 247).
10. Miller KD, Rugo H, Cobleigh M et al. Phase III trial of capecitabine plus bevacizumab versus capecitabine alone in women with previously treated metastatic breast cancer. Breast Cancer Res Treat 2002; 76: S37.
11. Talbot D, Moiseyenko V, Van Belle S et al. Randomised, phase II trial comparing oral capecitabine (Xeloda®) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. Br J Cancer 2002; 86: 13671372.[CrossRef][ISI][Medline]
12. OShaughnessy JA, Blum J, Moiseyenko V et al. Randomized, open-label, phase II trial of oral capecitabine (Xeloda®) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 2001; 12: 12471254.[Abstract]
13. Cassidy J, Twelves C, Van Cutsem E et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favourable profile compared with intravenous 5-FU/leucovorin. Ann Oncol 2002; 13: 566575.
14. Fazeny B, Zifko U, Meryn S et al. Vinorelbine-induced neurotoxicity in patients with advanced breast cancer pretreated with paclitaxela phase II study. Cancer Chemother Pharmacol 1996; 39: 150156.[CrossRef][ISI][Medline]
15. Livingston RB, Ellis GK, Gralow JR et al. Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1997; 15: 13951400.[Abstract]
16. Zelek L, Barthier S, Delord JP et al. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer 2001; 92: 22672272.[CrossRef][ISI][Medline]
17. Smorenburg C, Bontenbal M, Seynaeve C et al. Phase II study of weekly gemcitabine in patients with metastatic breast cancer relapsing or failing on both an anthracycline and a taxane. Breast Cancer Res Treat 2001; 66: 8387.[CrossRef][ISI][Medline]
18. Girre V, Dalenc F, Laurence V et al. Vinorelbine5-fluorouracil combination as second line chemotherapy in metastatic breast cancer (MBC) after anthracyclinetaxanes combination (AT). Ann Oncol 2000; 11 (Suppl 4): 24.
19. Payne SA. A study of the quality of life in cancer patients receiving palliative chemotherapy. Soc Sci Med 1992; 35: 15051509.[CrossRef][ISI][Medline]
20. OShaughnessy J, Miles D, Vukelja S et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20: 28122823.