The Oncologist, Vol. 7, Suppl 6, 29–35,
December 2002
© 2002 AlphaMed Press
Moving Forward with Capecitabine: a Glimpse of the Future
Laura Biganzolia,
Miguel Martinb,
Chris Twelvesc
a EORTC Investigational Drug Branch for Breast Cancer, Chemotherapy Unit, Institut Jules Bordet, Brussels, Belgium;
b Hospital Universitario San Carlos, Servicio de Oncologia Médica, Madrid, Spain;
c Cancer Research UK, Department of Medical Oncology, University of Glasgow and Beatson Oncology Centre, Glasgow, United Kingdom
Correspondence: Laura Biganzoli, M.D., EORTC Investigational Drug Branch for Breast Cancer, Chemotherapy Unit, Institut Jules Bordet, Boulevard de Waterloo 125, 1000 Brussels, Belgium. Telephone: 32-2-541-3188; Fax: 32-2-541-3199; e-mail: laura.biganzoli{at}bordet.be
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:
- Appreciate the emerging role of capecitabine monotherapy in the treatment of advanced breast cancer.
- Explain the current status of capecitabine monotherapy as first or second line therapy in patients with advanced breast cancer.
- Describe the rationale and current status of capecitabine combination treatment of breast cancer.
- Balance the safety profile of capecitabine with available alternative treatment options for the treatment of advanced breast cancer.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
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ABSTRACT
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Oral capecitabine is a useful chemotherapy for metastatic breast cancer, both as monotherapy and in combination with other cytotoxic drugs. The proven activity of capecitabine has provided the rationale to explore its use earlier in the course of the disease and in combination with other agents, particularly those known to further upregulate thymidine phosphorylase (TP) concentrations in tumor tissue.
The efficacy and safety of capecitabine monotherapy compares favorably with cyclophosphamide/methotrexate/5-fluorouracil in chemotherapy-naïve patients and with paclitaxel in anthracycline-pretreated patients. Therefore, for patients whose disease has progressed during or following anthracycline treatment, but for whom capecitabine/docetaxel combination therapy or taxane monotherapy is not appropriate, capecitabine monotherapy is an attractive alternative to established i.v. treatments.
In combination, capecitabine plus paclitaxel, which further upregulates TP in tumor tissue, has demonstrated high activity in two phase II studies in advanced/metastatic breast cancer. Similarly, combination with vinorelbine showed promising activity in pretreated metastatic breast cancer patients, and triple combinations with an anthracycline and a taxane or cyclophosphamide have proven to be highly active. In the future, capecitabine may be combined with novel biologic agents, such as trastuzumab and bevacizumab; the former combination has already shown encouraging results in a pilot trial. Confirmatory studies for many of these combinations and phase III trials versus standard therapy are now warranted.
Key Words. Capecitabine • Taxanes • Breast cancer • Trastuzumab • Vinorelbine • Anthracyclines
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INTRODUCTION
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Capecitabine is an active oral chemotherapy in metastatic breast cancer (MBC), both in combination with docetaxel in anthracycline-pretreated patients [1] and as monotherapy in heavily pretreated patients [2–5]. The activity of capecitabine provides the rationale for exploring its use in other breast cancer settings, such as earlier in the disease course or as a component of novel combination regimens. This article reviews studies evaluating capecitabine either as monotherapy or in combination with other cytotoxic or biologic agents, in a variety of settings, and provides a glimpse of future treatment settings in which capecitabine may play an important role.
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CAPECITABINE MONOTHERAPY AS SECOND-LINE TREATMENT
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A randomized, phase II trial was conducted to compare oral capecitabine, 1,250 mg/m2 twice daily on days 1-14, with i.v. paclitaxel, 175 mg/m2 on day 1, both given in 21-day cycles [6]. These are the standard, full-dose regimens for both agents. The study was discontinued prematurely because patients showed strong preferences for either an established i.v. treatment or a novel, oral agent, and therefore, refused to be randomized in the study. Nevertheless, the results of the study provide evidence of the activity of capecitabine in this setting.
The characteristics of the 41 evaluable patients (median age = 52 years, with a good performance status) were well balanced between treatment arms. Approximately half of the patients had progressed while on prior anthracycline therapy; the others had progressed within 12 months of anthracycline therapy. Almost two-thirds of the patients had been exposed to 5-fluorouracil (5-FU).
The efficacy results are summarized in Table 1
[6]. Due to the nature of the trial, which was a randomized phase II evaluation, no formal statistical analysis was performed. However, the activity of capecitabine compared favorably with that of paclitaxel. A 36% objective response rate was observed in patients receiving capecitabine, with three patients achieving a complete response. In the paclitaxel arm, the response rate was 26%, with no complete responses.
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Table 1. Summary of efficacy: single-agent capecitabine versus paclitaxel in patients with anthracycline-resistant MBC [6]
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As expected, capecitabine and paclitaxel monotherapies exhibited distinct safety profiles (Fig. 1). The side effects of capecitabine were similar to those described elsewhere in this supplement. Patients in the capecitabine arm experienced more gastrointestinal side effects and hand-foot syndrome, whereas those receiving paclitaxel experienced more myalgia, paresthesia, and alopecia, all of which were absent in the capecitabine arm [6]. The particularly low incidence of alopecia with capecitabine is an important feature of this compound. Alopecia is a significant, disturbing, and burdensome side effect of many chemotherapy regimens, and the prospect of hair loss is a cause of great concern for women receiving chemotherapy [7, 8]. The absence of alopecia with capecitabine is, therefore, likely to be of significant interest to patients.
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Figure 1. Single-agent capecitabine versus paclitaxel in anthracycline-resistant MBC: summary of safety.
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For patients who experienced significant toxicity at the standard dose of capecitabine, adverse events of grade 2 or higher severity were managed by treatment interruption and dose reduction [6]. In this respect, the twice-daily dosing schedule of capecitabine allows numerous opportunities for intervention.
A further advantage of capecitabine over paclitaxel was the low incidence of myelosuppression in the capecitabine arm [6]. The incidence of grade 3/4 neutropenia in the paclitaxel arm was 53% compared with only 9% in the capecitabine arm. Grade 3 leukocytopenia and thrombocytopenia, which also occurred in the paclitaxel arm, were absent in the capecitabine arm.
Capecitabine monotherapy, therefore, has favorable efficacy and safety compared with paclitaxel. In patients for whom capecitabine/docetaxel therapy may not be appropriate, capecitabine monotherapy is an attractive alternative to established i.v. treatments and warrants further investigation.
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CAPECITABINE MONOTHERAPY AS FIRST-LINE TREATMENT
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A second randomized, phase II study has evaluated capecitabine as first-line treatment for MBC [9]. In that trial, 95 patients aged 
55 years, who had not previously received chemotherapy for metastatic disease, were randomized (2:1) to standard capecitabine monotherapy (as described above) or to an i.v. CMF regimen (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and 5-FU 600 mg/m2 on day 1 of a 21-day cycle). The i.v. CMF regimen was chosen as a comparator rather than the classical Bonadonna regimen, as a specific older patient population was targeted for enrollment.
A total of 93 patients received treatment. Patients’ characteristics, including distribution of metastatic sites, were well balanced at baseline [9]. The patients were elderly (median age = 69-70 years) and most (80%-90%) had previously received antiestrogens for malignant disease.
The efficacy data for this study are presented in Table 2 [9]. The primary objective of the study, to achieve a response rate in the range of 30% with capecitabine, was met, and the objective response rate was 30%, including complete responses in 5% of patients. Furthermore, the time to disease progression and survival data were also encouraging [9].
In terms of safety, both regimens were generally well tolerated. The predominant adverse events were hand-foot syndrome and diarrhea with capecitabine and myelosuppression and alopecia with CMF [9]. All toxicities associated with capecitabine could be adequately managed with treatment interruption and dose modification, if necessary. The lower incidences of grade 3/4 neutropenia (8% versus 41%, respectively) and alopecia (8% versus 19%, respectively) with capecitabine compared with CMF represent an important benefit of capecitabine. Capecitabine, therefore, compares very favorably with every-21-days CMF in the first-line treatment setting.
As a result of these data, phase III studies of capecitabine monotherapy are ongoing or planned in the first-line and adjuvant settings. In an ongoing study in Australia and New Zealand, breast cancer patients are being randomized to the classical Bonadonna CMF regimen every 28 days or to one of two capecitabine regimens with identical planned dose intensities: either 1,000 mg/m2 twice daily on days 1-14 in a 21-day cycle or 666 mg/m2 twice daily every day (Fig. 2). The purpose of the trial is to evaluate the efficacy of capecitabine in the first-line setting, and the primary end point is quality of life (QoL)-adjusted time to disease progression.
In another ongoing phase III trial, led by the Cancer and Leukemia Group B (CALGB), women >65 years of age with early-stage breast cancer are being randomized to either capecitabine or CMF (or doxorubicin/cyclophosphamide, depending on the cardiac history of each patient). The primary end point is the 5-year relapse-free survival rate. Other end points include overall survival, QoL, physical function, compliance, treatment tolerance, and biologic markers of response.
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RATIONALE FOR CAPECITABINE COMBINATION THERAPY
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Capecitabine is suitable for combination with a variety of agents, particularly those known to further upregulate thymidine phosphorylase (TP) in tumor tissue [10]. Other motivations for combining capecitabine with other agents include its favorable safety profile, with a particularly low rate of myelosuppression, its potential to replace continuous infusion 5-FU in various combination regimens, and the potential to develop all-oral combinations.
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CAPECITABINE PLUS PACLITAXEL COMBINATION THERAPY
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The high efficacy and manageable safety profile of capecitabine/docetaxel combination therapy in anthracycline-pretreated patients suggest that other capecitabine/taxane combinations may be valuable [1]. Similarly to docetaxel, paclitaxel further upregulates TP in tumor tissue and shows synergy with capecitabine in tumor xenograft models [10]. Phase I studies confirmed the feasibility of capecitabine/ paclitaxel combination therapy and led to further clinical studies [11, 12].
Two phase II studies have demonstrated that capecitabine/paclitaxel combination therapy was highly effective in treating advanced/metastatic breast cancer [13, 14]. In both studies, the paclitaxel regimen was 175 mg/m2 on day 1 of a 21-day cycle. However, the capecitabine doses (given twice daily on days 1-14 of a 21-day cycle in both studies) differed: 1,000 mg/m2 in the first study, conducted in Europe [13], and 825 mg/m2 in the second, ongoing study, conducted in the U.S. [14].
In addition to the regimens, the treatment history of the patients also differed between studies. Patients in the European study were all previously exposed to anthracyclines, approximately half of them in the (neo-)adjuvant setting and the others in the metastatic setting [13]. In contrast, only 70% of those in the U.S. study had previously received anthracyclines, almost all of them in the (neo-) adjuvant setting [14]. A small proportion of patients in both studies (13%-15%) had previously received taxanes. Other patient characteristics were well balanced. The median age of the patients was 52-53 years, and the median performance status was 90. Approximately two-thirds of patients had visceral metastases and two or more organs involved [13, 14].
The current efficacy data for those studies are given in Table 3 [13, 14]. The overall response rate, 51% in both trials, is encouraging, and includes a substantial number of complete responses. The median time to disease progression was impressive in both studies and was, not surprisingly, slightly higher in the U.S. study, presumably because the patient population was less heavily pretreated in that trial. Overall survival data are currently available only for the European study and are encouraging.
The safety profile in both studies was similar to that observed in the capecitabine/docetaxel study [1]. Hand-foot syndrome and gastrointestinal adverse events were the predominant toxicities. Most adverse events were mild: the incidence of grade 4 toxicities was very low, and the incidence of grade 3 hand-foot syndrome was <10% [13, 14]. Clearly, the taxanes provide an attractive combination partner for capecitabine, and mature results from these trials are awaited with interest.
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CAPECITABINE PLUS VINORELBINE COMBINATION THERAPY
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Vinorelbine is active in MBC and is frequently used in combination with 5-FU. In an ongoing, phase I dose-finding study, 40 patients with pretreated MBC are receiving 21-day treatment cycles of capecitabine (500-1,250 mg/m2 twice daily on days 1-14) plus vinorelbine (12.5-22.5 mg/m2 on days 1 and 3) [15]. Nine dose levels have been evaluated, and the maximum tolerated dose has not been reached. Grade 3/4 neutropenia has been observed in 32% of cycles, and since antitumor activity has been seen at all dose levels, the investigators have decided not to increase doses further. Objective responses so far have been observed in 16 of 33 (48%) evaluable patients [15].
In a second phase I study, patients with anthracycline/taxane-pretreated metastatic disease are also receiving 21-day treatment cycles of capecitabine plus vinorelbine [16]. In that study, the regimens are capecitabine 1,000 or 1,250 mg/m2 twice daily on days 1-14, plus vinorelbine 25 or 30 mg/m2 on days 1 and 8. On the basis of data obtained from the 14 patients evaluated to date, the recommended dose is capecitabine 1,000 mg/m2, plus vinorelbine 25 mg/m2. Objective responses have currently been observed in five of nine (56%) evaluable patients [16]. At the recommended dose level, one dose-limiting toxicity (grade 4 neutropenia) was observed in six patients. Capecitabine/vinorelbine combination therapy appears feasible and active and is being evaluated in different settings at the recommended dose of vinorelbine 25 mg/m2, plus capecitabine 1,000 mg/m2, twice daily, days 1-14 every 21 days.
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CAPECITABINE IN ANTHRACYCLINE-CONTAINING COMBINATION THERAPIES
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Capecitabine has also been evaluated as a component of triple combinations. The primary rationale for combining capecitabine with anthracycline-based regimens is the absence of overlapping toxicities of the two agents.
In a phase I study, capecitabine (750-1,200 mg/m2 twice daily on days 1-14) given in a 21-day cycle in combination with epirubicin (100 mg/m2 on day 1) and cyclophosphamide (600 mg/m2 on day 1) (CEX) was investigated in 23 patients with previously untreated locally advanced/inflammatory or large operable breast cancer [17]. A maximum of six cycles was allowed.
At the highest dose level of capecitabine, only two patients were enrolled. Both patients suffered dose-limiting toxicities (grade 3 mucositis, nausea, and febrile neutropenia in one patient, grade 3 fatigue in one patient). Therefore, the previous dose level (capecitabine 1,050 mg/m2 twice daily) was expanded to 15 patients and was initially identified as the recommended dose level. However, due to a lower median dose intensity administered at this dose level, a capecitabine dose of 900 mg/m2 twice daily will be recommended for phase II/III trials. No grade 4 toxicities were observed, and the most frequent grade 3 toxicities were febrile neutropenia, nausea, mucositis, and fever, each occurring in 10%-25% of patients. The overall response rate at all dose levels was very high (83%). At the initially recommended dose level, the response rate was 80%. A randomized phase II study is now being considered by a French group in the neoadjuvant setting.
A triple combination regimen, consisting of capecitabine (1,000 mg/m2 twice daily on days 1-14) plus docetaxel (75 mg/m2 on day 1) plus epirubicin (75 mg/m2 on day 1) (TEX) in 21-day cycles, was identified in a phase I dose-finding trial [18] and, subsequently, evaluated as first-line therapy for previously untreated advanced/ metastatic breast cancer in a phase II study [19]. The objective response rates in the phase II study were 94% in 34 patients with stage III disease and 70% in 33 patients with stage IV disease, giving an overall response rate of 82%. Stable disease was achieved in a further 12% of the overall patient population. The TEX combination also had a predictable safety profile. The principal toxicities were alopecia, nausea, asthenia, stomatitis, and fever. There was a relatively high incidence of adverse events, but almost all were mild to moderate in intensity, with only two patients experiencing a grade 4 adverse event (stomatitis and febrile neutropenia). Furthermore, other than alopecia and febrile neutropenia, the incidences of all other grade 3 toxicities were <10% [19]. A multicenter, randomized, phase III trial comparing TEX with docetaxel plus epirubicin is ongoing.
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CAPECITABINE/BIOLOGIC AGENT COMBINATION THERAPIES
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Trastuzumab, a humanized, anti-HER-2 monoclonal antibody, is active as monotherapy in patients with HER-2-overexpressing MBC [20], and trastuzumab plus chemotherapy is now considered to be the standard therapy for patients with HER-2-positive tumors [21, 22]. Since trastuzumab and capecitabine have distinct safety profiles, there is a clear reason for investigating them in combination. Furthermore, capecitabine and trastuzumab have at least additive activity in a human breast cancer xenograft model that overexpresses HER-2 and is sensitive to trastuzumab monotherapy [23]. Capecitabine/trastuzumab combination therapy has been investigated in a pilot trial including 18 patients with anthracycline- and taxane-pretreated, HER-2-overexpressing MBC [24]. Patients received 21-day cycles of standard-dose trastuzumab (on days 1, 8, and 15) plus capecitabine (1,125 mg/m2 twice daily on days 1-14). In the 13 patients currently evaluable, the objective response rate is 62%. These encouraging results in a difficult-to-treat setting have provided the rationale for phase II clinical investigation of the combination. In a U.S. trial, a combination of capecitabine plus trastuzumab plus paclitaxel, with capecitabine at a dose of 825 mg/m2 twice daily and trastuzumab and paclitaxel each administered at their full single-agent doses, will be evaluated. A large international, randomized, phase II study will evaluate trastuzumab plus docetaxel, with or without capecitabine.
Another biologic agent, bevacizumab, has also attracted interest as a potential combination partner for capecitabine. Bevacizumab is a recombinant, humanized, monoclonal antibody directed against vascular endothelial growth factor and is active as monotherapy in patients with previously treated MBC [25].
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CONCLUSIONS
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Capecitabine, as either monotherapy or a component of combination regimens, is proving to be a highly useful agent for the treatment of breast cancer (Fig. 3). A series of clinical trials involving different comparators in different stages of breast cancer has shown that capecitabine is a highly active agent with an acceptable toxicity profile. Future and ongoing trials are likely to confirm the value of this highly active oral chemotherapy.
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Figure 3. Moving capecitabine combination regimens forward: summary of combinations under evaluation. Abbreviation: TAX = docetaxel/doxorubicin/ capecitabine.
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REFERENCES
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Received September 17, 2002;
accepted for publication October 4, 2002.
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Learning Objectives
Abstract
