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Capecitabine Monotherapy: Safe and Effective Treatment for Metastatic Breast Cancer
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     LEARNING OBJECTIVES

    After completing this course, the reader will be able to:

    Describe the pharmacology of capecitabine.

    Discuss the use of capecitabine as a single agent and in refractory disease.

    Discuss safety and dosing considerations

    Describe current adjuvant treatment with capecitabine.

     ABSTRACT

    Optimal management for metastatic breast cancer frequently involves cytotoxic chemotherapy. Over the years, several complex multidrug regimens have been developed that were based upon a rationale of synergistic antitumor activity and nonoverlapping toxicities. However, recently the clinical value of these complex regimens has been called into question as several drugs used alone (monotherapy) or in sequence (serial single agent) have been shown to be both efficacious and better tolerated. Capecitabine (an orally administered fluoropyrimidine carbamate) is one such agent that has been proven to be effective when used alone for metastatic breast cancer, metastatic colorectal cancer, and adjuvant colon cancer. In this review, published (or reported in abstract form) data examining various aspects of clinical response and tolerability with single-agent capecitabine for (primarily) first- and second-line metastatic breast cancer are examined. For the most part, response rates are comparable with those of the more complex regimens. Dose reductions from the labeled dose of 1,250 mg/m2 twice daily are relatively common. Toxicities (following dose reductions if needed) are generally manageable, even by more frail patients. Elderly patients are more likely to have impaired renal function or be receiving warfarin treatment, and special attention to these factors is warranted. Nonetheless, the drug administered alone is a reasonable choice when single-agent chemotherapy is entertained as a treatment option for metastatic breast cancer, including in the first-line setting.

     INTRODUCTION

    Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer-related deaths (following lung cancer), with 212,930 new cases and 40,870 cancer-related deaths projected for 2005 [1]. Five-year survival rates decrease with advancing disease stage: from 98% in localized disease to 80% with regional spreading to only 26% with metastatic disease. Chemotherapy plays an important role in breast cancer, whether in the neoadjuvant, adjuvant, or metastatic setting. Single chemotherapeutic agents included in the National Comprehensive Cancer Network (NCCN) listing of preferred single agents are anthracyclines (e.g., doxorubicin, epirubicin, pegylated liposomal doxorubicin), taxanes (e.g., paclitaxel, docetaxel), vinorelbine, and capecitabine, each of which may be used as a single agent for recurrent or metastatic disease [2]. Among the taxanes, for example, single-agent paclitaxel has been shown to be active in first-line (chemotherapy-naïve) patients with metastatic disease, yielding response rates of 25%–34% [3–5], while docetaxel has shown activity in previously treated (second-line) metastatic settings, with response rates of 33%–43% [6–8]. Bolus 5-fluorouracil (5-FU) infusions, with leucovorin, have been shown to have substantive activity, yielding response rates of 36% in chemotherapy-naïve patients [9] and 17%–23% in patients with prior chemotherapy [10–12]. Continuous infusion 5-FU with leucovorin has yielded response rates of around 29% [13]. However, the encouraging results associated with continuous infusion therapy for the treatment of breast cancer are accompanied by inconvenience and cost in patient quality of life (QoL) and medical resources.

    Capecitabine (Xeloda®; Hoffmann-La Roche Inc., Nutley, NJ) is a novel, orally administered fluoropyrimidine carbamate used to treat breast and colorectal cancer. Readily absorbed by the gastrointestinal tract, capecitabine is metabolized by the enzyme carboxylesterase in the liver, where it is converted to 5' deoxy-5-fluorocytidine (5' DFCR), which is then converted by the enzyme cytidine deaminase to 5' deoxy-5-fluorouridine (5' DFUR) [14, 15]. In tumor and normal tissues, the enzyme thymidine phosphorylase (TP) converts 5' DFUR to 5-FU. However, unlike parenterally administered 5-FU, oral capecitabine concentrates predominantly in tumor tissue as opposed to adjacent healthy tissue and plasma [15]. As a result, orally administered capecitabine enables physicians treating breast cancer to mimic the effect of continuous infusion 5-FU but in a convenient outpatient setting without the complications and costs associated with infusion pumps and parenteral therapies [16, 17]. Capecitabine was approved in 1998 by the U.S. Food and Drug Administration as a single agent for patients with metastatic breast cancer that is resistant to both paclitaxel and anthracyclines, and for those with breast cancer resistant to paclitaxel and for whom further anthracycline therapy is contraindicated [18]. Capecitabine is also approved for combination therapy with docetaxel for the treatment of patients with metastatic breast cancer in whom prior anthracycline-based therapy has failed. Standard dosing is 1,250 mg/m2 orally twice daily (bid), morning and evening, for 14 consecutive days in 3-week cycles. There has, however, been substantial research into the utility of single-agent capecitabine in both earlier stages of breast cancer and at lower doses than the standard dose. This paper summarizes the efficacy, safety, QoL effects, and pharmacoeconomics of single-agent capecitabine for the treatment of metastatic breast cancer.

    METHODOLOGY

    MEDLINE was searched for published clinical studies, and proceedings from the American Society of Clinical Oncology (ASCO), the San Antonio Breast Cancer Symposium (SABCS), the European Society for Medical Oncology (ESMO), and the European Cancer Conference (ECCO) were searched for abstracts pertaining to capecitabine as a single agent for the treatment of breast cancer. The most recent available efficacy, safety, and QoL data were used when possible. Missing data were designated as "not available" unless one could infer results from other supplied data. Measures of variance were employed where possible to provide a perspective of uncertainty for comparing data across studies with varying sample sizes. Where variance data for proportions were not provided in the study, 95% confidence intervals (95% CIs) were calculated using the proportion method [19]. If inferential statistics for comparisons of proportions within randomized controlled studies were not provided by the study authors, the Fisher’s exact test was employed to calculate these. Significance was set at 5% ( = .05) with two-tailed testing.

     METASTATIC DISEASE: FIRST-LINE

    Based on promising findings in patients previously treated for metastatic disease, single-agent oral capecitabine is being investigated for treating earlier treatment settings of breast cancer. One area of particular interest is the first-line treatment of elderly patients with metastatic disease.

    In a key randomized controlled trial (RCT) among elderly patients, O’Shaughnessy et al. [20] treated women 55 years of age with 3-week cycles of either oral capecitabine, 1,255 mg/m2 bid for 2 weeks on/1 week off (n = 61), or cyclophosphamide with methotrexate and 5-FU (CMF) (n = 32). Although not statistically significant, activity appeared greater in the single-agent capecitabine group than in the CMF group (objective response rate [ORR], 30% vs. 16%; p = .21), as were median time to progression (MTTP) (4.1 vs. 3.0 months) and median overall survival (MOS) (19.6 vs. 17.2 months). The incidence of all-grade diarrhea (47% vs. 22%; p = 0.02) and hand-foot syndrome (HFS) (43% vs. 0%; p <.0001) were significantly greater with capecitabine than with CMF; the incidence of grade 3 or 4 nausea, diarrhea, stomatitis, vomiting, alopecia, and fatigue/asthenia did not differ significantly between groups. Only grade 3 HFS was significantly greater in the capecitabine group (15% vs. 0%; p = .025). With respect to hematologic adverse events (AEs), substantially fewer patients treated with single-agent capecitabine developed grade 3 or 4 neutropenia (8% vs. 41%; p = .0005) and grade 4 neutropenia (2% vs. 22%; p = .002) than with CMF. However, there were three treatment-related deaths among patients treated with single-agent capecitabine (corticosteroid-induced diabetes mellitus, bronchopneumonia, and unknown cause).

    In an open-label study, Minea et al. [21] treated 63 elderly patients (median age, 70 years; range, 65–78 years), none of whom had undergone prior chemotherapy for metastatic disease, with first-line oral standard-regimen capecitabine. The therapy was active, yielding an ORR of 27% (95% CI, 17%–40%) and stable disease (SD) rate of 43% (95% CI, 31%–56%). There were no treatment-related deaths, and the most common grade 3 or grade 4 AEs included asthenia, 13% (95% CI, 6%–24%); diarrhea, 10% (95% CI, 4%–20%); vomiting, 6% (95% CI, 2%–16%); and mucositis, 3% (95% CI, 1%–12%), with grade 2 or 3 HFS in 24% (95% CI, 14%–36%) of patients. More recently, Bajetta et al. [22] treated 73 patients 65 years of age (93% chemotherapy-naïve for metastatic disease) with single-agent capecitabine. The first 30 patients received the standard dose and regimen, but because of two (7%) deaths, both a result of severe dehydration, the investigators decided to reduce the initial capecitabine dose to 1,000 mg/m2 bid for the next 43 patients (low-dose cohort). Activity was substantive and similar in both cohorts (low-dose cohort: complete response [CR] rate, 2%; ORR, 35%; SD rate, 46%; standard cohort: CR rate, 3%; ORR, 37%; SD rate, 33%). The MTTP were also similar (4.1 vs. 3.9 months), but the low-dose cohort appeared to have a greater median survival (16 vs. 10 months). The low-dose cohort also appeared to benefit from a more favorable safety profile than the standard-dose cohort, as demonstrated by lower incidences of grade 3 or 4 diarrhea (2% vs. 13%), dyspnea (5% vs. 10%), nausea (5% vs. 7%), and vomiting (0% vs. 3%). Grade 3 HFS was uncommon (2%). Only grade 3 or 4 fatigue appeared substantially more commonly in the low-dose cohort (12% vs. 7%). There was, however, one death resulting from heart failure, possibly associated with the study medication. These findings appear to show that single-agent capecitabine, particularly at the 1,000 mg/m2 bid dosage, is an effective first-line therapy for elderly patients with metastatic breast cancer.

     METASTATIC DISEASE: SECOND-LINE (OR LATER)

    Most studies of single-agent capecitabine for the treatment of metastatic breast cancer have been primarily among patients previously treated with an anthracycline (e.g., doxorubicin, epirubicin) and/or a taxane (e.g., docetaxel, paclitaxel). Such patients have a very poor prognosis, as exemplified in a recent study in which anthracycline- and taxane-resistant patients, following salvage chemotherapy with 48-hour continuous infusion 5-FU (biomodulated with high-dose leucovorin and in combination with cyclophosphamide), had overall 1- and 2-year survival rates of only 51% and 20%, respectively, and 0% after 28 months [23].

    Efficacy

    Response and survival data for previously treated (second-line or later) metastatic therapy with single-agent capecitabine are presented in Table 1 [24–51]. Most studies were small phase II studies with patient populations previously treated with an anthracycline and/or a taxane. Most patients initially received the standard dose of single-agent capecitabine, 1,250 mg/m2 bid for 14 days followed by 7 days of rest, although several studies employed lower initial starting doses of 1,000 mg/m2 bid [31–33, 41, 45] or 828 mg/m2 bid [47, 48]. Down-dosing of capecitabine was reported in fewer than half of the studies, but this proportion may be greater because of reporting deficiencies in abstracts. Where reported, capecitabine was often reduced to approximately 75% of the initial dose for approximately one quarter to one half of the patients in the studies.

    Overall, single-agent capecitabine was active in these poor-prognosis populations. Among these studies, the median CR rate was 3% (range, 0%–20%), and the median ORR was 28% (range, 9%–53%). Among prospective studies with at least 100 patients, the median CR rate was 2% (range, 0%–4%), the median ORR was 20% (range, 9%–35%), and the median SD rate was 43% (range, 35%–47%). Among all reported studies, the MTTP for these poor-prognosis patients was 4.7 months (range, 2.8–11.8 months), and the MOS was 11.0 months (range, 5.3–18.1 months). Among prospective studies with at least 100 patients, the MTTP was 3.5 months (range, 3.0–5.9 months) and the MOS was 11.9 months (range, 10.1–15.2 months).

    Single-agent capecitabine has also been shown to exhibit at least comparable activity with that of single-agent paclitaxel in patients previously treated with an anthracycline and/or 5-FU. In one randomized phase II clinical trial [42], 22 patients received oral capecitabine at a dose of 1,255 mg/m2 bid for 2 weeks on/1 week off for two cycles, and 19 patients received parenteral paclitaxel at a dose of 175 mg/m2 every 3 weeks. The CR rate and ORR were greater in the capecitabine group than in the paclitaxel group (14% vs. 0% and 36% vs. 26%, respectively), but these differences were not significant (p = .24 and p = .52). Survival data, as measured by MTTP for the capecitabine and paclitaxel groups (3.0 vs. 3.1 months) and MOS (7.6 vs. 9.4 months), were similar.

    In a recent retrospective analysis of 197 patients previously treated with an anthracycline, taxane, and/or vinorelbine (French compassionate-use program) [27], multivariate analyses showed that a favorable response to capecitabine therapy was associated with longer survival (relative risk [RR], 5.2;95% CI, 2.0–13.6; p =.001). Another retrospective study that included 113 anthracycline- and taxane-refractory patients [52] reported that those treated with single-agent capecitabine had a significantly longer MOS time than those treated with single-agent vinorelbine (6.2 vs. 3.4 months; p < .0001).

    Identifying patients who are most likely to respond to capecitabine therapy may substantially improve upon these findings. The HER-2/neu (also known as c-erbB-2) oncogene encodes a transmembrane tyrosine kinase receptor that is homologous to the epidermal growth factor receptor [53]. Amplification of the HER-2/neu gene, or overexpression of the HER-2 (p185HER2) protein, has been associated with a poor prognosis in breast cancer [53]. Sezgin et al. [32] treated 58 heavily pretreated metastatic breast cancer patients (97% of whom had prior anthracycline- and taxane-based therapy either in the adjuvant or metastatic settings; 72% of whom had at least three prior regimens) with capecitabine at a dose of 1,000 mg/m2 bid for 2 weeks on/1 week off to identify potential predictors of progression-free survival. Patients with HER-2/neu 2+, as measured by immunohistochemistry, had a significantly shorter progression-free survival time than patients with HER2/neu expression of 0 or 1+ (3.7 vs. 7.4 months; p = .012) and a nearly significant lower ORR (10% vs. 32%; p = .073). The authors concluded that capecitabine had substantial antitumor activity in patients whose tumor does not overexpress the HER-2 receptor.

    Safety

    Single-agent capecitabine was well tolerated in patients previously treated with an thracyclines or taxanes for metastatic breast cancer. Dose reductions of single-agent capecitabine were frequently reported among patients receiving an initial dose of the labeled 1,250 mg/m2 bid (days 1–14 every 3 weeks) [24, 28–30, 34, 40, 42, 45, 46, 50]. Such dose reductions were typically 25% and were observed in 12%–50% of patients in studies reporting dose reductions. However, only one study [26] reported dose reductions when lower initial doses were used.

    Grade 3 or 4 AEs for patients previously treated with anthracyclines or taxanes are presented in Table 2 [24–35, 37, 40–48, 50, 51, 54, 55]. Overall, the most frequently reported grade 3 or 4 nonhematologic AEs were HFS (median, 13%; range, 0%–42%), diarrhea (median, 7.5%; range, 0%–30%), nausea (median, 6.5%; range, 0%–35%), mucositis (median, 6%; range, 0%–12%), and vomiting (median, 4%; range, 0%–19%). Grade 3 or 4 paresthesia or neuropathy was reported in only one study (27% and 4%, respectively) [46]. Hematologic grade 3 or 4 AEs were uncommon in studies, as observed by a median neutropenia incidence of 1% and median rates of 0% for thrombocytopenia, leukopenia, and lymphocytopenia.

    A phase II RCT by Talbot et al. [42] compared the safety profile of single-agent capecitabine with that of single-agent paclitaxel in patients who had failed or were resistant to anthracycline-based therapy and/or who had undergone prior 5-FU therapy. The overall incidence of grade 3 AEs was lower but not statistically significant for those treated with single-agent capecitabine than for those treated with single-agent paclitaxel (36% vs. 68%; p = .06). Although there were no significant differences between the groups in the incidence of grade 3 or 4 nonhematologic AEs, patients treated with capecitabine had significantly fewer shifts from baseline to grade 3 or 4 neutropenia (9% vs. 53%; p = .005). Grade 3 neutropenia was also significant less with capecitabine than with paclitaxel (0% vs. 26%; p = .016), as was grade 3 leukopenia (0% vs. 21%; p = .038).

    In addition, HFS, commonly observed among patients treated with capecitabine, may be dosage-related. Among the 197 patients in the French compassionate-use program [27], 20% treated with greater than 1,250 mg/m2 bid capecitabine experienced severe HFS, compared with only 2% initially treated with lower-dose capecitabine.

    Elderly Patients

    In general, physicians need to monitor elderly patients being treated with capecitabine for potential adverse effects [18]. Recent studies by Longo et al. [31] and Zamora et al. [28] have shown that single-agent capecitabine is safe and active for the treatment of elderly patients with metastatic breast cancer who were previously treated with chemotherapy. Although there were no CRs, 20%–28% of elderly patients in those studies exhibited a partial response to single-agent capecitabine, and another 44%–50% exhibited SD, similar to the ORRs and SD rates observed overall in studies of single-agent capecitabine for second-line metastatic breast cancer. Dose reduction was needed for patients treated with capecitabine at a dose of 1,250 mg/m2 bid [28] but not for those treated with 1,000 mg/m2 bid [31]. The incidence of grade 3 HFS was greater with 1,250 mg/m2 bid dosing than with 1,000 mg/m2 dosing (18% vs. 7%), as was the incidence of grade 3 or 4 mucositis (12% vs. 7%). There were no reported cases of grade 3 or 4 diarrhea or hematologic toxicities with either dose level.

    Of note, with particular relevance to the elderly, the package insert prepared for U.S. distribution contains cautionary recommendations when prescribing doses of capecitabine for patients with moderate to severe renal dysfunction or for those receiving warfarin therapy.

    Quality of Life

    Single-agent oral capecitabine has been shown to significantly improve QoL in patients previously treated for metastatic breast cancer. In a small study, Jakob et al. [43] reported that half of the 12 patients treated with the standard oral capecitabine regimen had improved QoL scores, as measured by the European Organization for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ). A more recent study by Fumoleau et al. [30], who used the same regimen and questionnaire on 119 anthracycline- and taxane-resistant patients, reported significant improvements in mean Global Health Status from baseline (10 points) after 6 and 12 treatment cycles.

    There have been several reports from a large, ongoing Brazilian study of QoL [56–59]. Most recently, 611 anthracycline- and/or taxane-resistant patients with metastatic breast cancer received the standard regimen of oral capecitabine and were evaluated at baseline, week 7, week 13, and at end of treatment using the EORTC QLQ and BR-38 questionnaires [56, 60, 61]. Improvement in QoL was defined as an increase 10 points, and worsening QoL was defined by a decrease 10 points from baseline at one or more visits. Treatment with oral capecitabine led to significant improvements in patient global health status (p < .0001), physical functioning (p = .049), role functioning (p < .0001), emotional functioning (p < .0001), social functioning (p = .015), body image (p < .0001), sexual enjoyment (p = .015), financial problems (p = .002), and future perspectives (p < .0001). Patients treated with capecitabine also reported significant improvements in systemic therapy side effects (p < .0001) as well as in fatigue (p = .003), nausea and/or vomiting (p < .0001), pain (p < 0.0001), insomnia (p < .0001), appetite loss (p < .0001), constipation (p < .0001), diarrhea (p = .005), alopecia (p < .0001), breast symptoms (p < .0001), and arm symptoms (p = .0085). Approximately 70%–80% of patients reported improved or maintained QoL during treatment with capecitabine, with statistically significant improvements at each visit.

    Cost-Effectiveness

    Compared with other therapies for second-line (or later) metastatic breast cancer, single-agent oral capecitabine appears to be cost-effective. In a retrospective cohort study [62] matched by treatment, the medical and retail pharmacy claims of 100 patients with metastatic breast cancer treated with single-agent capecitabine were compared with those of 100 patients treated using other therapies, including vinorelbine, gemcitabine, cyclophosphamide, doxorubicin (with or with out cyclophosphamide), and trastuzumab. Oral capecitabine provided superior cost-effectiveness compared with other therapies with respect to the direct cost of cancer care per patient ($7,272 vs. $11,552), cost per day of effectiveness ($75 vs. $185), chemotherapy and supportive care costs per patient ($4,383 vs. $6,598), chemotherapy costs per patient ($3,453 vs. $4,065), hematopoietic growth factor costs per patient ($606 vs. $1,721), and antiemetics costs ($88 vs. $661).

    EARLIER-STAGE TREATMENT SETTINGS

    Kimishima et al. [63] treated 1,088 stage I or II breast cancer patients postoperatively with 5' DFUR (an intermediary of capecitabine) with or without cyclophosphamide. Overall, disease-free survival was significantly greater in the 5' DFUR/cyclophosphamide group than in the single-agent 5' DFUR group (log-rank test, p = .021). The 5' DFUR/cyclophosphamide group also had a greater 5-year disease-free survival rate (72% vs. 67%). Grade 3 or 4 AEs did not differ significantly between the treatment groups.

    Single-agent capecitabine is being actively investigated for the treatment of breast cancer in the adjuvant setting. The Cancer and Leukemia Group B (CALGB) 49907 study, a randomized, open-label, multicenter, phase III trial that calls for an accrual of 600–1,800 women 65 years of age with local or regional breast cancer, is designed to compare the efficacy and safety of single-agent capecitabine with those of standard chemotherapies, CMF or doxorubicin and cyclophosphamide (AC). In the capecitabine arm, patients are administered oral capecitabine at a dose of 1,000 mg/m2 bid for 2 weeks on/1 week off for 12 weeks, while in the standard chemotherapy arm, patients are administered either: oral cyclophosphamide at a dose of 100 mg/m2 on days 1–14, parenteral methotrexate at a dose of 40 mg/m2 on days 1 and 8, and parenteral 5-FU at a dose of 600 mg/m2 on days 1 and 8 of 4-week cycles or parenteral doxorubicin at a dose of 60 mg/m2 on day 1 and cyclophosphamide at a dose of 600 mg/m2 on day 1 of 3-week cycles for a duration of 12 weeks (Fig. 1).

     FUTURE DIRECTIONS AND CONCLUSIONS

    Although there are relatively few new trials of single-agent capecitabine for the treatment of breast cancer, capecitabine-based combination therapies are currently under investigation. In the past few years, there have been many publications of capecitabine combined with vinorelbine [64–70], taxanes [71–77], gemcitabine [78, 79], beva-cizumab [36], erlotinib [80], and oxaliplatin [81], as well as ongoing trials: the CALGB 49907 and US Oncology Study 01–062, which is evaluating capecitabine/docetaxel combination therapy versus single-agent docetaxel in the adjuvant setting, and the German AGO group adjuvant study, which is evaluating the role of capecitabine versus no treatment in elderly breast cancer patients [82]. In particular, capecitabine/trastuzumab combination therapy has shown promising efficacy and safety results for first- or second-line therapy in patients with HER2 overexpressing metastatic breast cancer [83, 84].

    Single-agent capecitabine has been shown to be an effective, safe, cost-effective agent that provides superior QoL for previously treated patients with metastatic breast cancer. Encouraging results have led to trials in first-line settings that have yielded promising efficacy and safety findings. Favorable findings in elderly patients with meta-static disease have, in turn, led to ongoing trials to assess the efficacy and safety of single-agent capecitabine for elderly patients in the adjuvant setting. Capecitabine continues to develop as an important chemotherapeutic agent for the treatment of breast cancer.

    DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

    Dr. Ershler has acted as a consultant for Amgen, Ortho Biotech, Roche, Pharmion, and Genentech and has performed contract work for Amgen.

    REFERENCES

    American Cancer Society. Cancer Facts and Figures 2005.

    National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Breast Cancer, Version 1.

    Paridaens R, Biganzoli L, Bruning P et al. Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organization for Research and Treatment of Cancer randomized study with cross-over. J Clin Oncol 2000;18:724–733.

    Sledge GW, Neuberg D, Bernardo P et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 2003;21:588–592.

    Bishop JF, Dewar J, Toner GC et al. Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol 1999;17:2355–2364.

    Nabholtz JM, Senn HJ, Bezwoda WR et al. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group. J Clin Oncol 1999;17:1413–1424.

    Sjostrom J, Blomqvist C, Mouridsen H et al. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised phase III study with crossover on progression by the Scandinavian Breast Group. Eur J Cancer 1999;35:1194–1201.

    Bonneterre J, Roche H, Monnier A et al. Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. Br J Cancer 2002;87:1210–1215.

    Margolin KA, Doroshow JH, Akman SA et al. Effective initial therapy of advanced breast cancer with fluorouracil and high-dose, continuous infusion calcium leucovorin. J Clin Oncol 1992;10:1278–1283.

    Doroshow JH, Leong L, Margolin K et al. Refractory metastatic breast cancer: salvage therapy with fluorouracil and high-dose continuous infusion leucovorin calcium. J Clin Oncol 1989;7:439–444.

    Loprinzi CL, Ingle JN, Schaid DJ et al. 5-Fluorouracil plus leucovorin in women with metastatic breast cancer. A phase II study. Am J Clin Oncol 1991;14:30–32.

    Swain SM, Lippman ME, Egan EF et al. Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. J Clin Oncol 1989;7:890–899.

    Cameron DA, Gabra H, Leonard RC. Continuous 5-fluorouracil in the treatment of breast cancer. Br J Cancer 1994;70:120–124.

    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;34:1274–1281.

    Schüller J, Cassidy J, Dumont E et al. Preferential activation of capecitabine in tumor following oral administration in colorectal cancer patients. Cancer Chemother Pharmacol 2000;45:291–297.

    Liu G, Franssen E, Fitch MI et al. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997;15:110–115.

    Borner M, Schsffski P, de Wit R et al. A randomized crossover trial comparing oral UFT (uracil/tegafur) + leucovorin (LV) and intravenous fluorouracil (FU) + LV for patient preference and pharmacokinetics in advanced colorectal cancer. Proc Am Soc Clin Oncol 2000;19:191a.

    Roche Laboratories Inc. Xeloda (capecitabine) Tablets Prescribing Information.

    Wilson E. Probable inference, the law of succession, and statistical inference. J Am Stat Assoc 1927;22:209–212.

    O’Shaughnessy JA, Blum J, Moiseyenko V et al. Randomized, open-label, phase II trial of oral capecitabine (Xeloda) versus a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 2001;12:1247–1254.[

    Minea L, Stanculeanu DL, Cringeanu A et al. Capecitabine monotherapy for elderly patients with metastatic breast cancer. J Clin Oncol 2004;22(suppl 14):76s.

    Bajetta E, Procopio G, Celio L et al. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 2005;23:2155–2161.

    Kalbakis K, Kouroussis C, Kakolyris S et al. Salvage chemotherapy with high-dose leucovorin (LV) and 48-hour continuous infusion (CI) of 5-fluorouracil (5-FU) in combination with conventional doses of cyclo-phosphamide (CPM) in patients with metastatic breast cancer (MBC) pre-treated with anthracycline and taxanes. Br J Cancer 2001;85:798–802.

    Lee SH, Lee J, Park J et al. Capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Med Oncol 2004;21:223–231.

    Kurnianda J, Haryadi A, Arayandono T et al. Efficacy of capecitabine (X) monotherapy in the anthracycline-pretreated metastatic breast cancer (MBC) preliminary results of phase II study (experience in a single institution). Ann Oncol 2004;15(suppl 3):iii41.

    Portela C, Costa N, Pereira D et al. Treatment of metastatic breast cancer with capecitabine-one centre experience. Ann Oncol 2004;15(suppl 3): iii48.

    Pierga JY, Fumoleau P, Brewer Y et al. Efficacy and safety of single agent capecitabine in pretreated metastatic breast cancer patients from the French compassionate use program. Breast Cancer Res Treat 2004;88:117–129.

    Zamora P, Alvarez de Mon M, Calvo L et al. Capecitabine (X) in elderly patients with metastatic breast cancer. Ann Oncol 2004;15(suppl 3):iii40.

    Wist EA, Sommer HH, Ostenstad B et al. Oral capecitabine in anthracycline- and taxane-pretreated advanced/metastatic breast cancer. Acta Oncol 2004;43:186–189.

    Fumoleau P, Largillier R, Clippe C et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 2004;40:536–542.

    Longo F, Magnolfi E, Borgomastro A et al. Capecitabine (X) in elderly patients (pts) with hormone-refractory metastatic breast cancer (MBC). J Clin Oncol 2004;22(suppl 14S):86s.

    Sezgin VC, Sanli UA, Karabulut B et al. Capecitabine (X) monotherapy in patients (pts) with pretreated metastatic breast cancer (MBC): is response correlated to cerbB-2 expression? J Clin Oncol 2004;22(suppl 14):66.

    Vaid AK, Gupta S, Doval DC et al. Capecitabine: Single institution experience from North India in metastatic breast cancer. J Clin Oncol 2004;22(suppl 14):80.

    Reichardt P, Von Minckwitz G, Thuss-Patience PC et al. Multicenter phase II study of oral capecitabine (Xeloda®) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol 2003;14:1227–1233.

    Bauer-Kosinka B, Glogowska I, Lemanska I et al. Capecitabine monotherapy in the treatment of patients with chemotherapy pre-treated metastatic breast cancer. Proc Am Soc Clin Oncol 2003;22:80.

    Hillian K, Koeppen H, Tobin P et al. The role of VEGF expression in response to bevacizumab plus capecitabine in metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 2003;22:191.

    Chu D, Li W. Capecitabine is effective and very well tolerated in Chinese patients with pretreated advanced or relapsed breast carcinoma. Proc Am Soc Clin Oncol 2003;22:60.

    Soto C, Reyes S, Delgadillo F et al. Capecitabine (X) plus docetaxel (T) versus capecitabine plus paclitaxel (P) versus sequential capecitabine then taxane in anthracycline-pretreated patients with metastatic breast cancer: early results. Proc Am Soc Clin Oncol 2003;22:8.

    Torrecillas L, Cortes P, Tokunaga C et al. Capecitabine monotherapy or combined with taxanes: early results in quality of life in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 2003;22:749.

    Venturini M, Bell R, Paridaens R et al. Capecitabine monotherapy is active, well tolerated and provides convenient outpatient therapy for patients with taxane-pretreated advanced breast cancer: findings from an expanded access program. Eur J Cancer Suppl 2003;1:S137.

    Bulusu V, Le Vay J, Hockney R et al. Oral capecitabine monotherapy in taxane and anthracycline pre-treated metastatic breast cancer (MBC): Suffolk Oncology Centre experience. Eur J Cancer Suppl 2003; 1:S140.

    Talbot DC, 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;86:1367–1372.

    Jakob A, Bokemeyer C, Knop S et al. Capecitabine in patients with breast cancer relapsing after high-dose chemotherapy plus autologous peripheral stem cell transplantation--a phase II study. Anticancer Drugs 2002;13:405–410.

    Semiglazov T, Gershanovich M, Semiglazov V. Oral capecitabine (Xeloda) in the treatment of anthracycline-refractory, anthracycline and docetaxel-refractory metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 2002;21:62b.

    Nadal J, Viniegara M, O’Connor J et al. Capecitabine is active as oral treatment for metastatic breast cancer (MBC): a single institutional experience. Ann Oncol 2004;13 (suppl 5):68.

    Blum JL, Dieras V, Lo Russo PM et al. Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 2001;92:1759–1768.

    Kusama M, Sano M, Ikeda T et al. A phase II study of Xeloda (capecitabine) in patients with advanced/metastatic breast carcinoma: the Cooperative Study Group of Capecitabine for Breast Carcinoma. Proc Am Soc Clin Oncol 2001;20:44b.

    Watanabe T, Katsumata N, Sasaki Y et al. A multicenter phase II trial of Xeloda (capecitabine) in patients with docetaxel-refractory advanced/metastatic breast cancer. Proc Am Soc Clin Oncol 2001;20:61b.

    Cervantes G, Torrecillas L, Erazo A et al. Capecitabine (XELODA) as treatment after failure to taxanes for metastatic breast cancer. Proc Am Soc Clin Oncol 2000;19:121a.

    Wong Z, Wong K, Chew L et al. Capecitabine as an oral chemotherapeutic agent in the treatment of refractory metastatic breast carcinoma (MBC). Proc Am Soc Clin Oncol 2000;19:120a.

    Blum JL, Jones SE, Buzdar AU et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999;17:485–493.

    Verma S, Clemons M, Dranitsaris G et al. Survival differences observed in anthracycline and taxane refractory metastatic breast cancer patients treated with capecitabine when compared with vinorelbine.

    Ross JS, Fletcher JA, Linette GP et al. The HER-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. The Oncologist 2003;8:307–325

    Largiller R, Etienne MC, Morlot P et al. Prospective analysis of dihydropyrimidine dehydrogenase (DPD) activity predicting capecitabine-related toxicities in metastatic breast cancer patients. Proc Am Soc Clin Oncol 2004;22:134.

    Sudaram S, Lancaster D, Silva J et al. Oral capecitabine is an active and well tolerated primary palliative treatment in patients with metastatic breast cancer who progress after high dose chemotherapy and autologous stem cell support. Proc Am Soc Clin Oncol 2000;19:58a.

    Segalla JGM, Oliveira CT, Lago S et al. Effect of capecitabine (X) on quality of life (QoL) in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol 2004;22(suppl 14):761s.

    Segalla G, Oliveira C, Lago S et al. Quality of Life (QoL) in patients with metastatic breast cancer (MBC) treated with capecitabine (Xeloda). Eur J Cancer Suppl 2003;1:S136.

    Beato CAM, Federico MH, Van Eyll B et al. Effects of capecitabine (X) on quality of life (QoL) in patients (pts) with metastatic colorectal cancer (MCRC). J Clin Oncol 2004;22(suppl 14):758s.

    Lago S. Quality of life (QoL) in patients with metastatic breast cancer (MBC) taking Xeloda (capecitabine). Proc Am Soc Clin Oncol 2003;22:745.

    Segalla J, Oliveira C, Cabral S et al. Capecitabine (X) improves quality of life (QoL) in patients (pts) with metastatic breast cancer (MBC).

    Segalla JM, Oliveira CT, Lago S et al. Quality of life (QoL) improvements in patients (pts) with metastatic breast cancer (MBC) treated with capecitabine (X). Ann Oncol 2004;15(suppl 3):170.

    Baran R, Dupere W, Susan M et al. Clinical and economic outcomes associated with metastatic breast cancer in managed care populations: capecitabine (Xeloda) versus comparison therapies. Proc Am Soc Clin Oncol 2002;21:33b.

    Kimishima I, Tominaga T, Hiroki K et al. Randomized controlled trial comparing oral doxifluridine (an intermediate metabolite of capecitabine) plus oral cyclophosphamide with doxifluridine in node positive breast cancer patients after curative resection. Proc Am Soc Clin Oncol 2002;21:47a.

    Xu B, Tian L, Wu Q et al. Capecitabine (X) combined with vinorelbine (V) in Chinese patients (pts) with metastatic breast cancer (MBC). J Clin Oncol 2004;22(suppl 14):62s.

    Clemons MJ, Verma S, Leung V et al. Palliative chemotherapy with vinorelbine or capecitabine in women with anthracycline and taxane refractory metastatic breast cancer. J Clin Oncol 2004;22(suppl 14):70s.

    Estevez LG, Batista N, Sanchez-Rovira P et al. Phase II study with the combination of capecitabine (C) and vinorelbine (V) in metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. J Clin Oncol 2004;22(suppl 14):63s.

    Gligorv J, Beerblock K, Selle F et al. Capecitabine and oral vinorelbine in metastatic breast cancer: preliminary experience. Proc Am Soc Clin Oncol 2003;22:88.

    Ghosn M, Chahine G., Kattan J et al. Phase II study of sequential administration of vinorelbine: capecitabine combination followed by weekly docetaxel as first line chemotherapy for advanced breast cancer. J Clin Oncol 2004;22 (14S):80s.

    Ahn JH, Kim SB, Kim TW et al. Capecitabine and vinorelbine in patients with metastatic breast cancer previously treated with anthracycline and taxane. J Korean Med Sci 2004;19:547–553.

    Stuart N, Bishop JL, Johnson SRD et al. Vinorelbine and capecitabine (VX) for advanced breast cancer: a phase II study showing good activity and potential for further development. Proc Am Soc Clin Oncol 2003;22:46.

    Llorca C, Mayordomo E, Ardrover I et al. Activity and safety of biweekly docetaxel plus capecitabine as first-line treatment for patients with metastatic breast cancer. J Clin Oncol 2004;22(suppl 14):73s.

    Chun JH, Lee HG, Lee ES et al. Frontline docetaxel (T)/capecitabine (X) combination therapy in patients (pts) with metastatic breast cancer (MBC): a phase II study. J Clin Oncol 2004;22(suppl 14):71s.

    Bellet M, Muñoz M, Pelegri A et al. Phase II study of capecitabine (C) in combination with docetaxel (D) as neoadjuvant treatment in patients with locally advanced breast cancer (IIIA and IIIB stage). J Clin Oncol 2004;22(suppl 14):64s.

    Soto C, Reyes S, Delgadillo F et al. Capecitabine (X) plus docetaxel (T) vs capecitabine plus paclitaxel (P) vs sequential capecitabine then taxane in anthracycline pretreated patients (pts) with metastatic breast cancer: early results. Proc Am Soc Clin Oncol 2003;22:8.

    Malfair-Taylor S, Verma S, Barnett J et al. Cost-effective analysis of capecitabine and docetaxel (DC) versus taxanes alone in the treatment of anthracycline resistant metastatic breast cancer (MBC): perspectives from two Canadian provinces. Proc Am Soc Clin Oncol 2003;22:558.

    Mackey JR, Tonkin K, Scarfe AG et al. Final results of a phase II clinical trial of weekly docetaxel (T) in combination with capecitabine (X) in anthracycline pre-treated metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 2003;22:42.

    Ramaswamy B, Rhoades CA, Kendra KL et al. Phase II trial of weekly docetaxel (D) and prolonged capecitabine (C) in metastatic breast cancer (MBC) patients (pts). Proc Am Soc Clin Oncol 2003;22:59.

    Andres R, Mayordomo J, Isla D et al. Capecitabine plus gemcitabine is an active combination for patients with metastatic breast cancer refractory to anthracyclines and taxanes. Proc Am Soc Clin Oncol 2003;22:89.

    Manga G, Lopez-Criado P, Mendez M et al. Gemcitabine (G) plus capecitabine (C) in previously treated metastatic breast cancer (MBC) patients: results from a phase II GOTI trial. Proc Am Soc Clin Oncol 2003;22:66.

    Venturini M, Catzeddu T, Del Mastro L et al. Erlotinib given sequentially to capecitabine and vinorelbine as first-second line chemotherapy in metastatic breast cancer patients: a dose finding study. J Clin Oncol 2004;22(suppl 14):84s.

    Gebbia N, Fulfaro F, Badalamenti G et al. A phase 2 study of oxaliplatin (O) – capecitabine (C) chemotherapy in metastatic breast cancer (MBC) patients pretreated with anthracyclines and taxanes. J Clin Oncol 2004;22(suppl 14):53s.

    Biganzoli L, Aapro M. Elderly breast cancer patients: adjuvant chemotherapy and adjuvant endocrine therapy. Gynakol Geburtshilfliche Rundsch. 2005;45:137–42.

    Yamamoto T, Iwase S, Kitamura K et al. Multicenter phase II study of trastuzumab (H) and capecitabine (X) as first- or second-line treatment in HER2 over-expressing metastatic breast cancer (Japan Breast Cancer Study Group: JBCSG-003). J Clin Oncol, 2005;23:78s.

    Schaller G, Bangemann N, Weber J et al. Efficacy and safety of trastuzumab plus capecitabine in a German multicentre phase II study of pre-treated metastatic breast cancer. J Clin Oncol 2005;23:57s.(William B. Ershler)