Significant advances in the management of metastatic breast
cancer have been made over the last decade. Not only have new chemotherapy,
endocrine therapies, and biologic therapies provided patients with better
treatment options, but supportive measures, such as hematopoietic growth factors
and more effective antiemetics, have also made treatment more tolerable.
Though metastatic breast cancer remains a disease that is not
curable with currently available therapies, one avenue of clinical research has
focused on the development of drugs that have effective antitumor activity and
the potential for greater patient convenience and acceptance. One such
example is the development of capecitabine (Xeloda), an oral fluoropyrimidine,
that has been approved by the FDA and is commercially available for the
treatment of metastatic breast cancer.
5-fluorouracil (5-FU) has been an integral component of
cytotoxic chemotherapy regimens for breast cancer in both the adjuvant and
advanced-disease setting for several decades. Infusional 5-FU offers
antitumor activity in some patients with metastatic disease who have been
heavily pretreated (response rates of approximately 20%).[3,4] One of the
constraints associated with 5-FU is schedule dependency and poor oral
As discussed by others in this supplement, strategies have been
developed to enhance the absorption of 5-FU by using a prodrug or by inhibiting
the degradation of 5-FU in the gastrointestinal tract. Capecitabine was
developed as an oral drug that would simulate the effect of infusional 5-FU, and
at the same time have greater tumor selectivity. The latter property exploits
the observation that many tumors have higher levels of thymidine synthase (TS)
compared to normal tissues.
Capecitabine is an oral precursor of 5´-deoxy-5-fluorouridine
(5´-DFUR) that is absorbed intact through the intestinal mucosa.[7,8]
Capecitabine is not affected by the TS present in the intestinal mucosa, and as
a result, less diarrhea is reported compared to that associated with 5-FU.
Capecitabine is then metabolized in the liver by carboxylesterase to
5´-deoxy-5-fluorocytidine (5´-DFCR). 5´-DFCR is converted to 5´-DFUR by
cytidine deaminase, an enzyme located primarily in the liver and tumor
tissue. 5´-DFUR is then converted to 5-FU by TS in the tumor cells.
The net effect of this multistep metabolic process is higher
concentrations of 5-FU in tumor tissue compared to adjacent normal tissue.[6,10]
This has been confirmed in animal models and in human colorectal liver
metastases.[8,11] Capecitabine produces plasma concentrations comparable to
continuous-infusion 5-FU administered at 300 mg/m2/day.
The pivotal trial of capecitabine was conducted in patients with
metastatic breast cancer who had disease progression on paclitaxel (Taxol).
For the majority of patients participating in the trial, capecitabine
represented the third or fourth treatment for metastatic disease. The primary
objective of this study was to determine the overall objective response rate to
capecitabine. Secondary objectives were to determine the duration of response,
time-to-disease progression, survival, toxicity, and clinical benefit
Capecitabine was administered at a dose of 2,510 mg/m2/day in
two divided doses. A 21-day treatment cycle consisted of 14 consecutive days
of capecitabine, followed by 7 days without treatment. The dosing schedule used
in this trial was determined from the results of a phase I, dose-escalated trial
of capecitabine. Dose adjustments were based on grade 2 or 3 toxicities. A
total of 162 patients were recruited to participate in this trial from 25
centers in the United States and Canada. The median age of patients was 55.8
years and the median Karnofsky score was 86%. Of the 162 patients, 135 had
measurable disease (83%), and 27 of the 162 patients had only evaluable disease
(17%). The median time from diagnosis of breast cancer to recurrence was 917
days, and to enter into the study was 1,276 days.
The patient population of this trial was typical of those with
metastatic disease. The majority of patients had multiorgan metastases, with 43%
reporting liver metastases. All patients had prior treatment with paclitaxel,
and 84% had received doxorubicin. In addition, 67% of patients had received
prior tamoxifen (Nolvadex) therapy. Patients were categorized based on their
response to prior paclitaxel therapy: disease progression while receiving
paclitaxel (primary resistance) and disease progression within 1 to 12 months of
completing paclitaxel therapy (failure).
The overall objective response rate with capecitabine in this
trial was 20% (complete response rate, 2%; partial response rate, 18%). An
additional 40% of patients maintained a status of stable disease. There was
little difference in overall response rate with capecitabine therapy, whether it
was administered as third- or fourth-line therapy (third-line, 18%; fourth-line,
20%). Of the 27 patients with measurable disease who responded to capecitabine,
all were primarily refractory to paclitaxel, all had received prior doxorubicin
therapy, and 67% had been treated with 5-FU. Even of the 43 patients who were
resistant to both treatment with an anthracycline and paclitaxel, the response
rate was a respectable 25%. The median duration of response was 241 days and
the median survival was 384 days.
Clinical benefit response was assessed in three categories: pain
score, analgesic consumption, and Karnofsky performance status. Each of
these parameters was objectively assessed at baseline and then throughout the
trial. It was required that a response be sustained for 4 weeks in order to be
scored as a response. In the analysis of clinical benefit response, 20% of
patients showed improvement in each of the parameters, and an additional 31% of
patients remained stable. For those patients showing an improvement,
clinical benefit responses lasted more than 18 weeks.
Treatment with capecitabine was generally well tolerated in this
heavily pretreated group of patients with metastatic breast cancer. Grade 3 or 4
toxicities are listed in Table 1. Diarrhea and palmar-plantar erythrodysesthesia
(PPE) were the most common side effects, occurring in 15% and 11% of patients,
respectively. Only 3% of patients experienced grade 4 toxicity, and 7% of
patients withdrew from the study due to treatment-related events.
Other Phase II Trials
A second multicenter, single-arm, phase II study of
capecitabine, using the same dose and schedule, in a similar taxane-refractory
population of 75 patients with metastatic breast cancer confirmed the efficacy
and safety of capecitabine. The response rate was 24% (confidence interval
[CI]: 14%-35%). Docetaxel (Taxotere)-refractory patients achieved a response
rate to capecitabine similar to the paclitaxel-refractory patients. Response
duration, time-to-disease progression, and survival were similar to those
reported in the previous study. Diarrhea (18%), PPE (18%), and nausea (11%) were
the only treatment-related adverse events that occurred at a grade 3 or 4
intensity of > 10%. Alopecia did not occur and myelosuppression was
A smaller randomized phase II trial evaluated the efficacy of
capecitabine at the same dose regimen (2,510 mg/m2/day) in patients pretreated
with an anthracycline, using paclitaxel at a dose of 175 mg/m2 every 3 weeks, as
the reference arm. In this trial, which was terminated early due to
recruitment difficulties, 8 patients showed objective responses for an overall
response rate of 36% (CI: 17%-59%) among 22 patients treated with capecitabine,
with a median response duration of 9.4 months and time-to-disease progression of
3 months. There was a 23% incidence of grade 3 and 4 toxicities.
Results from these clinical trials confirmed the activity of
capecitabine in heavily pretreated patients with metastatic breast cancer and
led to the FDA approval of capecitabine as treatment for paclitaxel-resistant,
metastatic breast cancer. The registered dose is 2,510 mg/m2 administered in two
divided doses for 14 days every 21 days.
1. Liu G, Franssen E, Fitch MI, et al: Patient preferences for
oral versus intravenous palliative chemotherapy. J Clin Oncol 15:110-115, 1997.
2. Heidelberger C, Chaudhari N, Danneberg P, et al: Fluorinated
pyrimidines: A new class of tumor-inhibitory compounds. Nature 179:663-666,
3. Cameron D, Gabra H, Leonard R: Continuous 5-fluorouracil in
the treatment of breast cancer. Br J Cancer 70:120-124, 1994.
4. Chu L, Sutton L, Peterson B, et al: Continuous-infusion
5-fluorouracil as first-line therapy for metastatic breast cancer. J Infus
Chemother 6:211-216, 1996.
5. Christophidis N, Vajda F, Lucas I, et al: Fluorouracil
therapy in patients with carcinoma of the large bowel: A pharmacokinetic
comparison of various rates and routes of administration. Clin Pharmacokinet
6. Yoshimura A, Kuwazuru Y, Furukawa T, et al: Purification and
tissue distribution of human thymidine phosphorylase; high expression in
lymphocytes, reticulocytes and tumors. Biochim Biophys Acta 1034:107-113, 1990.
7. Budman DR, Meropol NJ, Reigner B, et al: Preliminary studies
of a novel oral fluoropyrimidine carbamate: Capecitabine. J Clin Oncol
8. Ishiwaka T, Sawada N, Sekiguchi N, et al: Xeloda
(capecitabine), a new oral flouropyrimidine carbamate with an improved efficacy
profile over other flouropyrimidines (abstract). Proc Am Soc Clin Oncol 16:226a,
9. 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 34:1274-1281, 1998.
10. Leyva A, Kraal I, Lankelma J, et al: High uridine
phosphorylase activity in human melanoma tumor. Anticancer Res 3:227-231, 1983.
11. Cao S, Lu K, Ishitsuka H, et al: Antitumor efficacy of
capecitabine against fluorouracil-sensitive and -resistant tumors (abstract).
Proc Am Soc Clin Oncol 16:795a, 1997.
12. Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II
study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin
Oncol 17:485-493, 1999.
13. Twelves J, Budman D, Creaven P, et al: Pharmacokinetics and
pharmacodynamics of capecitabine in two phase I studies (abstract). Proc Am Soc
Clin Oncol 15:496a, 1996.
14. Blum J, Buzdar A, Dieras V, et al: A multicenter phase II
trial of Xeloda (capecitabine) in taxane-refractory metastatic breast cancer
(abstract). Proc Am Soc Clin Oncol 18:403a, 1999.
15. O’Reilly S, Moiseyenko V, Talbot D, et al: A randomized
phase II study of Xeloda (capecitabine) vs paclitaxel in breast cancer patients
failing previous anthracycline therapy (abstract). Proc Am Soc Clin Oncol
16. O’Shaughnessy J, Moiseyenko V, Bell D, et al: A randomized
phase II study of Xeloda (capecitabine) vs CMF as first-line chemotherapy of
breast cancer in women aged greater than 55 years (abstract). Proc Am Soc Clin
Oncol 17:398a, 1998.
17. O’Shaughnessy J, Blum J: A retrospective evaluation of the
impact of dose reduction in patients treated with Xeloda (capecitabine)
(abstract). Proc Am Soc Clin Oncol 19:400a, 2000.
18. Michaud L, Gauthier M, Wojdylo J, et al: Improved
therapeutic index with lower dose capecitabine in metastatic breast cancer
patients (abstract). Proc Am Soc Clin Oncol 19:402a, 2000.
19. Khoury P, Villalona-Calero M, Blum J, et al: Phase I study
of capecitabine in combination with paclitaxel in patients with previously
treated metastatic breast cancer (abstract). Proc Am Soc Clin Oncol 17:793a,