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(Drug information on 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 absorption.
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(Drug information 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 response.
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(Drug information on doxorubicin). In addition, 67% of patients had received prior tamoxifen(Drug information on 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(Drug information on 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 uncommon.
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.