Oral Capecitabine in Taxol-Refractory Breast Cancer

LOS ANGELES--For patients with refractory metastatic breast cancer, ideal therapy would offer palliation with ease of administration and limited side effects. The new agent capecitabine (Xeloda) can be taken orally at home, making it unique among currently available salvage regimens for metastatic breast cancer, Joanne L. Blum, MD, PhD, of Texas Oncology, Dallas, said at the 34th Annual Meeting of the American Society of Clinical Oncology (ASCO).

She reported the results of an open-label phase II trial of capecitabine in heavily pretreated patients. "For patients with metastatic breast cancers refractory to anthracyclines and taxanes, effective treatments without severe side effects are limited," she said. "The ideal agent would offer a reasonable chance for response without a substantial risk of prohibitive toxicities."

Capecitabine is a novel, selectively tumor-activated fluoropyrimidine carbamate. It is an oral prodrug of 5-flourouracil (5-FU) that is first metabolized in the liver, limiting systemic exposure to 5-FU (see box). With capecitabine, concentrations of 5-FU in tumor have been shown to be much higher than in plasma.

Capecitabine Maximizes Tumor Exposure to 5-FU

After oral administration and gastrointestinal absorption, capecit-abine (Xeloda) is first metabolized in the liver to 5-fluoro-5´-deoxycytidine, Dr. Joanne Blum said at ASCO. The 5-fluoro-5´-deoxycytidine is then converted to 5-fluoro-5´-deoxyuridine by cytidine deaminase, principally located in hepatic and neoplastic tissue. The 5-fluoro-5´-deoxyuridine is then metabolized to 5-fluorouracil (5-FU) by the tumor-associated angiogenic factor thymidine phosphorylase, thus minimizing systemic exposure to 5-FU.

"Pharmacokinetic studies have shown that intratumoral concentrations of 5-FU are higher than plasma levels," Dr. Blum said. "This tumor-selective generation of 5-FU with low systemic exposure is hypothesized to improve the therapeutic ratio for capecitabine."

The trial, conducted at 25 centers in the United States and Canada, enrolled 162 patients who had progressed after receiving two or three prior chemotherapy regimens, one of which had to include paclitaxel (Taxol). Most patients (84%) had received prior doxorubicin; other prior treatments included cyclophosphamide, 5-FU, methotrexate, and vinorel-bine (Navelbine).

Sixty-two of the women were pre-menopausal and 100 were postmenopausal. The median time from initial diagnosis to recurrence was 2.5 years.

Capecitabine was given twice daily, to a total dose of 2,510 mg/m²/day, in 3-week cycles (2 weeks on the drug followed by a 1-week rest period).

Responses were seen in 27 (20%) of the 135 patients with measurable disease (3 complete and 24 partial responses) and occurred in visceral, soft tissue, and breast involvement sites. Disease remained stable in 54 patients (40%). "Therefore, 60% had responses or remained stable," Dr. Blum said. She noted that 46 of these patients (34%) had progressive disease within the first 6 weeks of capecitabine treatment (8 patients had missing or incomplete data).

Of the 27 patients with clinically evaluable disease, 5 (19%) had a tumor response; 12 (44%) were stable; and 10 (37%) progressed on capecitabine.

Overall, the median duration of response was 241 days and median survival was 384 days. "So, in summary," Dr. Blum said, "a strong response was seen in a heavily pretreated patient population with an excellent duration of response and long survivals." In addition, she said, 47% of symptomatic patients had a significant pain response with capecitabine.

In general, adverse events were easily managed with dose reductions, she said. Diarrhea, hand-foot syndrome, and stomatitis were the most common treatment-related adverse events. Grade 4 adverse events occurred in 4% of patients, and 7% withdrew due to treatment-related events; 10% required hospitalization, primarily for dehydration secondary to diarrhea. No alopecia or significant myelosuppression was reported, and there were no treatment-related deaths.

"Capecitabine offers treatment without patients’ having to endure venipunc-ture, IV infusion, and long intervals in the chemotherapy infusion suite or long-duration infusional therapy via indwelling catheters and pumps," Dr. Blum said. "Patients have expressed a striking 9 to 1 preference for oral palliative therapy."

Discussant William Gradishar, MD, Northwestern University, said that "the duration of survival in this heavily pretreated patient population was quite good at 1 year. Most important, palliation was achieved; about 50% of patients had better pain control on capecitabine."