Docetaxel/Capecitabine Bests Single-Agent Docetaxel in Metastatic Breast Cancer

ORLANDO—Adding capecitabine (Xeloda) to docetaxel (Taxotere) (XT) significantly improves response rates, time to progression, and overall survival, compared with docetaxel alone in patients with metastatic breast cancer, according to results of a phase III study of the combination.

Lead investigator Joyce O’Shaughnessy, MD, co-director of breast cancer research at Baylor-Sammons Cancer Center and US Oncology, Dallas, updated the results of the trial at an industry-sponsored symposium held in conjunction with the 38th Annual Meeting of the American Society of Clinical Oncology. The study findings were recently published in the Journal of Clinical Oncology (20:2812-2823, 2002).

"The capecitabine/docetaxel combination is the first cytotoxic combination that has been shown to have a survival advantage over single-agent docetaxel," Dr. O’Shaughnessy commented. "Both drugs are very active single agents, and I would argue that they are two of the very few cytotoxic agents we have that can impact the natural history of metastatic breast cancer."

Distinct Mechanisms

Dr. O’Shaughnessy noted that the two agents have distinct mechanisms of action and limited overlap of toxicities. Moreover, taxanes further upregulate thymidine phosphorylase—and thus promote the tumor-selective accumulation of fluorouracil (5-FU)—and capecitabine/taxane combinations have shown clear synergistic activity in preclinical studies.

Study Protocol

In the phase III trial of the capecitabine/docetaxel combination, 511 anthracycline-pretreated women with measurable metastatic breast cancer were randomized to receive either full-dose docetaxel (100 mg/m² on day 1) or 75 mg/m² of docetaxel on day 1 and full-dose capecitabine (1,250 mg/m² bid on days 1 to 14, with 7 days off).

Patients who responded or had stable disease at the end of two 21-day cycles were kept on the regimen until disease progression or the development of unacceptable toxicity. The primary endpoint of the study was time to disease progression or death.

The response rate achieved with the capecitabine/docetaxel combination was significantly better than that obtained with single-agent docetaxel—42% vs 30%, respectively. Time to progression also was significantly improved with the combination—6.1 months vs 4.2 months, a 35% risk reduction.

Survival Data

Survival data showed that 57% of the women taking docetaxel plus capecitabine were alive at 1 year, compared with 47% of the women taking docetaxel alone. Median survival was 14.5 months with the combination vs 11.5 months for docetaxel alone, a 23% reduced risk of death.

The survival benefit of the combination treatment was not affected by whether it was given as first, second-, or third-line therapy.

Dr. O’Shaughnessy noted that the survival curves split very early, with deaths in the docetaxel-only group beginning to be seen at about the 2-month mark. These early deaths on the single-agent treatment suggest that while single-agent, sequential therapy with docetaxel followed by capecitabine—or capecitabine followed by docetaxel—may be reasonable for some women, not all women will benefit from a crossover (see related story on page 20).

Toxicity

As might be expected, the docetaxel/capecitabine combination was more toxic than single-agent docetaxel. Patients on the combination treatment had substantially more stomatitis, diarrhea, and hand-foot syndrome. Neutropenic fever was slightly more common among patients taking docetaxel alone.

The percentage of patients hospitalized for treatment-related adverse events was similar: 29% for patients on the combination vs 26% for those on single-agent docetaxel.

Twenty-five percent of patients taking the combination withdrew from the study because of treatment-related adverse events vs 18% of the patients on docetaxel alone.

Patients taking docetaxel plus capecitabine had a slightly higher treatment-related death rate—1.6% vs 0.4% for docetaxel alone. But patients on the combination fared somewhat better in terms of 60-day, all-cause mortality—2.0% vs 3.5% for those on docetaxel alone. The researchers found little difference between the two groups in terms of the number of grade 3-4 toxicities that occurred over time.

An analysis of the impact of dose reduction on patient outcome suggests that the survival benefits of the capecitabine/docetaxel regimen are maintained at lower doses (see figure below).

Dr. O’Shaughnessy reported that 47% of patients on the combination therapy required a 25% dose reduction in both capecitabine and docetaxel at some point during treatment. An additional 17% required a second 25% dose reduction.

Most patients received full-dose docetaxel until cycle 4. In contrast, most initial capecitabine dose reductions occurred by cycle 2.

"This tells us that the survival advantage that we see with the capecitabine/docetaxel combination was, in fact, achieved with a delivered dose intensity of 75% of the starting dose for the vast majority of the trial," Dr. O’Shaughnessy said. "That’s 950
mg/m² twice daily instead of 1,250 mg/m²."

The 25% dose reductions cut the incidence of grade 3-4 toxicities in half. An additional 25% dose reduction had only a modest effect on hand-foot syndrome, the primary grade 3 toxicity.

Capecitabine After Docetaxel Monotherapy

In further analyses, the researchers evaluated the survival impact of poststudy chemotherapy after docetaxel alone. They looked at 164 patients who had received docetaxel monotherapy and then received single-agent therapy with one of the following: capecitabine, 5-FU, vinorelbine (Navelbine), an anthracycline, trastuzu-mab (Herceptin), paclitaxel (Taxol), and docetaxel.

In a comparison of capecitabine after docetaxel monotherapy vs "anything but capecitabine" (most of which was either vinorelbine or 5-FU), the hazard ratio for death was 0.5 among the capecitabine-treated patients. Overall survival duration was 21 months in the capecitabine group, compared with 12.3 months among patients receiving other agents.

A similar comparison of vinorelbine vs "anything but vinorelbine, excluding capecitabine" found no survival advantage for vinorelbine.

"This is really an exploratory analysis, but what this says to me is that capecitabine is one of those drugs that influences the natural history of metastatic breast cancer, and we really have only a few of those," she said. "And it does suggest to me that giving docetaxel sequentially with capecitabine is a very reasonable treatment approach for some patients."

Overall, she added, the phase III study found that docetaxel plus capecitabine is associated with superior response rates, a longer time to progression, and a median survival improvement of 3 months. Moreover, these improvements can be achieved with a manageable safety profile with appropriate dose reductions.

One question is left to answer, she said: "Is the survival benefit mainly due to the fact that capecitabine is a very important drug and that no matter where you get it in the course of your metastatic breast cancer, it’s going to have an impact on survival? Or—and/or—is it due to the fact that this is a synergistic treatment combination that will yield superior survival, compared to sequential single agents?"