Capecitabine and Docetaxel in Advanced Breast Cancer: Analyses of a Phase III Comparative Trial

ABSTRACT: A recent phase III trial demonstrated that the combination ofcapecitabine (Xeloda) and docetaxel (Taxotere) significantly improved objectivetumor response rate, time to disease progression, and overall survival comparedwith single-agent docetaxel in anthracycline pretreated patients with advanced breast cancer. Early separation of survivalcurves suggests that combined treatment prevented early mortality seen withsingle-agent docetaxel and, thus, that the capecitabine/docetaxel combinationmay be more beneficial than sequential treatment in some patients in thissetting. Dose reduction of the combination (eg, to capecitabine at 950 mg/m²)did not reduce effectiveness of treatment and was associated with reducedtoxicity; study of the combination in the adjuvant setting has been initiatedwith a lower capecitabine starting dose. Poststudy treatment with capecitabine in patients in the docetaxel-alone group was associated with significantlyimproved survival compared with poststudy treatment with all other cytotoxicagents, suggesting that some patients may benefit from sequential therapy withdocetaxel and capecitabine. No difference in reduction of risk for death wasseen according to whether combined treatment was given as first-, second-, orthird-line therapy. The capecitabine/docetaxel combination appears to influencethe natural history of metastatic breast cancer in a significant manner; itremains to be determined whether the benefits of the combination reflectadditive or synergistic effects and whether greater benefit may be derived fromsequential or combined treatment in overall populations or patient subgroups.[ONCOLOGY 16(Suppl 12):17-22, 2002]

A recent phase III trial demonstrated that the combination of capecitabine (Xeloda) and docetaxel (Taxotere) significantly improves response rate, time to disease progression, and overall survival compared with single-agent docetaxel in patients with anthracycline pretreated metastatic breast cancer.[1] This trial marks the first report of a significant improvement in survival with a cytotoxic combination over docetaxel alone in this setting. Analyses of data from the trial suggest that whereas some types of toxicity were increased with the capecitabine/docetaxel combination, a reduced capecitabine dose may be as effective as the starting dose in this trial and may be associated with reduced toxicity. Additional analyses indicate that effectiveness of the combination in this trial was independent of whether treatment was given as first-line or subsequent therapy, and that survival was positively affected in study patients if poststudy chemotherapy consisted of capecitabine vs other cytotoxic agents.

Response, Time to Disease Progression, and Overall Survival

In a phase III trial, patients with histologically or cytologically confirmed breast cancer who had unresectable locally advanced or metastatic disease and recurrent disease after anthracycline treatment were randomized to 21-day cycles of capecitabine at 1,250 mg/m² twice daily on days 1 to 14 plus docetaxel at 75 mg/m² on day 1 (n = 255), or to docetaxel at 100 mg/m² on day 1 (n = 256).[1] Patients exhibiting tumor response or stable disease after 6 weeks of treatment continued treatment until disease progression or unacceptable toxicity occurred. The primary study end point was time to disease progression or death. Capecitabine/docetaxel treatment was associated with a significantly greater objective tumor response rate of 42% (95% confidence interval [CI] = 36%-48%) vs 30% (95% CI = 24%-36%) (P = .006). Combined treatment significantly reduced risk of disease progression, with a hazard ratio of 0.652 (95% CI = 0.545-0.780, P = .0001); median time to disease progression in the capecitabine/docetaxel group vs the docetaxel group was 6.1 vs 4.2 months (Figure 1A). Capecitabine/docetaxel treatment also significantly improved overall survival, with a hazard ratio for death of 0.775 (95% CI = 0.634-0.947, P = .0126); median survival durations were 14.5 months in the combination group and 11.5 months in the single-agent docetaxel group (Figure 1B). One-year survival was 57% with combination treatment and 47% with docetaxel alone.

It is of interest that the survival curves for the two study groups show early separation (Figure 1B). One potential implication of this finding is that concurrent treatment with the two agents provided benefit in the form of prevention of early mortality on docetaxel treatment that may not have been realized with sequential treatment with docetaxel followed by capecitabine; the finding thus suggests that there is at least a subset of patients who may derive preferential benefit from treatment with the doublet compared with sequential therapy.

Toxicity of Capecitabine/Docetaxel vs Docetaxel

Treatment-related adverse events occurred in 98% of patients receiving capecitabine/docetaxel and in 94% of those receiving docetaxel alone. Grade 3 treatment-related adverse events were more common (71% vs 49%) and grade 4 treatment-related adverse events were less common (25% vs 31%) with combination treatment. The most common grade 3 or 4 treatment-related adverse events are shown in Table 1.[1] Hand-foot syndrome, stomatitis, and gastrointestinal complaints were more common in the combination group, with the frequency of hand-foot syndrome (24% vs 1%) accounting for the difference between treatment groups with regard to rate of grade 3 toxicity. Neutropenic fever was more common in the docetaxel group.

Analysis of grade 3 or 4 adverse events over time shows little difference between combination and docetaxel groups during the first cycle of treatment; the difference in the second cycle (36% vs 19%) was primarily due to an increase in hand-foot syndrome frequency from 2% in the fist 3 weeks to 13% in the second cycle in the combination group. There were minor differences between the combination and docetaxel groups with regard to hospitalization for treatment-related adverse events (28% vs 26%), withdrawals due to treatment-related adverse events (26% vs 20%), treatment-related deaths (1.2% vs 0.4%), and death from any cause during the first 60 days of treatment (2.0% vs 3.5%).

Dose of Capecitabine/Docetaxel

An issue to be considered based on findings in the trial is whether the starting dose of capecitabine/docetaxel was appropriate. Dose reductions of 25% from the initial dose occurred for 34% of patients in the single-agent docetaxel group; for patients in the combination group, 25% dose reductions for capecitabine alone occurred in 3% of patients, for docetaxel alone in 12% of patients, and for both in 47% of patients. A further 25% dose reduction was made in 7% of patients in the docetaxel group and for capecitabine alone in 17% of patients, docetaxel alone in 2% of patients, and both in 2% of patients in the combination group. Overall, dose reductions were required in 65% of the combination group (4% capecitabine alone, 10% docetaxel alone, and 51% both drugs) and in 36% of the docetaxel group.

The received vs planned dose profile over time in the treatment groups is shown in Figure 2. This profile indicates that the majority of dose reductions for docetaxel in the combination group occurred at the fourth cycle of treatment and the majority of dose reductions for capecitabine occurred at the second cycle, with the capecitabine dose intensity being 75% or less of the planned dose for most of the study duration. In the combination group, overall median delivered doses were 77% of the planned dose for capecitabine and 87% for docetaxel. The median delivered dose in the docetaxel group was 100%.

The capecitabine dose reductions did not affect efficacy of combination treatment. The hazard ratio for disease progression or death for patients with vs without capecitabine dose reduction was 0.84 (P = .4253), representing a nonsignificant 16% decrease in risk among those with a dose reduction. Time to disease progression and overall survival among combination patients receiving the second cycle of treatment at full capecitabine dose or reduced capecitabine dose compared with the docetaxel group are shown in Figure 3. Median times to disease progression were 6.1 months in combination patients without capecitabine dose reduction at the second cycle and 6.5 months in those with dose reduction; median survival durations were 13.1 and 14.5 months, respectively. The hazard ratio for disease progression or death for dose reduction vs no dose reduction in the single-agent docetaxel group was 0.99 (P = .9520).

Based on these analyses, US Oncology is planning to evaluate the capecitabine/docetaxel combination in the adjuvant setting using a reduced capecitabine dose-ie, a dose reflecting the majority of exposure to the drug in the current trial. In this trial, patients are to receive standard doxorubicin/cyclophosphamide (Cytoxan, Neosar) at 60 mg/m² and 600 mg/m², respectively, followed by either docetaxel at 100 mg/m² on day 1 every 3 weeks or capecitabine at 950 mg/m² bid on days 1 to 14 plus docetaxel at 75 mg/m² on day 1 every 3 weeks.

It is noteworthy that dose reduction of the capecitabine was accompanied by reduced toxicity (Table 2). The proportions of cycles during which grade 3 and 4 toxicity occurred were reduced by approximately half with a 25% dose reduction, and the proportion of cycles during which no toxicity occurred was approximately doubled.

Effect of Poststudy Chemotherapy on Survival

In total, 180 patients in the capecitabine/docetaxel group and 164 patients in the docetaxel group received additional chemotherapy after completion of the study (Table 3), with more patients in both groups receiving vinorelbine (Navelbine) than any other single cytotoxic agent. An exploratory analysis of risk for death among patients in the docetaxel group who subsequently received capecitabine vs all other agents shows that capecitabine treatment was associated with a significant 50% reduction in risk (hazard ratio = 0.5, P = .0046), with median overall survival being 21.0 months in those receiving capecitabine and 12.3 months in those receiving all other agents.[2] By comparison, there was no impact on survival for vinorelbine use vs all other agents excluding capecitabine (hazard ratio 1.0, P = .94), with median survival being 13.5 months in patients receiving vinorelbine and 12.5 months in those receiving all other agents except capecitabine.

These data, together with the findings on the benefits of combined study treatment, suggest that capecitabine is capable of altering the natural history of metastatic breast cancer in a significant manner, a characteristic of relatively few cytotoxic agents. They also thus suggest that sequential treatment with docetaxel and capecitabine is a reasonable approach in some subset of patients.

Effect of Setting of Study Therapy on Survival Benefit

In total, 35% of the combination group and 31% of the docetaxel group received study therapy as first-line treatment for metastatic disease and 65% and 68%, respectively, received it as second- or third-line treatment (two patients received it as fourth-line treatment). The reduction in risk for death conferred by combination treatment vs single-agent docetaxel (overall, hazard ratio of 0.775) did not differ appreciably according to treatment setting, with the hazard ratios for death in the combination group being 0.774 among patients receiving study therapy as first-line treatment, 0.769 for those receiving it as second-line treatment, and 0.746 for those receiving it as third-line treatment.

Conclusion

A pivotal phase III trial comparing capecitabine/docetaxel with docetaxel in anthracycline-pretreated patients with metastatic breast cancer showed significant improvements in response rate, time to disease progression, and overall survival with combination therapy. Capecitabine/docetaxel is the first cytotoxic combination to significantly improve survival over docetaxel alone in this setting. Data from the trial indicate that a lower starting dose of capecitabine (950 mg/m²) may maintain advantages of combined treatment in terms of reducing risk for disease progression and death while reducing toxicity. It is known that taxanes increase upregulation of thymidine phosphorylase, the key activating enzyme for capecitabine, and synergy in vivo has been demonstrated for capecitabine/taxane combinations.[3] It remains an issue whether the survival benefit observed with capecitabine/docetaxel is due mainly to additive effects of capecitabine or synergistic effects of the combination.

The early separation of survival curves in this study indicates that the combination prevented early mortality in a subset of patients treated with single-agent docetaxel, suggesting the potential for combined therapy to prevent deaths that might occur with sequential treatment with docetaxel and capecitabine. The reduction in risk for death in single-agent docetaxel patients receiving poststudy capecitabine suggests benefits of sequential therapy. It thus remains to be determined whether combined therapy is superior to sequential therapy in this setting or whether particular subgroups of patients may derive greater benefit from one approach or the other.

References:

1.O’Shaughnessy J, Miles D, Vukelja S, et al: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 20:2812-2823, 2002.

2. Miles D, Ayoub J-PM, O’Shaughnessy JA, et al: Survival benefit with Xeloda (Capecitabine)/docetaxel vs docetaxel: Analysis of post-study therapy (abstract 442). Breast Cancer Res Treat 69:287, 2001.

3. Sawada N, Ishikawa T, Fukase Y, et al: Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by Taxol/Taxotere in human cancer xenografts. Clin Cancer Res 4:1013-1019, 1998.

1. Tonkin K, Scarfe A, Koski S, et al: Preliminary results of a phase I/II study of weekly docetaxel (Taxotere) combined with intermittent capecitabine (Xeloda) for patients with anthracycline pretreated metastatic breast cancer (abstract 2016). Proc Am Soc Clin Oncol 20:67b, 2001.

2. Kurosumi M, Tabei T, Suemasu K, et al: Enhancement of immunohistochemical reactivity for thymidine phosphorylase in breast carcinoma cells after administraction of docetaxel as a neoadjuvant chemotherapy in advanced breast cancer patients. Oncol Rep 7(5):945-948, 2000.

3. Nadella P, Shapiro C, Otterson GA, et al: Pharmacobiologically based scheduling of capecitabine and docetaxel results in antitumor activity in resistant human malignancies. J Clin Oncol 20:2616-2623, 2002.