There are a number of options for the use of active drugs in chemotherapy for metastatic breast cancer. Data from numerous clinical trials have shown significant response rates in first-line treatment with a number of single agents, and lower response rates when the individual agents are used in second-line treatment. Debate continues over whether active single agents or combinations should (1) be used concurrently with an additional active drug, (2) be used in sequence, or (3) be used in combination in intermittent therapy. Available data suggest that sequential treatment produces outcomes similar to those seen with concurrent combination treatment while resulting in reduced toxicity and improved quality of life.
Capecitabine (Xeloda) is a new oral fluoropyrimidine that is selectively activated in tumor tissues. The drug was designed to produce greater tumor levels of fluorouracil(Drug information on fluorouracil) (5-FU), simulating the effect of continuous-infusion 5-FU, by exploiting the high levels of the activating enzyme thymidine phosphorylase observed in tumors compared with normal tissue. The pharmacokinetic and safety profiles of capecitabine(Drug information on capecitabine) are similar to those of continuous-infusion 5-FU. As with continuous-infusion 5-FU, dose-limiting toxicities of the agent include hand-foot syndrome, diarrhea, and fatigue. Initial phase II studies of capecitabine at 1,250 mg/m² twice daily for 14 days every 3 weeks established a role for this agent in taxane-refractory metastatic breast cancer. In a study of 162 patients, Blum et al reported a response rate of 20%, including a 29% response rate in patients refractory to both paclitaxel(Drug information on paclitaxel) and anthracyclines, and stable disease in 43% of patients. Grade 3 or 4 hand-foot syndrome occurred in 10% of patients and grade 3 or 4 diarrhea occurred in 14%.[1]
In a study of 100 patients, all of whom had progressed following treatment with paclitaxel or docetaxel(Drug information on docetaxel) (Taxotere), Thuss-Patience et al reported a response rate of 18% and stable disease in 48% of patients. Grade 3 or 4 hand-foot syndrome occurred in 13% of patients, and grade 3 or 4 diarrhea occurred in 3%.[2] Hence, single-agent use is supported by available data, but the optimal use of capecitabine as a single agent or in combination in metastatic breast cancer remains to be fully defined.
Single Agents vs Combinations
Most available data in the metastatic breast cancer setting indicate that there is little difference in overall outcome between concurrent combination therapy and sequential therapy. For example, in a trial performed by Joensuu et al that compared epirubicin(Drug information on epirubicin) (Ellence) followed by mitomycin(Drug information on mitomycin) (Mutamycin) at disease progression with cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar)/epirubicin/5-FU (CEF) followed by mitomycin/vinblastine (MV), response rates were 48% with epirubicin and 16% with mitomycin in the sequential single-agent arm, and 55% and 7% with CEF and MV, respectively, in the sequential combinations arm.[3] In addition to the overall response rates thus being similar, no significant difference in time to disease progression or overall survival was observed between the groups overall or with regard to single-agent mitomycin vs MV. Quality of life, however, was better in the single-agent sequential therapy group than in the combination sequential therapy group. Findings such as these—showing similar outcomes with sequential and concurrent combinations—raise the issue of whether selection of therapy from among active concurrent or sequential combinations might optimally be guided by consideration of the toxicity of the regimens or their effect on quality of life.
A recent study by Heidemann et al included an admirable attempt to quantify the overall clinical impact of treatment by utilizing a modified Brunner’s score to measure the effects on disease, quality of life, and toxicity. This composite score reflected individual scores for time to disease progression, and change in World Health Organization performance status, a subjective measure of quality of life over the duration of treatment, and selected toxicities (nausea, vomiting, and alopecia) were tracked over the duration of treatment.[4] The study found that 5-FU/epirubicin/cyclophosphamide (FEC) produced a slightly higher response rate than single-agent mitoxantrone(Drug information on mitoxantrone) (Novantrone), but no differences in time to disease progression or overall survival were observed.
The mitoxantrone group, however, exhibited a significantly better modified Brunner’s score of 3.92 vs -2.07 (P = .0001), reflecting scores of 5.72 vs 6.34 (P = .0996) for time to disease progression, -0.75 vs -2.84 (P = .0638) for change in performance status, 1.76 vs 2.43 (P = .0778) for subjective measurement of quality of life, and -2.81 vs -8.00 (P = .0001) for toxicity. Thus, on the basis of these findings, single-agent mitoxantrone might even be preferred over the FEC combination. This scoring system can be adjusted for use in individual trials (eg, according to toxicities likely to be encountered with particular regimens). Although the score may not be considered by all practitioners to be a definitive or adequate measure of quality of life, its use represents recognition of both the importance of capturing overall clinical impact of treatment, and the need for such a measure in choosing between treatments that have similar response rate, time to progression, or survival.
The benefits of capecitabine treatment in anthracycline-refractory metastatic breast cancer were demonstrated in a recent phase III trial comparing the combination of capecitabine at 1,250 mg/m² on days 1 to 14 plus docetaxel at 75 mg/m² on day 1 every 3 weeks with single-agent docetaxel at 100 mg/m² on day 1.[5] Combination treatment was associated with significantly better response rate (42% vs 30%, P = .006), time to disease progression (median: 6.1 vs 4.2 months; hazard ratio for progression: 0.652, P = .0001), and overall survival (median duration: 14.5 vs 11.5 months; hazard ratio for death: 0.775, P = .0126). Capecitabine/docetaxel is thus the first cytotoxic drug combination to exhibit a survival advantage over docetaxel alone in this setting.
It is currently unknown whether the sequential use of docetaxel and capecitabine might provide benefits similar to those observed with the concurrent combination. However, it is of interest that an analysis of the effect of poststudy chemotherapy on patient survival suggests a marked benefit of subsequent capecitabine treatment in patients in the single-agent docetaxel arm.[6] Of 164 patients in the docetaxel group receiving poststudy chemotherapy, 46 received capecitabine. Comparing this subset with all patients receiving other chemotherapy, the patients receiving capecitabine had a median overall survival of 21 vs 12.3 months (P = .0046) and a hazard ratio for death of 0.5. Although this analysis was unplanned and includes a relatively small number of patients receiving poststudy capecitabine, the findings suggest a pronounced effect for sequential docetaxel and capecitabine, and the possibility that single-agent sequential treatment with the two agents could provide benefits similar to those seen with the concurrent combination.
Similar suggestive findings were made in Eastern Cooperative Oncology Group study 1193, in which patients with metastatic breast cancer received doxorubicin(Drug information on doxorubicin) at 60 mg/m², paclitaxel at 175 mg/m², or doxorubicin/paclitaxel at 50 mg/m² and 150 mg/m², respectively, as first-line treatment.[7] Response rate (46% vs 34% and 33%) and time to disease progression (median: 8 vs 6.2 and 5.9 months) were greater with combination treatment than with single-agent doxorubicin and single-agent paclitaxel; however, with crossover between single-agent treatment arms (response rates of 20% in the initial doxorubicin group and 14% in the initial paclitaxel group), there was no significant difference between overall survival in the combination group (median: 22.4 months) and that in the single-agent groups (medians: 20.1 months for the doxorubicin group and 22.2 months for the paclitaxel group). Thus, these findings also tend to support the notion that sequential single-agent treatment ultimately provides outcomes similar to those achieved with concurrent combinations. As sequential single-agent therapy is likely to be associated with reduced toxicity and, perhaps, improved quality of life compared with concurrent combination treatment, it should be strongly considered for use in this setting.
Single-Agent Adjuvant Therapy
The potential merits of single-agent vs combination treatment in the adjuvant setting also continue to be debated. Cancer and Leukemia Group B (CALGB) study 40101 is currently assessing both the optimal duration of adjuvant therapy and the effects of single-agent vs combination treatment. In this 2 by 2 factorial design trial, patients will receive doxorubicin/cyclophosphamide for four or six cycles or single-agent paclitaxel for 12 or 18 weeks.
A number of findings suggest that capecitabine may have a role as single-agent adjuvant therapy. A randomized phase II trial evaluating capecitabine (n = 22) vs paclitaxel (n = 19) as adjuvant therapy in metastatic breast cancer showed a response rate of 36% (95% CI = 17%-59%) vs 26% (95% CI = 9%-51%), complete response rate of 14% vs 0%, median duration of response of 9.4 vs 9.4 months, and median time to disease progression of 3.0 months (95% CI = 1.4-6.8 months) vs 3.1 months (95% CI = 2.5-6.5 months).[8] In another randomized phase II trial, capecitabine treatment was associated with prolonged time to disease progression (median 4.1 versus 3.0 months) compared with cyclophosphamide/methotrexate/5-FU (CMF) (Figure 1).[9]
Based on these findings, CALGB has recently initiated a trial (study 49907) comparing standard doxorubicin/cyclophosphamide (AC) for four cycles or standard CMF for six cycles with capecitabine at 1,000 mg/m² twice daily for eight cycles as adjuvant therapy in patients over 65 years with node-positive disease or node-negative, estrogen receptor/progestin receptor-negative disease. The selection of AC or CMF as standard treatment is to be at the discretion of each study center, based on repeated findings of the equivalence of the two regimens in the adjuvant setting.
The use of a somewhat reduced dose of capecitabine in this trial is based on an analysis of dose reductions in four phase II trials employing the standard dose of 1,250 mg/m² twice daily for 14 days every 3 weeks.[10] In this analysis, 131 (41%) of 321 patients receiving capecitabine had 25% or 50% dose reductions, with the median time to the first and second dose reductions being 49 and 105 days, respectively. The overall objective response rate in all 321 patients was 22%. Among the 131 patients with dose reductions, response was observed in 42 (32%); time to treatment failure was 107 days in those with no response and 234 days in those with respons, and median survival was 255 and 350 days, respectively.
Among the 190 patients who had no dose reductions, response was observed in 28 (15%); time to treatment failure was 48 days in those without response and 216 days in those with response, and median survival was 192 and 243 days, respectively. Although such an analysis reflects bias in that the group of patients without dose reductions includes a proportion with early disease progression and the group with dose reduction is likely to include patients receiving treatment for a longer duration, these data nevertheless at least suggest that use of a reduced dose of capecitabine does not adversely affect response rates, time to treatment failure, or overall survival.
Conclusions
Available data suggest that sequential use of single agents active in advanced breast cancer produces outcomes similar to those achieved with concurrent combined treatment. Use of single agents is likely to be associated with reduced toxicity and may be associated with better quality of life compared with concurrent combination therapy. Single-agent treatment is thus a reasonable approach to chemotherapy in this setting. Future studies evaluating the single-agent vs combination approach might do well to increase focus on measures of quality of life and toxicity that allow a distinction between treatments on the basis of overall clinical impact if no differences in disease-related outcomes can be detected.
Capecitabine has proven to be a convenient and effective agent in advanced breast cancer and has been shown to be safe in combination use. Whether its optimal use is in single-agent or concurrent combination therapy remains to be determined. The recent phase III trial demonstrating the superiority of the capecitabine/docetaxel combination over single-agent docetaxel in anthracycline-pretreated patients has established an important role for capecitabine in this setting. Although no specific comparison of concurrent vs sequential use of capecitabine and docetaxel has been performed, an analysis of survival based on poststudy chemotherapy in patients from the single-agent docetaxel group indicates a marked benefit with capecitabine treatment vs treatment with all other agents, and thus suggests that sequential use of the agents might produce outcome similar to concurrent use. Available data indicating similar effectiveness of capecitabine compared with paclitaxel and CMF have prompted a study comparing standard AC or CMF with single-agent capecitabine in the adjuvant setting. Additional trials are examining the use of capecitabine in combination in adjuvant therapy. Results of these trials should provide important information on how best to use this valuable agent in advanced breast cancer.
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