Single-Agent vs Combination Therapy in Advanced Breast Cancer: Potential Roles of Capecitabine

ABSTRACT: Available data on the use of active chemotherapy agents inadvanced breast cancer suggest that sequential single-agent therapy isassociated with outcomes similar to those achieved with concurrent combinationtherapy. Since the use of single agents is likely to be associated with reducedtoxicity and may be associated with improved quality of life, this approachshould be strongly considered when assessing treatment options. Capecitabine (Xeloda)is an effective agent in advanced breast cancer, with a recent phase III trialdemonstrating significant advantages of capecitabine/docetaxel (Taxotere) oversingle-agent docetaxel in response rate, time to disease progression, andoverall survival in anthracycline-pretreated patients. Analysis of survivalbased on poststudy chemotherapy showed a significant survival benefit in arelatively small group of single-agent docetaxel patients who subsequentlyreceived capecitabine compared with all other poststudy chemotherapy, suggestingthe potential for marked benefits with sequential treatment. On the basis ofdata demonstrating the effectiveness of single-agent capecitabine, a trial hasbeen initiated to compare single-agent capecitabine with standard combinationadjuvant therapy in elderly high-risk patients. [ONCOLOGY 16(Suppl 12):13-16,2002]

There are a number of optionsfor the use of active drugs inchemotherapy for metastatic breast cancer. Data from numerous clinical trialshave shown significant response rates in first-line treatment with a number ofsingle agents, and lower response rates when the individual agents are used insecond-line treatment. Debate continues over whether active single agents orcombinations 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 tothose seen with concurrent combination treatment while resulting in reducedtoxicity and improved quality of life.

Capecitabine (Xeloda) is a new oral fluoropyrimidine that isselectively activated in tumor tissues.The drug was designed to produce greater tumor levels of fluorouracil (5-FU),simulating the effect of continuous-infusion 5-FU, by exploiting the high levelsof the activating enzyme thymidine phosphorylase observed in tumors comparedwith normal tissue. The pharmacokinetic and safety profiles of capecitabine aresimilar to those of continuous-infusion 5-FU. As with continuous-infusion 5-FU,dose-limiting toxicities of the agent include hand-foot syndrome, diarrhea, andfatigue. Initial phase II studies of capecitabine at 1,250 mg/m² twice daily for14 days every 3 weeks established a role for this agent in taxane-refractorymetastatic breast cancer. In a study of 162 patients, Blum et al reported aresponse rate of 20%, including a 29% response rate in patients refractory toboth paclitaxel and anthracyclines, and stable disease in 43% of patients. Grade3 or 4 hand-foot syndrome occurred in 10% of patients and grade 3 or 4 diarrheaoccurred in 14%.[1]

In a study of 100 patients, all of whom had progressed followingtreatment with paclitaxel or docetaxel (Taxotere), Thuss-Patience et al reporteda response rate of 18% and stable disease in 48% of patients. Grade 3 or 4hand-foot syndrome occurred in 13% of patients, and grade 3 or 4 diarrheaoccurred in 3%.[2] Hence, single-agent use is supported by available data, butthe optimal use of capecitabine as a single agent or in combination inmetastatic breast cancer remains to be fully defined.

Single Agents vs Combinations

Most available data in the metastatic breast cancer settingindicate that there is little difference in overall outcome between concurrentcombination therapy and sequential therapy. For example, in a trial performed byJoensuu et al that compared epirubicin (Ellence) followed by mitomycin (Mutamycin)at disease progression with cyclophosphamide (Cytoxan, Neosar)/epirubicin/5-FU (CEF)followed by mitomycin/vinblastine (MV), response rates were 48% with epirubicinand 16% with mitomycin in the sequential single-agent arm, and 55% and 7% withCEF and MV, respectively, in the sequential combinations arm.[3] In addition tothe overall response rates thus being similar, no significant difference in timeto disease progression or overall survival was observed between the groupsoverall or with regard to single-agent mitomycin vs MV. Quality of life,however, was better in the single-agent sequential therapy group than in thecombination sequential therapy group. Findings such as these—showing similaroutcomes with sequential and concurrent combinations—raise the issue ofwhether selection of therapy from among active concurrent or sequentialcombinations might optimally be guided by consideration of the toxicity of theregimens or their effect on quality of life.

A recent study by Heidemann et al included an admirable attemptto quantify the overall clinical impact of treatment by utilizing a modifiedBrunner’s score to measure the effects on disease, quality of life, andtoxicity. This composite score reflected individual scores for time to diseaseprogression, and change in World Health Organization performance status, asubjective measure of quality of life over the duration of treatment, andselected toxicities (nausea, vomiting, and alopecia) were tracked over theduration of treatment.[4] The study found that 5-FU/epirubicin/cyclophosphamide(FEC) produced a slightly higher response rate than single-agent mitoxantrone (Novantrone),but no differences in time to disease progression or overall survival wereobserved.

The mitoxantrone group, however, exhibited a significantlybetter modified Brunner’s score of 3.92 vs -2.07 (P = .0001), reflectingscores 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) forsubjective measurement of quality of life, and -2.81 vs -8.00 (P = .0001)for toxicity. Thus, on the basis of these findings, single-agent mitoxantronemight even be preferred over the FEC combination. This scoring system can beadjusted for use in individual trials (eg, according to toxicities likely to beencountered with particular regimens). Although the score may not be consideredby all practitioners to be a definitive or adequate measure of quality of life,its use represents recognition of both the importance of capturing overallclinical impact of treatment, and the need for such a measure in choosingbetween treatments that have similar response rate, time to progression, orsurvival.

The benefits of capecitabine treatment in anthracycline-refractorymetastatic breast cancer were demonstrated in a recent phase III trial comparingthe combination of capecitabine at 1,250 mg/m² on days 1 to 14 plus docetaxel at75 mg/m² on day 1 every 3 weeks with single-agent docetaxel at 100 mg/m² on day1.[5] Combination treatment was associated with significantly better responserate (42% vs 30%, P = .006), time to disease progression (median: 6.1 vs 4.2months; 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 toexhibit a survival advantage over docetaxel alone in this setting.

It is currently unknown whether the sequential use of docetaxeland capecitabine might provide benefits similar to those observed with theconcurrent combination. However, it is of interest that an analysis of theeffect of poststudy chemotherapy on patient survival suggests a marked benefitof subsequent capecitabine treatment in patients in the single-agent docetaxelarm.[6] Of 164 patients in the docetaxel group receiving poststudy chemotherapy,46 received capecitabine. Comparing this subset with all patients receivingother chemotherapy, the patients receiving capecitabine had a median overallsurvival 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 ofpatients receiving poststudy capecitabine, the findings suggest a pronouncedeffect for sequential docetaxel and capecitabine, and the possibility thatsingle-agent sequential treatment with the two agents could provide benefitssimilar to those seen with the concurrent combination.

Similar suggestive findings were made in Eastern CooperativeOncology Group study 1193, in which patients with metastatic breast cancerreceived doxorubicin at 60 mg/m², paclitaxel at 175 mg/m², or doxorubicin/paclitaxelat 50 mg/m² and 150 mg/m², respectively, as first-line treatment.[7] Responserate (46% vs 34% and 33%) and time to disease progression (median: 8 vs 6.2 and5.9 months) were greater with combination treatment than with single-agentdoxorubicin and single-agent paclitaxel; however, with crossover betweensingle-agent treatment arms (response rates of 20% in the initial doxorubicingroup and 14% in the initial paclitaxel group), there was no significantdifference between overall survival in the combination group (median: 22.4months) and that in the single-agent groups (medians: 20.1 months for thedoxorubicin group and 22.2 months for the paclitaxel group). Thus, thesefindings also tend to support the notion that sequential single-agent treatmentultimately provides outcomes similar to those achieved with concurrentcombinations. As sequential single-agent therapy is likely to be associated withreduced toxicity and, perhaps, improved quality of life compared with concurrentcombination treatment, it should be strongly considered for use in this setting.

Single-Agent Adjuvant Therapy

The potential merits of single-agent vs combination treatment inthe adjuvant setting also continue to be debated. Cancer and Leukemia Group B (CALGB)study 40101 is currently assessing both the optimal duration of adjuvant therapyand the effects of single-agent vs combination treatment. In this 2 by 2factorial design trial, patients will receive doxorubicin/cyclophosphamide forfour or six cycles or single-agent paclitaxel for 12 or 18 weeks.

A number of findings suggest that capecitabine may have a roleas single-agent adjuvant therapy. A randomized phase II trial evaluatingcapecitabine (n = 22) vs paclitaxel (n = 19) as adjuvant therapy in metastaticbreast 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 of9.4 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 anotherrandomized phase II trial, capecitabine treatment was associated with prolongedtime to disease progression (median 4.1 versus 3.0 months) compared withcyclophosphamide/methotrexate/5-FU (CMF) (Figure1).[9]

Based on these findings, CALGB has recently initiated a trial(study 49907) comparing standard doxorubicin/cyclophosphamide (AC) for fourcycles or standard CMF for six cycles with capecitabine at 1,000 mg/m² twicedaily for eight cycles as adjuvant therapy in patients over 65 years withnode-positive disease or node-negative, estrogen receptor/progestin receptor-negativedisease. The selection of AC or CMF as standard treatment is to be at thediscretion of each study center, based on repeated findings of the equivalenceof the two regimens in the adjuvant setting.

The use of a somewhat reduced dose of capecitabine in this trialis based on an analysis of dose reductions in four phase II trials employing thestandard dose of 1,250 mg/m² twice daily for 14 days every 3 weeks.[10] In thisanalysis, 131 (41%) of 321 patients receiving capecitabine had 25% or 50% dosereductions, with the median time to the first and second dose reductions being49 and 105 days, respectively. The overall objective response rate in all 321patients was 22%. Among the 131 patients with dose reductions, response wasobserved in 42 (32%); time to treatment failure was 107 days in those with noresponse and 234 days in those with respons, and median survival was 255 and 350days, respectively.

Among the 190 patients who had no dose reductions, response wasobserved in 28 (15%); time to treatment failure was 48 days in those withoutresponse and 216 days in those with response, and median survival was 192 and243 days, respectively. Although such an analysis reflects bias in that thegroup of patients without dose reductions includes a proportion with earlydisease progression and the group with dose reduction is likely to includepatients receiving treatment for a longer duration, these data nevertheless atleast suggest that use of a reduced dose of capecitabine does not adverselyaffect response rates, time to treatment failure, or overall survival.

Conclusions

Available data suggest that sequential use of single agentsactive in advanced breast cancer produces outcomes similar to those achievedwith concurrent combined treatment. Use of single agents is likely to beassociated with reduced toxicity and may be associated with better quality oflife compared with concurrent combination therapy. Single-agent treatment isthus a reasonable approach to chemotherapy in this setting. Future studiesevaluating the single-agent vs combination approach might do well to increasefocus on measures of quality of life and toxicity that allow a distinctionbetween treatments on the basis of overall clinical impact if no differences indisease-related outcomes can be detected.

Capecitabine has proven to be a convenient and effective agentin advanced breast cancer and has been shown to be safe in combination use.Whether its optimal use is in single-agent or concurrent combination therapyremains to be determined. The recent phase III trial demonstrating thesuperiority of the capecitabine/docetaxel combination over single-agentdocetaxel in anthracycline-pretreated patients has established an important rolefor capecitabine in this setting. Although no specific comparison of concurrentvs sequential use of capecitabine and docetaxel has been performed, an analysisof survival based on poststudy chemotherapy in patients from the single-agentdocetaxel group indicates a marked benefit with capecitabine treatment vstreatment with all other agents, and thus suggests that sequential use of theagents might produce outcome similar to concurrent use. Available dataindicating similar effectiveness of capecitabine compared with paclitaxel andCMF have prompted a study comparing standard AC or CMF with single-agentcapecitabine in the adjuvant setting. Additional trials are examining the use ofcapecitabine in combination in adjuvant therapy. Results of these trials shouldprovide important information on how best to use this valuable agent in advancedbreast cancer.

References:

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3. Joensuu H, Holli K, Heikkinen M, et al: Combinationchemotherapy versus single-agent therapy as first- and second-line treatment inmetastatic breast cancer: A prospective randomized trial. J Clin Oncol16:3720-3730, 1998.

4. Heidemann E, Stoeger H, Souchon R, et al: Balance of time toprogression, quality of life, and overall survival: More gain from treatmentwith mitoxantrone (N) than with the combination of fluorouracil, epirubicin,cyclophosphamide (FEC). Results of a multicenter randomized trial (abstract284). Proc Am Soc Clin Oncol 19:74a, 2000.

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