The demonstration of the activity of capecitabine (Xeloda) in advanced breast cancer and of the ability of capecitabine/docetaxel (Taxotere) to improve tumor response, time to disease progression, and survival in this
ABSTRACT: The demonstration of the activity of capecitabine (Xeloda) in advanced breastcancer and of the ability of capecitabine/docetaxel (Taxotere) to improve tumorresponse, time to disease progression, and survival in this setting has promptedconsiderable interest in examining uses of capecitabine in adjuvant andneoadjuvant therapy. Trials are planned to compare capecitabine/docetaxel withdocetaxel after AC in the adjuvant and neoadjuvant settings, weekly paclitaxelvs capecitabine/docetaxel followed by fluorouracil (5-FU)/epirubicin (Ellence)/cyclophosphamideand local surgery in both adjuvant and neoadjuvant settings, and AC orcyclophosphamide/methotrexate/5-FU vs single-agent capecitabine in adjuvanttherapy of elderly patients with node-positive or high-risk node-negativedisease. Results of these trials should provide important information on therange of uses of capecitabine in treating breast cancer. [ONCOLOGY16(Suppl 12):23-28, 2002]
There is considerable rationalefor evaluating the combination of capecitabine (Xeloda) and a taxane in the adjuvant setting in breast cancer.Capecitabine is activated by thymidine phosphorylase, which exists in higherconcentrations in tumor tissues. Taxanes have been shown in preclinical systemsto upregulate thymidine phosphorylase, which would result in the accumulation ofhigher tumor concentrations of capecitabine. The expectation of increasedantitumor activity has been borne out in a recent phase III trial showing thatdocetaxel (Taxotere)/capecitabine resulted in significant improvement in tumorresponse, time to disease progression, and overall survival compared withdocetaxel alone in anthracycline-pretreated stage IV disease. These positiveresults and the promise of significant antitumor effects have prompted thedesign of numerous studies assessing capecitabine in combination with a taxaneor alone in adjuvant or neoadjuvant therapy.
Several years ago, investigators at the University of Washington, Seattle,developed a program of continuous chemotherapy to supply dose- dense treatment,primarily involving doxorubicin and cyclophosphamide (Cytoxan, Neosar). Therationale for such an approach consisted of several observations. First, weeklyadministration of doxorubicin produces cytotoxic concentrations of the drug thatpersist for several days (formerly believed to be about 4 to 5 days, nowrecognized as about 2 to 3 days). Second, daily administration ofcyclophosphamide produces continuous cytotoxic concentrations of activemetabolites.
Third, human solid tumors have a turnover that is relatively slow (ie,compared with that observed in mouse models), and may thus be more responsive totreatment focused on providing active drug concentration for prolongedcontinuous time periods (ie, the dose-dense approach) than to treatment focusedon providing higher concentrations more intermittently. Fourth, it was observedthat "metronomic" cyclophosphamide exerts an antitumor effectindependent of cytotoxicity in some preclinical breast cancer models (ie, whenthe cell line was resistant to cyclophosphamide); these and other findings havesuggested that metronomic/continuous treatment with cyclophosphamide might exertan antiangiogenic effect. These considerations prompted the performance of pilotstudies to assess the effects of continuous, dose-dense treatment withfluorouracil (5-FU), doxorubicin (Adriamycin), and cyclophosphamide (FAC) innode-positive primary breast cancer. The first 30 patients treated (first study)received 5-FU at 300 mg/m²/wk, doxorubicin at 20 mg/m²/wk, and cyclophosphamideat 60 mg/m²/d for 24 weeks; patients received granulocyte colony-stimulatingfactor (G-CSF [Neupogen]) 6 days per week (FAC+G). A high rate of grade 2hand-foot syndrome (57%) in these first 30 patients led to removal offluorouracil from the regimen.
The next 23 patients treated (second study) received a regimen of doxorubicinat 24 mg/m²/wk for 20 weeks (total dose of 480 mg/m², as in the first 30patients) and cyclophosphamide at 60 mg/m²/d; these patients also received G-CSF6 days per week (AC+G). Erythropoietin therapy was added to treatment shortlyafter the first study was begun; all 23 patients receiving AC+G received weeklyerythropoietin treatment. No taxane consolidation was used. Patients withestrogen receptor (ER)-positive status received tamoxifen (Nolvadex) treatment.Overall, patients had a median of 4 positive nodes (range: 1 to 22) and 18 (43%)of the 43 evaluated for HER2/neu receptor status were HER2/neu-positive.
The target dose intensity of doxorubicin was 15 mg/m²/wk, based on findingsin a Cancer and Leukemia Group B (CALGB)/Intergroup trial indicating anadvantage of planned dose intensity of this level over lower planned doseintensities. Mean weekly doses of doxorubicin were 18.8 mg/m² (median: 18.5mg/m², range: 12 to 24 mg/m²) in all 53 patients, 17.7 mg/m² (median 17.6mg/m²,range: 12 to 21 mg/m²) in the 30 FAC+G patients, and 20.1 mg/m² (median: 21mg/m², range: 14 to 24 mg/m²) in the 23 AC+G patients. Grade 3 toxicitiesconsisted of neutropenia in 22% to 30%, anemia in 0% to 17%, nausea/vomiting in0% to 10%, hand-foot syndrome in 4% to 7%, and stomatitis in 3% to 13%. Grade 4toxicities consisted of neutropenia in 10%, with 3% of patients requiringhospitalization for febrile neutropenia, and anemia in 0% to 3%.
Patients had a median follow-up of 64 months (range: 8 to 100 months). At 5 years, disease-free survival among the total group was 85%, with an apparent plateau in the survival curve after 5 years (Figure 1). Informal comparison of this outcome with 5-year event-free survival rates (62% to 65%) in earlier National Surgical Adjuvant Breast and Bowel Project (NSABP) trials using standard AC as control treatment in node-positive patients suggests a marked improvement with the continuous therapy approach (Table 1).[3,4] This difference in outcome does not appear to be related to reduced nodal involvement, as the current study population had a smaller proportion of patients with one to three positive nodes and a greater proportion with four to nine positive nodes.
In addition to these findings, a Seattle/Southwest Oncology Group (SWOG)study in patients with stage III/inflammatory breast cancer showed that anidentical continuous AC+G regimen produced a 24% pathologic complete responserate and a 50% major pathologic response rate overall. A SWOG randomized trialcomparing continuous AC+G with standard AC in patients with locally advanced andinflammatory breast cancer is ongoing.
Several groups have planned or initiated trials to assess the effects ofcapecitabine in adjuvant or neoadjuvant therapy.
US Oncology Trial
In a trial to be performed by US Oncology, patients with resected stage II breast cancer are to be randomized to standard AC for four cycles, followed by docetaxel for four cycles; or to standard AC for four cycles, followed by docetaxel/capecitabine for four cycles (Figure 2).
In another trial of similar design planned by NSABP in the neoadjuvant setting, patients with operable breast cancer are to be randomized to standard AC for four cycles, docetaxel for four cycles, and surgery; or to standard AC for four cycles, docetaxel/capecitabine for four cycles, and surgery (Figure 3).
M. D. Anderson Trial
In an adjuvant/neoadjuvant trial conducted at the University of Texas M. D. Anderson Cancer Center, patients with stage I to IIIA disease in the adjuvant setting or stage IIA to IIIA disease in the neoadjuvant setting are to be randomized to weekly paclitaxel for 12 cycles or capecitabine/docetaxel for four cycles, with both arms then receiving 5-FU/epirubicin (Ellence)/cyclophosphamide (FEC) for four cycles followed by surgery or radiation therapy; patients with ER-positive tumors are to receive endocrine therapy (Figure 4). The selection of weekly paclitaxel for the initial single-agent taxane arm is based on findings of a recent trial showing that weekly paclitaxel was superior to paclitaxel every 3 weeks when all patients subsequently received identical FEC therapy. The pathologic complete response rate was doubled, from 14% to 28%, on the weekly arm.
Finally, CALGB study 49907 is to assess adjuvant therapy in patients 65 years or older with node-positive or high-risk node-negative disease. Patients are to be randomized to either standard AC for four cycles or cyclophosphamide/methotrexate/5-FU for six cycles depending on investigator preference vs capecitabine for six cycles (Figure 5).
The activity exhibited by capecitabine in breast cancer and the resultsachieved in advanced disease with the capecitabine/docetaxel combination suggesta number of approaches to using this interesting drug in the adjuvant andneoadjuvant settings. At the same time, accumulating evidence that continuous,dose-dense AC or FAC treatment may provide better outcomes than standardregimens indicates the need to examine this approach in the adjuvant setting.Trials are planned to assess capecitabine in combination with docetaxel or alonein adjuvant or neoadjuvant treatment. Findings in these trials should provideimportant information on the range of uses of capecitabine in treating breastcancer.
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2. Wood WC, Budman DR, Korzun AH, et al: Dose and dose intensity of adjuvantchemotherapy for stage II, node-positive breast carcinoma. N Engl J Med330:1253-1259, 1994.
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5. Ellis GK, Green SJ, Livingston RB, et al: Neoadjuvant doxorubicin,cyclophosphamide and G-CSF (AC + G) for locally advanced breast cancer: ASouthwest Oncology Group Phase II study. Proc Am Soc Clin Oncol 19:85a, 2000.
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