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Current and Planned Trials With Capecitabine in Adjuvant/Neoadjuvant Therapy of Breast Cancer

Current and Planned Trials With Capecitabine in Adjuvant/Neoadjuvant Therapy of Breast Cancer

ABSTRACT: 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 setting has prompted considerable interest in examining uses of capecitabine in adjuvant and neoadjuvant therapy. Trials are planned to compare capecitabine/docetaxel with docetaxel after AC in the adjuvant and neoadjuvant settings, weekly paclitaxel vs capecitabine/docetaxel followed by fluorouracil (5-FU)/epirubicin (Ellence)/cyclophosphamide and local surgery in both adjuvant and neoadjuvant settings, and AC or cyclophosphamide/methotrexate/5-FU vs single-agent capecitabine in adjuvant therapy of elderly patients with node-positive or high-risk node-negative disease. Results of these trials should provide important information on the range of uses of capecitabine in treating breast cancer. [ONCOLOGY 16(Suppl 12):23-28, 2002]

There is considerable rationale
for 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 higher
concentrations in tumor tissues. Taxanes have been shown in preclinical systems
to upregulate thymidine phosphorylase, which would result in the accumulation of
higher tumor concentrations of capecitabine. The expectation of increased
antitumor activity has been borne out in a recent phase III trial showing that
docetaxel (Taxotere)/capecitabine resulted in significant improvement in tumor
response, time to disease progression, and overall survival compared with
docetaxel alone in anthracycline-pretreated stage IV disease.[1] These positive
results and the promise of significant antitumor effects have prompted the
design of numerous studies assessing capecitabine in combination with a taxane
or alone in adjuvant or neoadjuvant therapy.

Rationale

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). The
rationale for such an approach consisted of several observations. First, weekly
administration of doxorubicin produces cytotoxic concentrations of the drug that
persist for several days (formerly believed to be about 4 to 5 days, now
recognized as about 2 to 3 days). Second, daily administration of
cyclophosphamide produces continuous cytotoxic concentrations of active
metabolites.

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 to
treatment focused on providing active drug concentration for prolonged
continuous time periods (ie, the dose-dense approach) than to treatment focused
on providing higher concentrations more intermittently. Fourth, it was observed
that "metronomic" cyclophosphamide exerts an antitumor effect
independent of cytotoxicity in some preclinical breast cancer models (ie, when
the cell line was resistant to cyclophosphamide); these and other findings have
suggested that metronomic/continuous treatment with cyclophosphamide might exert
an antiangiogenic effect. These considerations prompted the performance of pilot
studies to assess the effects of continuous, dose-dense treatment with
fluorouracil (5-FU), doxorubicin (Adriamycin), and cyclophosphamide (FAC) in
node-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 cyclophosphamide
at 60 mg/m²/d for 24 weeks; patients received granulocyte colony-stimulating
factor (G-CSF [Neupogen]) 6 days per week (FAC+G). A high rate of grade 2
hand-foot syndrome (57%) in these first 30 patients led to removal of
fluorouracil from the regimen.

The next 23 patients treated (second study) received a regimen of doxorubicin
at 24 mg/m²/wk for 20 weeks (total dose of 480 mg/m², as in the first 30
patients) and cyclophosphamide at 60 mg/m²/d; these patients also received G-CSF
6 days per week (AC+G). Erythropoietin therapy was added to treatment shortly
after the first study was begun; all 23 patients receiving AC+G received weekly
erythropoietin treatment. No taxane consolidation was used. Patients with
estrogen 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 findings
in a Cancer and Leukemia Group B (CALGB)/Intergroup trial indicating an
advantage of planned dose intensity of this level over lower planned dose
intensities.[2] Mean weekly doses of doxorubicin were 18.8 mg/m² (median: 18.5
mg/m², range: 12 to 24 mg/m²) in all 53 patients, 17.7 mg/m² (median 17.6
mg/m²,
range: 12 to 21 mg/m²) in the 30 FAC+G patients, and 20.1 mg/m² (median: 21
mg/m², range: 14 to 24 mg/m²) in the 23 AC+G patients. Grade 3 toxicities
consisted of neutropenia in 22% to 30%, anemia in 0% to 17%, nausea/vomiting in
0% to 10%, hand-foot syndrome in 4% to 7%, and stomatitis in 3% to 13%. Grade 4
toxicities consisted of neutropenia in 10%, with 3% of patients requiring
hospitalization 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[5] in patients with stage III/inflammatory breast cancer showed that an
identical continuous AC+G regimen produced a 24% pathologic complete response
rate and a 50% major pathologic response rate overall. A SWOG randomized trial
comparing continuous AC+G with standard AC in patients with locally advanced and
inflammatory breast cancer is ongoing.

Trials of Capecitabine in the Adjuvant Setting

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