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Taxane Plus Doxorubicin Not Well Tolerated in Early Breast Cancer

Taxane Plus Doxorubicin Not Well Tolerated in Early Breast Cancer

PHILADELPHIA, PENNSYLVANIA- Adjuvant treatment with Adriamycin/Taxotere (AT) did not improve outcome over standard treatment with doxorubicin/cyclophosphamide (AC) for women with early-stage breast cancer, Lori J. Goldstein, MD, of Fox Chase Cancer Center reported (abstract 512). Both regimens tested in a phase III Eastern Cooperative Oncology Group trial (E2197) produced better-than-expected results, but toxicity was higher in the AT group. Neutropenia associated with fever and infection occurred in 28% of the AT group and in 10% of the AC group. There were 18 cases of congestive heart failure in the AT group and 10 cases in the AC group, but this was not considered statistically significant. Disease-free and overall survival curves for the two regimens overlapped. Subgroup Analysis The trial opened in July 1998 and "closed rapidly due to great accrual" in January 2000, Dr. Goldstein said. Patients were balanced for age, hormone receptor status, menopausal status, nodes, surgery, as well as grade and size of the tumor. The median age was 51 years (range, 24-85 years). Sixty- four percent of patients were estrogen receptor positive (ER+) and 65% of tumors were lymph node negative. "The ER/PR subgroups were prespecified at randomization designed to balance the treatment arms," Dr. Goldstein noted. Patients were randomized to receive AT (doxorubicin 60 mg/m2 plus docetaxel 60 mg/m2) with ciprofloxacin (Cipro) support or AC (doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2) every 3 weeks for four cycles. Tamoxifen was given for 5 years postchemotherapy to all patients with ER+ and/or PR+ tumors. Subgroup analysis found no significant effect for nodes, tumor size, age, menopausal status, grade, type of surgery, or race. Nor were there any significant interactions between the treatment and the subgroups. Data for disease-free survival "suggest that the PR-negative tumors may potentially benefit from AT, but this study was not powered to statistically detect these differences," Dr. Goldstein reported. The pattern was the same for overall survival, she said, and supports the hypothesis "that in ER+ tumors, the large benefit presented by tamoxifen overwhelms the potential benefit of taxane therapy... The prognosis of these tumors is so good, it is difficult to detect a difference between these two chemotherapy arms. Taken together, along with the genomic health data, these data support the hypothesis that the biology of a tumor may predict the benefit to individual therapies." The Case for Taxanes "Given their single-agent activity, relative non-cross-resistance, partially nonoverlapping toxicities, and different mechanisms of action, there was a clear rationale for combining taxanes with doxorubicin," Dr. Goldstein explained. The selection of AT was "based on the relative cardiac safety of this combination," and several ran- domized trials supported such investigation. In a discussion of the trial, Gabriel N. Hortobagyi, MD, Director of the Breast Cancer Research Program at M. D. Anderson Cancer Center in Houston, referred to several trials that have demonstrated a clear advantage to using taxanes in the adjuvant setting for high-risk breast cancer. "The addition of a taxane clearly improves event-free survival, relapse-free survival, and probably overall survival in patients with high-risk primary breast cancer," he observed. "Whether this can be readily translated to a lower risk population awaits additional trials but is probably likely." Why was E2197 a negative study? Dr. Hortobagyi offered several possibilities, including insufficient duration of therapy and inadequate dose of docetaxel. He also speculated on whether the sequential use of anthracyclines and taxanes might be better than simultaneous use of these agents. "AT x 4 remains unproven, more toxic than AC x 4, unlikely to match TAC (Taxotere [docetaxel], Adriamycin [doxorubicin], and cyclophosphamide) x 6 or any of the other regimens. Therefore, I would propose that it should not be used outside of a clinical trial and probably not even in a clinical trial since there are more effective and probably better tolerated regimens," he said. "On the basis of our increased biological knowledge and our better understanding that there are biologic methods to select differences in subsets of different patients, we should concentrate on how to identify the optimal regimens for individual tumors and stop getting involved in these large trials in which one size is supposed to fit all patients."

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