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Review Weekly Paclitaxel Improves Disease-Free and Overall Survival in the Adjuvant Treatment of Breast Cancer Rachel E. Raab, MD; Joseph A. Sparano, MD Department of Medical Oncology, Montefiore-Einstein Cancer Center, Bronx, New York The Eastern Cooperative Oncology Group (ECOG) recently published their data comparing the efficacy of paclitaxel and docetaxel and a schedule of either weekly or every 3 weeks in the adjuvant treatment of breast cancer. 1 The benefit of adjuvant chemotherapy in reducing the risk of recurrence and death from operable breast cancer is well known. A meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group revealed that anthracycline-based chemotherapy reduced the annual breast cancer death rate by about 38% for women younger than 50 years of age and by about 20% for women 50 to 69 years of age. 2 None of the randomized trials included in this meta- The benefit of adjuvant chemotherapy in reducing the risk of recurrence and death from operable breast cancer is well known. analysis involved taxanes. The benefit of adjuvant taxane therapy was established by two trials: the NSABP B-28 and the CALGB 9344. 3,4 The NSABP B-28 trial randomized patients to receive adjuvant therapy with either four cycles of doxorubicin and cyclophosphamide or four cycles of doxorubicin and cyclophosphamide followed by four cycles of pac- 10 The American Journal of Hematology/Oncology litaxel given every 3 weeks. Although no overall survival benefit was demonstrated, a significant improvement in disease-free survival was shown for patients receiving adjuvant paclitaxel. The CALGB 9344 trial demonstrated not only a benefit in disease-free survival for patients receiving adjuvant paclitaxel following doxorubicin and cyclophosphamide therapy but also a benefit in overall survival. The results of these trials led to the approval of paclitaxel for the adjuvant treatment of nodepositive breast cancer. Another taxane, docetaxel, is also approved for the adjuvant treatment of breast cancer. A randomized phase III trial comparing docetaxel plus doxorubicin and cyclophosphamide (TAC) with fluorouracil plus doxorubicin and cyclophosphamide (FAC) demonstrated improved disease-free and overall survival in women receiving TAC. 5 In metastatic breast cancer, phase III trials have demonstrated that weekly paclitaxel 6 or every- 3-week docetaxel 7 is superior to paclitaxel every 3 weeks. There have been no data, however, from randomized trials in the adjuvant setting comparing docetaxel with paclitaxel or weekly versus every-3week therapy. The ECOG study compared adjuvant paclitaxel versus docetaxel and an every-3-week schedule with a weekly schedule in patients with axillary lymph node–positive or high-risk, lymph node–negative breast cancer. 7 The standard of care was considered paclitaxel every 3 weeks, and the factorial design of the trial allowed for comparison with three experimental arms: paclitaxel weekly for 12 cycles, docetaxel every 3 weeks for four cycles, or docetaxel weekly for 12 cycles. For a more detailed discussion, please see the following: Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008;358:1663-1671.
Figure Paclitaxel 175 mg/m2 every 21 days for 4 doses n=1253 Randomization scheme. Trial Design Eligible patients had operable, histologically confirmed adenocarcinoma of the breast with histologically involved lymph nodes (tumor stage T1, T2, or T3 and nodal stage N1 or N2) or high-risk, axillary lymph node–negative disease (T2 or T3, N0) without distant metastases. Adequate organ function was required. Exclusion criteria included history of myocardial infarction, congestive heart failure, heart disease, pregnancy, or history of hypersensitivity reaction to paclitaxel or docetaxel. Full inclusion and exclusion criteria can be found online in the supplementary appendix of the original article. A total of 5052 patients were enrolled, of whom 4950 (98%) were eligible. All patients received doxorubicin (60 mg/m 2 of body surface area) and cyclophosphamide (600 mg/m 2 of body surface area) every 3 weeks for four cycles. Patients were then randomized to one of four treatment arms (Figure). Women who had breast-sparing surgery received radiotherapy according to accepted standards of care, and patients who had a modified radical mastectomy received radiotherapy at the discretion of the treating physician. All women with hormone receptor– positive disease received tamoxifen 20 mg daily for 5 years. The protocol was modified in 2005 to allow for a change to an aromatase inhibitor prior to completion of 5 years of tamoxifen or to begin an aromatase inhibitor after completing 5 years of tamoxifen. Operable breast cancer, lymph node positive or high-risk node negative N=4950 Doxorubicin 60 mg/m 2 + cyclophosphamide 600 mg/m2 every 21 days for 4 cycles Paclitaxel 80 mg/m2 weekly for 12 doses n=1231 Docetaxel 100 mg/m2 every 21 days for 4 doses n=1236 Weekly paclitaxel and breast cancer Docetaxel 35 mg/m2 every 21 days for 12 doses n=1230 The primary end point of the study was diseasefree survival, which was defined as the time from randomization to disease recurrence and included death from recurrence, death without recurrence, and contralateral breast cancer. The study had 86% power to detect a 17.5% reduction in the hazard rate for failure among the docetaxel groups or with weekly instead of every-3-week dosing. All eligi- The primary end point of the study was disease-free survival. ble patients undergoing randomization were included in the efficacy analysis, and all treated patients were included in the adverse events analysis. The log-rank test was used for analysis of disease-free and overall survival. Kaplan-Meier analysis was used to estimate distributions of events with respect to time. Cox proportional hazards models were used to estimate hazard ratios November 2008 • Vol 7 • Supplement 5 11
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Review - Haymarket Media Group

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