Since 1998, the standard of care for patients with node-positive breast cancer in the United States and other parts of the world has been treatment with doxorubicin and cyclophosphamide followed by the taxane (paclitaxel) every three weeks. Herceptin is added for HER+ disease. This treatment regimen was based on an intergroup study demonstrating that the addition of paclitaxel to doxorubicin and cyclophosphamide (AC) led to rates of disease-free survival of 70 percent and overall survival of 80 percent at five years, as compared with 65 percent and 77 percent, respectively, for doxorubicin and cyclophosphamide alone, with modest differences in the rate of toxic effects.
The evidence for weekly paclitaxel comes from ECOG 1199 trial, a randomized trial of doxorubicin and cyclophosphamide (AC) chemotherapy followed by 1 of 4 taxane-based treatments — paclitaxel given either weekly or every 3 weeks, or docetaxel given either weekly or every 3 weeks.
Consistent with previous reports, the updated data showed that most of these regimens could be delivered effectively; only weekly docetaxel was associated with < 80% dose delivery. The side-effect profiles of the various treatments differed in ways predictable from extensive use of these regimens in breast cancer. For example, every-3-weeks docetaxel produced the highest rates of neutropenia and febrile neutropenia, whereas weekly paclitaxel had the highest rate of neuropathy.
The primary study end point was a comparison of paclitaxel vs docetaxel and a comparison of weekly vs every-3-weeks therapy, based on the 2 x 2 randomization scheme. The primary end points were all negative — that is, there was no overall difference between the taxanes or the schedules in the aggregate.
However, analysis of each of the 4 treatment arms does suggest emerging winners and losers. In particular, weekly paclitaxel and every-3-weeks docetaxel had the lowest rates of disease recurrence, whereas weekly paclitaxel had the highest 5-year overall survival and was the only treatment with statistically significant improvement in overall survival compared with every-3-weeks paclitaxel.
This is now one of several trials that has shown that the every-3-weeks schedule of AC followed by paclitaxel (P) (AC → P) every three weeks is an inferior treatment program. In CALGB 9741, every-2-weeks AC → P was shown to be superior to an every-3-weeks regimen.
Breast Cancer Disease Site Group. Adjuvant systemic therapy for node-negative breast cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2003 May 1 [online update]. 22 p. (Practice guideline report; no. 1-8). [79 references]
nccn.org, breast cancer
Sparano JA, Wang M, Martino S, et al. Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in operable breast cancer: results of Intergroup Trial E1199. Proc Am Soc Clin Oncol. 2007;25:6s. Abstract 516.
Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21:1431-1439. Abstract
Loesch DM, Greco F, O’Shaughnessy J, et al. A randomized, multicenter phase III trial comparing doxorubicin + cyclophosphamide followed by paclitaxel or doxorubicin + paclitaxel followed by weekly paclitaxel as adjuvant therapy for high-risk breast cancer. Proc Am Soc Clin Oncol. 2007;25:7s. Abstract 517.
Verill MW, Lee J, Cameron DA, et al. Anglo-Celtic IV: first results of a UK National Cancer Research Network randomized phase III pharmacogenetic trial of weekly compared to 3 weekly paclitaxel in patients with locally advanced or metastatic breast cancer (ABC). Proc Am Soc Clin Oncol. 2007;25:33s. Abstract LBA1005.
Joseph A. Sparano, M.D., Molin Wang, Ph.D., Silvana Martino, D.O., Vicky Jones, M.D., Edith A. Perez, M.D., Tom Saphner, M.D., Antonio C. Wolff, M.D., George W. Sledge, Jr., M.D., William C. Wood, M.D., and Nancy E. Davidson, M.D.Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer. N Engl J Med 2008; 358:1663-1671