The End of an Era: Shall We Move Forward?

Systemic adjuvant chemotherapy is a critical means for eradicating occult micrometastatic disease after surgery and has had a significant public health impact. The 2000 Early Breast Cancer Trialist’ Collaborative Group overview of polychemotherapy in breast cancer demonstrated that anthracycline-based regimens were superior to nonanthracycline-based therapies with improved disease-free survival (DFS) and overall survival (OS). The next generation of randomized clinical trials evaluated paclitaxel and docetaxel. These agents were well established in the treatment of metastatic breast cancer and lacked cross-resistance with the anthracyclines, which supported their evaluation in the adjuvant setting. Using these studies, a metaanalysis showed that the addition of a taxane to an anthracyclinebased regimen improved DFS and OS in high-risk patients regardless of age, menopausal status, the number of nodes involved, hormonereceptor status, and the type of taxane. There are now several effective anthracycline-taxane combinations and anthracycline-based regimens used in patients with high-risk disease. These include dosedense (dd) doxorubicin (A) plus cyclophosphamide (C) 3 by dd paclitaxel, AC3 weekly paclitaxel, AC3 docetaxel, docetaxel plus AC (TAC), A3docetaxel3C plus methotrexate and fluorouracil (F; CMF), F plus epirubicin (E) and C (FEC)3docetaxel, FEC3weekly paclitaxel, EC3 docetaxel, CEF, and E3 CMF. In the article that accompanies this editorial, Eiermann et al reported the results of the large randomized study Breast Cancer International Research Group (BCIRG) 005. They enrolled more than 3,000 patients with invasive human epidermal growth factor receptor 2 (HER2) –normal breast carcinoma and at least one lymph node involved and randomly assigned them to one of two chemotherapy regimens. These included AC (60/600 mg/m) 43 docetaxel (100 mg/m) 4 or TAC (75/50/500 mg/m) 6, and all cycles were given every 3 weeks. Antibiotic prophylaxis was mandatory for those on TAC but not for patients treated with AC3docetaxel. At a median follow-up of 65 months, the efficacy seemed equal, with a DFS of 78.6% and 78.9% and OS of 88.9% and 88.1% for AC3 docetaxel and TAC, respectively. In subgroups defined by hormone receptor status or the number of involved nodes, there were no differences observed with either DFS or OS. As expected, there were differences in toxicities according to the regimen. For example, TAC was associated with a higher febrile neutropenia (FN) rate (17.4% v 7.7%; P .001), despite the mandatory use of prophylactic antibiotics and a higher usage of filgrastim (44% of patients on TAC and 28% of those on AC 3 docetaxel). There was more fluid retention, hand-foot skin reaction, myalgia, and sensory neuropathy in the group receiving AC3docetaxel, possibly as a result of the higher dose of docetaxel per treatment cycle. The authors conclude that both regimens are equal in efficacy and represent appropriate treatment options. For clinicians, it is reasonable to ask how this should influence practice when a range of other evidence-based regimens exist that have not been directly compared. To provide additional background, I will expand the discussion beyond the docetaxel-containing regimens that Eiermann et al focused on and also consider those using paclitaxel. To review, paclitaxel was well studied in the adjuvant setting. Once every 3 week AC3 paclitaxel was accepted as a control regimen in three large studies that established the superiority for the novel schedules of administration. The Cancer and Leukemia Group B (CALGB) 9741 established the advantages of dd (every 2 weeks) treatments using full-dose AC3 paclitaxel or sequential single agents such as A3 paclitaxel3 C. The Eastern Cooperative Oncology Group (ECOG) 1199 established the superiority of 12 doses of weekly paclitaxel or every 3 week docetaxel over standard every 3 week paclitaxel all after AC. The National Cancer Institute of Canada MA.21 compared dd EC 3 paclitaxel (and CEF) against the standard AC3 paclitaxel and found advantages as well. Additionally, the Gruppo Espanola para la Investigation del Cancer de Mama (GEICAM) 9906 showed that FEC3 weekly paclitaxel was superior to FEC alone, but this was best considered a first generation trial in that it asked about the inclusion of a taxane rather than a comparison of taxane-based regimens. Across these studies, the FN rates were much lower with the use of paclitaxel (dd and weekly) as compared either directly or indirectly with those using docetaxel. The varying use of prophylactic antibiotics and growth factor support across studies was a notable confounder of course. However, even among the regimens specifying growth factor support from cycle 1, differences appeared. For example, the FN rate was only 2% with dd chemotherapy in CALGB 9741, 1% with AC3weekly paclitaxel in ECOG 1199, and 5.1% with FEC 3 weekly paclitaxel in GEICAM 9906. This compared favorably with the FN rate of 17.4% in the TAC arm and 7.7% in the AC3 docetaxel arm of the study by Eiermann et al (consistent with other docetaxel-containing regimens). Additionally, ECOG 1199 showed that weekly paclitaxel was better tolerated than both of the two docetaxel arms (AC3 docetaxel and AC3 weekly docetaxel) with only 28% of patients on weekly paclitaxel (P .32) versus 71% of patients receiving docetaxel every 3 weeks (P .001) and 45% on weekly docetaxel (P .001) experiencing grades 3 and 4 toxicities when compared with control. On the basis of the apparent toxicity differences across these regimens, a JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S