For the phase III trial, based on the results of the pilot trial, sonographic evaluation of response after two cycles of TAC was chosen instead of clinical evaluation and patients with only favorable prognostic factors were excluded (T2, ER/PR positive, G2, N0, >35 years). In addition, the hypothesis that a longer treatment might enhance the pCR rate is incorporated in the responder arm testing six versus eight cycles of TAC. As NX could not significantly improve the pCR in non-responding patients but showed a better toxicity profile than TAC, a non-inferiority design has been chosen for the phase III trial in that subset of patients.
Recruitment and treatment of the patients was not only carried out in university hospitals, which is clearly stated in the list of authors. The patients were not selected and the administration of TAC and NX was manageable in the outpatient setting of university hospitals as well as general or district hospitals. Because of the high rate or febrile neutropenia in the TAC arm with antibiotic prophylaxis only, the phase III trial included (pegylated)-GSF prophylaxis [1].
The pCR rate of NX was 3.1% (confidence interval, CI 0.1% to 16.2%) and for TAC 7.3% (CI 1.5% to 19.9%). The difference is not statistically different because of the wide and widely overlapping confidence intervals. Furthermore, we observed an imbalance in hormone sensitivity of patients' tumor in favor of TAC. Therefore it cannot be concluded that NX is less effective than TAC in the non-responding cohort. This will only be answered by the phase III study, which closed recruitment in June 2005 after registration of 2100 patients.
The idea of in vivo adaption of preoperative chemotherapy has also been studied by other groups. In the Aberdeen trial, patients who responded to the first part of the treatment were randomized to continue preoperatively with the same therapy or to change to a non-cross-resistant regimen including a taxane. In the NSABP-B27 [2] trial, only those patients who showed a partial remission after four cycles of TAC benefited from a longer treatmen and the addition of docetaxel. The M. D. Anderson group randomized patients with a residual tumor exceeding 1 cm3 to postoperative therapy depending on their response to the neoadjuvant therapy [3
]. The Aberdeen and M. D. Anderson trials were able to demonstrate a survival benefit to changing the therapy. So far it is not yet clear which groupthe responders or non-respondersbenefits most from changing to a non-cross-resistant regimen.
German Breast Group, Schleussner str. 42, 63263 Neu-Isenburg, Germany
(* Email: minckwitz{at}germanbreastgroup.de)
References
1. von Minckwitz G, Blohmer JU, Löhr A et al. Primary prophylaxis with 3 weekly pegfilgrastim and ciprofloxacin effectively prevent (febrile) neutropenia and infection during neoadjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide (TAC) in breast cancer patients. ASCO Ann Meeting 2005; Abst 8008.
2. Bear HD, Andersom S, Smith RE et al. A randomized trial comparing preoperative (preop) doxorubicin/cyclophosphamide (AC) to preop AC followed by preop docetaxel (T) and to preop AC followed by postoperative (postop) T in patients (pts) with operable carcinoma of the breast: results of NSABP B-27. Breast Cancer Res Treat 2004; 88: 16 (Abstr).
3. Thomas E, Holmes FA, Smith TL et al. The use of alternate, non-cross-resistant adjuvant chemotherapy on the basis of pathologic response to a neoadjuvant doxorubicin-based regimen in women with operable breast cancer: long-term results from a prospective randomized trial. J Clin Oncol 2004; 22: 22942302.
|