Commentary (Buzdar): Optimizing Adjuvant Chemotherapy in Early-Stage Breast Cancer

This review of adjuvant chemotherapy by Perez and Muss is concise and complete. For the most part, the authors present the data in a balanced way. The role of adjuvant chemotherapy has been established in breast cancer. Appropriate utilization of adjuvant chemotherapy can significantly reduce the risk of disease recurrence and improve survival. These benefits are associated with adjuvant chemotherapy regardless of the age of the patient, nodal status, or hormonal status of cancer. The 15-year update of chemotherapy trials by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) has clearly demonstrated that about 6 months of anthracyclinebased polychemotherapy reduces the annual breast cancer death rate by approximately 38% (standard error [SE] = 5%) for women younger than 50 years old and by 20% (SE = 4%) for those aged 50 to 69 years.[1] Few women aged ≥ 70 years have been included and evaluated in the chemotherapy trials to adequately define the benefit of adjuvant chemotherapy in this subset of patients. In the EBCTCG Overview, triple-drug combinations such as FAC (fluorouracil [5-FU], doxorubicin [Adriamycin], cyclophosphamide) or FEC (fluorouracil, epirubicin [Ellence], cyclophosphamide) were significantly superior to CMF (cyclophosphamide, methotrexate, 5-FU) chemotherapy. Randomized studies have shown that AC (doxorubicin and cyclophosphamide) has efficacy similar to CMF and may not be as effective as FAC or FEC combinations. Role of Taxanes
A number of subsequent studies have evaluated the role of taxanes (paclitaxel or docetaxel [Taxotere]) in adjuvant therapy. The data from these trials have been consistent, illustrating that the inclusion of taxanes can further improve the disease-free and overall survival of patients with early- stage breast cancer.[2-5] In these adjuvant trials, taxanes have been utilized either sequentially or concomitantly with other drugs. A proportional reduction in risk of recurrence and improvement in survival have been of similar magnitude whether the taxanes were administered sequentially or concomitantly. The concomitant administration taxanes with anthracyclines, as evaluated in the TAC combination (docetaxel, doxorubicin, cyclophosphamide), has been associated with a significantly increased risk of febrile neutropenia and anemia. Efforts to reduce the risk of infections and anemia have resulted in an increased utilization of hematopoetic growth factors in the adjuvant setting. This approach has enhanced the cost and complexity of adjuvant therapy. Sequential utilization of taxanes is better tolerated by patients, with a markedly reduced need of growth factors. Dose-dense therapy has been evaluated in numerous trials, which, except for one large study,[6-9] have failed to demonstrate any clinical benefit of this approach. Lack of Evidence
The recommendations of the authors regarding dose-dense and TAC adjuvant therapy in node-positive disease are not based on any strong evidence. These two therapeutic approaches can be associated with increased costs of therapy, and their long-term safety remains to be defined, as all safety data in studies of dose-dense therapy were limited to a small subset of patients. A number of ongoing trials are comparing dosedense therapy and the TAC combination to conventional schedules of administration. The data from these trials will improve our knowledge regarding optimal chemotherapy delivery. It is possible that the small benefit observed with dose-dense therapy is related to more frequent administration of paclitaxel, as this drug has an established schedule-dependent efficacy. Weekly administration of this drug has been associated with higher objective response rates in patients with metastatic disease,[10] and in the neadjuvant setting, a higher pathologic complete response in the breast and axilla were observed.[11] There is no evidence that the efficacy of docetaxel is enhanced by weekly administration, which should be avoided. Dose escalation and the dose-dense approach with cyclophosphamide and anthracyclines beyond conventional doses have consistently demonstrated no further benefit. Conclusions
From the available data, one can conclude that anthracycline-based therapies are superior, and inclusion of one of the taxanes in the adjuvant setting can further reduce the risk of recurrence and death. In patients with HER2-positive disease, inclusion of trastuzumab (Herceptin) can further favorably change the natural history of breast cancer. In patients with hormone- receptor-positive disease, inclusion of an appropriate endocrine therapy should be an integral part of overall adjuvant therapy.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687- 1717, 2005.
2. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:963-964, 2003.
3. Mamounas EP, Bryant J, Lembersky BC, et al: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. J Clin Oncol 23:3686-3696, 2005.
4. Martin M, Pienkowski T, Mackey J, et al: TAC improves disease free survival and overall survival over FAC in node positive early breast cancer patients, BCIRG 001: 55 months follow-up (abstract 43). Breast Cancer Res Treat 76(suppl 1), 2002.
5. Buzdar AU, Singletary SE, Valero V, et al: Evaluation of paclitaxel in adjuvant chemotherapy for patients with operable breast cancer: Preliminary data of a prospective randomized trial. Clin Cancer Res 8:1073-1079, 2002.
6. 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 21:1431-1439, 2003.
7. Schneeweiss A, Schuetz F, Rudlowski C, et al: Dose-dense primary systemic chemotherapy with gemcitabine plus epirubicin sequentially followed by docetaxel for early breast cancer: Final results of a phase I/II trial. Anticancer Drugs 16:1023-1028, 2005.
8. Fountzilas G, Skarlos D, Dafni U, et al: Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: A randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 16:1762-1771, 2005.
9. von Minckwitz G, Raab G, Caputo A, et al: Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: The GEPARDUO study of the German Breast Group. J Clin Oncol 23:2676-2685, 2005.
10. Seidman AD, Berry D, Cirrincione C, et al: CALGB 9840: Phase III study of weekly (W) paclitaxel (P) via 1-hour (h) infusion versus standard (S) 3 h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC (abstract 512). Proc Am Soc Clin Oncol 22(14S):6s, 2004.
11. Green MC, Buzdar AU, Smith T, et al: Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23:5983-5992, 2005.