Affiliation of authors: Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston.
Correspondence to: Gabriel N. Hortobagyi, M.D., Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 56, Houston, TX 77030 (e-mail: ghortoba{at}mdanderson.org).
RESPONSE
The letter by Pedrazzoli et al. endorses the conclusions of our randomized, high-dose chemotherapy trial for high-risk primary breast cancer. It also underlines our plea that definitive conclusions about the efficacy of high-dose chemotherapy be reserved until the mature results of large randomized trials become available.
Furthermore, Pedrazzoli et al. propose that high-dose chemotherapy might be more effective for patients with breast cancer who respond to conventional treatment. This type of analysis is erroneous and misleading. Patients with advanced breast cancer who respond to conventional therapy have a better prognosis than those who do not (1). This is true whether they receive high-dose chemotherapy or not (1,2). However, in the absence of compelling evidence that high-dose chemotherapy improves outcomes in the overall group of patients with advanced disease, it is inappropriate to conclude that response to conventional therapy selects patients who will benefit from high-dose chemotherapy.
Patients who still demonstrate multiple, positive axillary lymph nodes after preoperative chemotherapy have an unfavorable prognosis (3). In our study, eligible patients who received preoperative chemotherapy had responded to preoperative therapy, but they still had four or more positive axillary lymph nodes. When this study was designed, only patients at very high risk of recurrence were acceptable candidates for high-dose chemotherapy, which in the late 1980s was associated with a substantial (5%8%) treatment-related mortality rate.
The results of our study showed no differences in outcome for the overall randomly assigned groups and for the subsets whom we planned to analyze prospectively. Many additional subset analyses could be undertaken retrospectively. However, considering the small sample size and the retrospective and unplanned nature of additional analyses (such as a search for prognostic factors), any results would be tentative at best. We thought that the presentation of the overall results, based on the planned analyses, would best serve our readers.
We discussed the nonmyeloablative character of the high-dose CEP (cisplatin, etoposide, and cyclophosphamide) therapy on page 231 of our paper. Although Pedrazzoli et al. suggest that other high-dose regimens might have greater antitumor efficacy, the evidence in support of this statement is lacking. The report of the North American Bone Marrow Transplant Registry found no statistically significant differences among the various preparatory regimens in use today (4). Furthermore, the second reference used by Pedrazzoli et al. to suggest the superiority of other "single, more intensive, and possibly more active regimens" failed to show any difference between conventional dose and high-dose chemotherapy (5).
We again conclude that, on the basis of our small randomized trial, we were able to rule out a large (>30%) difference in progression-free and overall survival rates in patients with high-risk breast cancer. Definitive conclusions about the therapeutic worth of high-dose chemotherapy for primary and/or metastatic breast cancer await the mature results of ongoing, large, randomized clinical trials.
REFERENCES
1 Rahman ZU, Frye DK, Smith TL, Asmar L, Theriault RL, Buzdar AU, et al. Results and long term follow-up for 1581 patients with metastatic breast carcinoma treated with standard dose doxorubicin-containing chemotherapy: a reference. Cancer 1999;85:10411.[Medline]
2 Dunphy FR, Spitzer G, Fornoff JE, Yau JC, Huan SD, Dicke KA, et al. Factors predicting long-term survival for metastatic breast cancer patients treated with high-dose chemotherapy and bone marrow support. Cancer 1994;73:215767.[Medline]
3 Kuerer HM, Sahin AA, Hunt KK, Newman LA, Breslin TM, Ames FC, et al. Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoad juvant chemotherapy. Ann Surg 1999;230:728.[Medline]
4 Antman KH, Rowlings PA, Vaughan WP, Pelz CJ, Fay JW, Fields KK, et al. High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America. J Clin Oncol 1997;15:18709.[Abstract]
5 Rodenhuis S, Richel DJ, van der Wall E, Schornagel JH, Baars JW, Koning CC, et al. Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement. Lancet 1998;352:51521.[Medline]
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