Affiliation of authors: Ospedale Niguarda Ca' Granda, Dipartimento di Oncologia-Ematologia, Divisione di Oncologia Medica Falck, Milan, Italy.
Correspondence to: Paolo Pedrazzoli, M.D., Divisione di Oncologia Medica Falck, Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3, I-20162 Milano, Italy (e-mail: pedraz{at}tin.it).
In the February 2 issue of the Journal, Hortobagyi et al. (1) reported on a randomized trial of high-dose chemotherapy (HDCT) and stem-cell support versus conventional chemotherapy in high-risk patients with breast cancer, who showed no clinically or statistically significant difference in relapse-free or overall survival. This trial was based on previous phase II studies (2) that showed a substantial advantage for patients treated with HDCT in comparison with historical control subjects. The authors enrolled only 78 patients because they expected a overly optimistic 3-year difference of 30% between the two groups. The present study and other recent reports (3) clearly show that improvements, if any, of HDCT on the outcome of high-risk patients with breast cancer are likely to be slight. For this reason, all the clinicians working in this field, including the authors of the paper, agree that the results of large randomized trials (which have now completed their accrual) must be awaited to finally understand the role of the HDCT approach in the treatment of breast cancer. This attitude is even more necessary in view of the reported serious irregularities in the only randomized study showing a statistically significant survival advantage for this type of approach as adjuvant therapy for high-risk patients (4).
In addition, we believe that major medical journals should consider the policy of not publishing small, albeit randomized, studies that at this point, are likely to add little clinical information to this issue.
It has been reported that HDCT with stem-cell transplantation is more effective in patients with advanced breast cancer who respond to conventional treatment (5). Furthermore, lymph node status and the degree of tumor remission after primary chemotherapy in patients with operable breast cancer represent the most important prognostic factors for relapse-free survival (6).
Similar to stage IV disease, the benefits of HDCT intensification in patients with stage II or III disease may well be modest in those who respond poorly to primary chemotherapy. Zambelli et al. (7) have recently reported discouraging results with HDCT in high-risk (10 lymph nodes involved at surgery) patients with breast cancer whose tumors respond poorly to neoadjuvant anthracycline-containing regimens.
In the study by Hortobagyi et al. (1), randomization included 30 patients with axillary lymph node involvement after four cycles of preoperative chemotherapy, but the authors did not specify whether tumor response was a criterion for accrual. Moreover, the authors do not appear to consider additional prognostic factors, including c-erbB-2 status and proliferative capacity. Given the small number of patients studied, these drawbacks might have hampered the evaluation of clinical results.
Finally, in the study by Hortobagyi et al., patients in the HDCT arm were given two cycles of high-dose, nonmyeloablative chemotherapy with stem-cell rescue. In contrast, the uncontrolled studies of HDCT that showed a survival advantage in patients with breast cancer (2) relied on single, more intensive, and possibly more active regimens.
REFERENCES
1
Hortobagyi GN, Buzdar AU, Theriault RL, Valero V, Frye D, Booser DJ, et al. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 2000;92:22533.
2 Gianni AM, Siena S, Bregni M, Di Nicola M, Orefice S, Cusumano F, et al. Efficacy, toxicity and applicability of high-dose sequential chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved axillary nodes: five-year results. J Clin Oncol 1997;15:231221.[Abstract]
3 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]
4 Weiss RB, Rifkin RM, Stewart FM, Theriault RL, Williams LA, Herman AA, et al. High-dose chemotherapy for high-risk primary breast cancer: an on-site review of the Bezwoda study. Lancet 2000;355:9991003.[Medline]
5 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]
6 Bonadonna G, Valagussa P, Brambilla C, Ferrari L, Moliterni A, Terenziani M, et al. Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 1998;16:93100.[Abstract]
7 Zambelli A, Da Prada GA, Pedrazzoli P, Ponchio L, Robustelli della Cuna G. Poor outcome of patients with resectable breast cancer receiving adjuvant high-dose sequential chemotherapy following preoperative treatment. Anticancer Res 1999;19:23736.[Medline]
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