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Journal of Clinical Oncology, Vol 17, Issue 11 (November), 1999: 3374-3388
© 1999 American Society for Clinical Oncology

RAPID PUBLICATIONS

Further Evaluation of Intensified and Increased Total Dose of Cyclophosphamide for the Treatment of Primary Breast Cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-25

Bernard Fisher, Stewart Anderson, Arthur DeCillis, Nikolay Dimitrov, James N. Atkins, Louis Fehrenbacher, Patrick H. Henry, Edward H. Romond, Keith S. Lanier, Enrique Davila, Carl G. Kardinal, Leslie Laufman, H. Irving Pierce, Neil Abramson, Alan M. Keller, John T. Hamm, D.L. Wickerham, Mirsada Begovic, Elizabeth Tan-Chiu, Wei Tian, Norman Wolmark

From the National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA.

Address reprint requests to Bernard Fisher, MD, Scientific Director, National Surgical Adjuvant Breast and Bowel Project, Allegheny University of the Health Sciences, 4 Allegheny Center, Suite 602, Pittsburgh, PA 15212-5234, email bernard.fisher{at}nsabp.org, or to Stewart Anderson, PhD, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto St, Pittsburgh, PA 15261, email sja@pitt.edu.

ABSTRACT

PURPOSE: In 1989, the National Surgical Adjuvant Breast and Bowel Project initiated the B-22 trial to determine whether intensifying or intensifying and increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination would benefit women with primary breast cancer and positive axillary nodes. B-25 was initiated to determine whether further intensifying and increasing the cyclophosphamide dose would yield more favorable results.

PATIENTS AND METHODS: Patients (n = 2,548) were randomly assigned to three groups. The dose and intensity of doxorubicin were similar in all groups. Group 1 received four courses, ie, double the dose and intensity of cyclophosphamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group 1, administered in two courses (intensified); group 3 received double the dose of cyclophosphamide (intensified and increased) given in group 1. All patients received recombinant human granulocyte colony-stimulating factor. Life-table estimates were used to determine disease-free survival (DFS) and overall survival.

RESULTS: No significant difference was observed in DFS (P = .20), distant DFS (P = .31), or survival (P = .76) among the three groups. At 5 years, the DFS in groups 1 and 2 (61% v 64%, respectively; P = .29) was similar to but slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Survival in group 1 was concordant with that in groups 2 (78% v 77%, respectively; P = .71) and 3 (78% v 79%, respectively; P = .86). Grade 4 toxicity was 20%, 34%, and 49% in groups 1, 2, and 3, respectively. Severe infection and septic episodes increased in group 3. The decrease in the amount and intensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in all groups.

CONCLUSION: Because intensifying and increasing cyclophosphamide two or four times that given in standard clinical practice did not substantively improve outcome, such therapy should be reserved for the clinical trial setting.




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