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

Purpose: In 1989, the National Surgical Adjuvant Breast and Bowel Project i nitiated the B-22 trial to determine whether intensifying or intensifying a nd increasing the total dose of cyclophosphamide in a doxorubicin-cyclophos phamide combination would benefit women with primary breast cancer and posi tive axillary nodes. B-25 was initiated to determine whether further intens ifying and increasing the cyclophosphamide dose would yield more favorable results. Patients and Methods: patients(n = 2,548)were randomly assigned to three gr oups. The dose and intensity of doxorubicin were similar in all groups. Gro up 1 received four courses, ie, double the dose and intensity of cyclophosp hamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group I,administered in two courses (intensi fied); group 3 received double the dose of cyclophosphamide (intensified an d increased) given in group 1. All patients received recombinant human gran ulocyte colony-stimulating factor. Life-table estimates were used to determ ine disease-free survival [DFS) and overall survival. Results: No significant difference war observed in DFS (P = .20), distant D FS (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 bu r slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Su rvival in group I was concordant with that in groups 2 (78% v 77%, respecti vely; P = .71) and 3 (78% v 79%, respectively; P = .86). Grade 4 toxicity w as 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 in tensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in al l groups. Conclusion: Because intensifying and increasing cyclophosphamide two or fou r times that given in standard clinical practice did not substantively impr ove outcome, such therapy should be reserved for the clinical trial setting . (C) 1999 by American Society of Clinical Oncology.