Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial.
BACKGROUND
Breast cancer patients with four or more positive axillary lymph nodes who are treated with conventional adjuvant therapy have a poor prognosis. In uncontrolled studies, high-dose chemotherapy produced much better results than conventional therapy. We compared the benefits of a single cycle of high-dose chemotherapy and the benefits of conventional chemotherapy in patients with high-risk breast cancer in a prospective, unblinded, randomized trial.


METHODS
Between February 23, 1995, and June 29, 1999, 605 patients with breast cancer who had four or more positive lymph nodes were randomly assigned to treatment (307 to high-dose therapy and 298 to conventional therapy). The conventional chemotherapy regimen was four cycles of doxorubicin (75 mg/m2) followed by eight cycles of CMF (cyclophosphamide [600 mg/m2], methotrexate [50 mg/m2], and 5-fluorouracil [600 mg/m2]), all given intravenously on day 1 of a 21-day cycle. The high-dose regimen was four cycles of doxorubicin (75 mg/m2), followed by a single cycle of intermediate-dose cyclophosphamide (4000 mg/m2) supported by filgrastim (300 microg/day) for up to 10 days followed by high-dose cyclophosphamide (6000 mg/m2) and thiotepa (800 mg/m2). Peripheral blood progenitor cells were harvested by leukapheresis after treatment with cyclophosphamide and filgrastim and then re-infused after the high-dose cycle. Log-rank tests were used to compare survival rates. All statistical analyses were two-sided.


RESULTS
At a median follow-up of 6 years, no statistically significant differences were detected between the arms in 5-year relapse-free survival (high-dose arm = 57%, 95% confidence interval [CI] = 51% to 63%; conventional-dose arm = 54%, 95% CI = 48% to 61% (P =.73) or in 5-year overall survival (high-dose arm = 62%, 95% CI = 56% to 68%; conventional-dose arm = 64%, 95% CI = 57% to 70%) (P =.38).


CONCLUSIONS
Autograft-supported, high-dose therapy is not superior to conventional chemotherapy in patients with breast cancer who have multiple involved lymph nodes. This conclusion should be viewed in the context of improving the success of conventional chemotherapy.
Leonard
Robert C F
RC
South West Wales Cancer Institute, Singleton Hospital, Swansea, Wales, UK. r.c.f.leonard@swan.ac.uk
Lind
Michael
M
Twelves
Christopher
C
Coleman
Robert
R
van Belle
Simon
S
Wilson
Charles
C
Ledermann
Jonathan
J
Kennedy
Ian
I
Barrett-Lee
Peter
P
Perren
Timothy
T
Verrill
Mark
M
Cameron
David
D
Foster
Elizabeth
E
Yellowlees
Ann
A
Crown
John
J
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D000069585:Filgrastim; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006412:Hematopoietic Stem Cells; D006801:Humans; D007937:Leukapheresis; D008207:Lymphatic Metastasis; D008408:Mastectomy; D015412:Mastectomy, Segmental; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D011446:Prospective Studies; D018714:Radiotherapy, Adjuvant; D011994:Recombinant Proteins; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D003520:Cyclophosphamide; D000069585:Filgrastim; D005472:Fluorouracil; D008727:Methotrexate