Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer.
BACKGROUND
Chemotherapy regimens that combine anthracyclines and taxanes result in improved disease-free and overall survival among women with operable lymph-node-positive breast cancer. The effectiveness of concurrent versus sequential regimens is not known.


METHODS
We randomly assigned 5351 patients with operable, node-positive, early-stage breast cancer to receive four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (sequential ACT); four cycles of doxorubicin and docetaxel (doxorubicin-docetaxel); or four cycles of doxorubicin, cyclophosphamide, and docetaxel (concurrent ACT). The primary aims were to examine whether concurrent ACT was more effective than sequential ACT and whether the doxorubicin-docetaxel regimen would be as effective as the concurrent-ACT regimen. The secondary aims were to assess toxic effects and to correlate amenorrhea with outcomes in premenopausal women.


RESULTS
At a median follow-up of 73 months, overall survival was improved in the sequential-ACT group (8-year overall survival, 83%) as compared with the doxorubicin-docetaxel group (overall survival, 79%; hazard ratio for death, 0.83; P=0.03) and the concurrent-ACT group (overall survival, 79%; hazard ratio, 0.86; P=0.09). Disease-free survival was improved in the sequential-ACT group (8-year disease-free survival, 74%) as compared with the doxorubicin-docetaxel group (disease-free survival, 69%; hazard ratio for recurrence, a second malignant condition, or death, 0.80; P=0.001) and the concurrent-ACT group (disease-free survival, 69%; hazard ratio, 0.83; P=0.01). The doxorubicin-docetaxel regimen showed noninferiority to the concurrent-ACT regimen for overall survival (hazard ratio, 0.96; 95% confidence interval, 0.82 to 1.14). Overall survival was improved in patients with amenorrhea for 6 months or more across all treatment groups, independently of estrogen-receptor status.


CONCLUSIONS
Sequential ACT improved disease-free survival as compared with doxorubicin-docetaxel or concurrent ACT, and it improved overall survival as compared with doxorubicin-docetaxel. Amenorrhea was associated with improved survival regardless of the treatment and estrogen-receptor status. (ClinicalTrials.gov number, NCT00003782.)
Swain
Sandra M
SM
National Surgical Adjuvant Breast and Bowel Project, Washington Cancer Institute at Washington Hospital Center, Washington, DC 20010, USA. sandra.m.swain@medstar.net
Jeong
Jong-Hyeon
JH
Geyer
Charles E
CE
Costantino
Joseph P
JP
Pajon
Eduardo R
ER
Fehrenbacher
Louis
L
Atkins
James N
JN
Polikoff
Jonathan
J
Vogel
Victor G
VG
Erban
John K
JK
Rastogi
Priya
P
Livingston
Robert B
RB
Perez
Edith A
EA
Mamounas
Eleftherios P
EP
Land
Stephanie R
SR
Ganz
Patricia A
PA
Wolmark
Norman
N
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D000568:Amenorrhea / Q000139:chemically induced*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage*; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D017697:Premenopause; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage*
D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; D003520:Cyclophosphamide