5 VERSUS MORE THAN 5 YEARS OF TAMOXIFEN THERAPY FOR BREAST-CANCER PATIENTS WITH NEGATIVE LYMPH-NODES AND ESTROGEN RECEPTOR-POSITIVE TUMORS

Background: In 1982, the National Surgical Adjuvant Breast and Bowel P roject initiated a randomized, double-blinded, placebo-controlled tria l (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen recep tor-positive tumors and no axillary lymph node involvement. The findin gs indicated that tamoxifen therapy provided substantial benefit to pa tients with early stage disease. However, questions arose about how lo ng the observed benefit would persist, about the duration of therapy n ecessary to maintain maximum benefit, and about the nature and severit y of adverse effects from prolonged treatment. Purpose: We evaluated t he outcome of patients in the B-14 trial through 10 years of follow-up . In addition, the effects of 5 years versus more than 5 years of tamo xifen therapy were compared. Methods: In the trial, patients were init ially assigned to receive either tamoxifen at 20 mg/day (n = 1404) or placebo (n = 1414). Tamoxifen-treated patients who remained disease fr ee after 5 years of therapy were then reassigned to receive either ano ther 5 years of tamoxifen (n = 322) or 5 years of placebo (n = 321). A fter the study began, another group of patients who met the same proto col eligibility requirements as the randomly assigned patients were re gistered to receive tamoxifen (n = 1211). Registered patients who were disease free after 5 years of treatment were also randomly assigned t o another 5 years of tamoxifen (n = 261) or to 5 years of placebo (n = 249). To compare 5 years with more than 5 gears of tamoxifen therapy, data relating to all patients reassigned to an additional 5 years of the drug were combined. Patients who were not reassigned to either tam oxifen or placebo continued to be followed in the study. Survival, dis ease-free survival, and distant disease-free survival (relating to fai lure at distant sites) were estimated by use of the Kaplan-Meier metho d; differences between the treatment groups were assessed by use of th e logrank test. The relative risks of failure (with 95% confidence int ervals [CIs]) were determined by use of the Cox proportional hazards m odel. Reported P values are two-sided. Results: Through 10 years of fo llow-up, a significant advantage in disease-free survival (69% versus 57%, P<.0001; relative risk = 0.66; 95% CI = 0.58-0.74), distant disea se-free survival (76% versus 67%, P<.0001; relative risk = 0.70; 95% C I = 0.61-0.81), and survival (80% versus 76%, P = .02; relative risk = 0.84; 95% CI = 0.71-0.99) was found for patients in the group first a ssigned to receive tamoxifen. The survival benefit extended to those 4 9 years of age or younger and to those 50 years of age or older. Tamox ifen therapy was associated with a 37% reduction in the incidence of c ontralateral (opposite) breast cancer (P = .007). Through 4 years afte r the reassignment of tamoxifen-treated patients to either continued-t herapy or placebo groups, advantages in disease-free survival (92% ver sus 86%, P = .003) and distant disease-free survival (96% versus 90%, P = .01) were found for those who discontinued tamoxifen treatment. Su rvival was 96% for those who discontinued tamoxifen compared with 94% for those who continued tamoxifen treatment (P = .08). A higher incide nce of thromboembolic events was seen in tamoxifen-treated patients (t hrough 5 years, 1.7% versus 0.4%). Except for endometrial cancer, the incidence of second cancers was not increased with tamoxifen therapy. Conclusions and Implications: The benefit from 5 years of tamoxifen th erapy persists through 10 years of follow-up. No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years.