Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham D L, Wolmark N, Costantino J, Redmond C, Fisher E R, Bowman D M, Deschênes L, Dimitrov N V, Margolese R G, Robidoux A, Shibata H, Terz J, Paterson A H, Feldman M I, Farrar W, Evans J, Lickley H L
University of Pittsburgh School of Medicine, PA 15261, USA.
J Natl Cancer Inst. 1996 Nov 6;88(21):1529-42. doi: 10.1093/jnci/88.21.1529.
In 1982, the National Surgical Adjuvant Breast and Bowel Project initiated a randomized, double-blinded, placebo-controlled trial (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement. The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease. However, questions arose about how long the observed benefit would persist, about the duration of therapy necessary to maintain maximum benefit, and about the nature and severity of adverse effects from prolonged treatment.
We evaluated the 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 tamoxifen therapy were compared.
In the trial, patients were initially assigned to receive either tamoxifen at 20 mg/day (n = 1404) or placebo (n = 1414). Tamoxifen-treated patients who remained disease free after 5 years of therapy were then reassigned to receive either another 5 years of tamoxifen (n = 322) or 5 years of placebo (n = 321). After the study began, another group of patients who met the same protocol eligibility requirements as the randomly assigned patients were registered to receive tamoxifen (n = 1211). Registered patients who were disease free after 5 years of treatment were also randomly assigned to another 5 years of tamoxifen (n = 261) or to 5 years of placebo (n = 249). To compare 5 years with more than 5 years 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 tamoxifen or placebo continued to be followed in the study. Survival, disease-free survival, and distant disease-free survival (relating to failure at distant sites) were estimated by use of the Kaplan-Meier method; differences between the treatment groups were assessed by use of the logrank test. The relative risks of failure (with 95% confidence intervals [CIs]) were determined by use of the Cox proportional hazards model. Reported P values are two-sided.
Through 10 years of follow-up, a significant advantage in disease-free survival (69% versus 57%, P < .0001; relative risk = 0.66; 95% CI = 0.58-0.74), distant disease-free survival (76% versus 67%, P < .0001; relative risk = 0.70; 95% CI = 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 assigned to receive tamoxifen. The survival benefit extended to those 49 years of age or younger and to those 50 years of age or older. Tamoxifen therapy was associated with a 37% reduction in the incidence of contralateral (opposite) breast cancer (P = .007). Through 4 years after the reassignment of tamoxifen-treated patients to either continued-therapy or placebo groups, advantages in disease-free survival (92% versus 86%, P = .003) and distant disease-free survival (96% versus 90%, P = .01) were found for those who discontinued tamoxifen treatment. Survival was 96% for those who discontinued tamoxifen compared with 94% for those who continued tamoxifen treatment (P = .08). A higher incidence of thromboembolic events was seen in tamoxifen-treated patients (through 5 years, 1.7% versus 0.4%). Except for endometrial cancer, the incidence of second cancers was not increased with tamoxifen therapy.
The benefit from 5 years of tamoxifen therapy persists through 10 years of follow-up. No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years.
1982年，国家乳腺与肠道外科辅助治疗项目启动了一项随机、双盲、安慰剂对照试验（B-14），以确定辅助性他莫昔芬治疗对雌激素受体阳性、无腋窝淋巴结受累的原发性可手术乳腺癌患者的有效性。研究结果表明，他莫昔芬治疗为早期疾病患者带来了显著益处。然而，出现了一些问题，如观察到的益处能持续多久、维持最大益处所需的治疗持续时间，以及长期治疗的不良反应的性质和严重程度。
我们通过10年的随访评估了B-14试验中患者的结局。此外，比较了5年与超过5年他莫昔芬治疗的效果。
在试验中，患者最初被分配接受20毫克/天的他莫昔芬（n = 1404）或安慰剂（n = 1414）。接受他莫昔芬治疗5年后仍无疾病的患者，随后被重新分配接受另外5年的他莫昔芬（n = 322）或5年的安慰剂（n = 321）。研究开始后，另一组符合与随机分配患者相同方案资格要求的患者登记接受他莫昔芬（n = 1211）。接受5年治疗后无疾病的登记患者也被随机分配接受另外5年的他莫昔芬（n = 261）或5年的安慰剂（n = 249）。为了比较5年与超过5年的他莫昔芬治疗，将所有重新分配接受另外5年药物治疗的患者的数据合并。未重新分配接受他莫昔芬或安慰剂治疗的患者继续在研究中接受随访。使用Kaplan-Meier方法估计生存、无病生存和远处无病生存（与远处部位失败相关）；使用对数秩检验评估治疗组之间的差异。使用Cox比例风险模型确定失败的相对风险（95%置信区间[CI]）。报告的P值为双侧。
经过10年的随访，首次分配接受他莫昔芬治疗的患者在无病生存（69%对57%，P <.0001；相对风险 = 0.66；95% CI = 0.58 - 0.74）、远处无病生存（76%对67%，P <.0001；相对风险 = 0.70；95% CI = 0.61 - 0.81）和生存（80%对76%，P =.02；相对风险 = 0.84；95% CI = 0.71 - 0.99）方面具有显著优势。生存益处扩展到49岁及以下和50岁及以上的患者。他莫昔芬治疗使对侧（对侧）乳腺癌的发病率降低了37%（P =.007）。在将接受他莫昔芬治疗的患者重新分配到继续治疗或安慰剂组后的4年中，停止他莫昔芬治疗的患者在无病生存（92%对86%，P =.003）和远处无病生存（96%对90%，P =.01）方面具有优势。停止他莫昔芬治疗的患者生存率为96%，继续他莫昔芬治疗的患者生存率为94%（P =.08）。接受他莫昔芬治疗的患者中血栓栓塞事件的发生率较高（5年期间，1.7%对0.4%）。除子宫内膜癌外，他莫昔芬治疗未增加第二癌症的发病率。
他莫昔芬5年治疗的益处持续到10年的随访期。继续他莫昔芬治疗超过5年没有额外益处。
