来曲唑和他莫昔芬单独及序贯用于绝经后甾体激素受体阳性乳腺癌患者的评价：中位随访 8.1 年的 BIG 1-98 随机临床试验。

Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up.

机构信息

International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

出版信息

Lancet Oncol. 2011 Nov;12(12):1101-8. doi: 10.1016/S1470-2045(11)70270-4. Epub 2011 Oct 20.

DOI:10.1016/S1470-2045(11)70270-4

PMID:22018631

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3235950/

Abstract

BACKGROUND

Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up.

METHODS

BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005, after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to letrozole of patients (n=619) in the tamoxifen arm. Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.govNCT00004205.

FINDINGS

8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0-12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0-12·4), letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74-0·92], overall survival HR 0·79 [0·69-0·90], DRFI HR 0·79 [0·68-0·92], BCFI HR 0·80 [0·70-0·92]; intention-to-treat disease-free survival HR 0·86 [0·78-0·96], overall survival HR 0·87 [0·77-0·999], DRFI HR 0·86 [0·74-0·998], BCFI HR 0·86 [0·76-0·98]). At a median follow-up of 8·0 years from randomisation (range 0-11·2) for the comparison of the sequential groups with letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI.

INTERPRETATION

For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability.

FUNDING

Novartis, United States National Cancer Institute, International Breast Cancer Study Group.

摘要

背景

激素受体阳性早期乳腺癌绝经后妇女存在持续的、长期的乳腺癌复发和死亡风险。因此，需要对这类患者人群进行内分泌治疗评估的临床试验进行长期随访。我们报告了乳房国际集团（BIG）1-98 研究在中位随访 8.1 年时的有效性结局更新。

方法

BIG 1-98 是一项随机、3 期、双盲试验，纳入了激素受体阳性早期乳腺癌的绝经后妇女，比较了他莫昔芬或来曲唑单药治疗 5 年、或两种药物序贯治疗 2 年（先用一种药物，后用另一种药物），然后再用 3 年另一种药物的治疗方案。随机分组采用随机区组设计，根据两臂或四臂随机分组方案、参与机构和化疗使用情况进行分层。患者、研究者、数据管理员和医学审查员均不知情。主要疗效终点是无病生存（事件包括浸润性乳腺癌复发、第二原发癌[对侧乳房和非乳房]或无先前癌症事件的死亡）。次要终点包括总生存、远处无复发生存期（DRFI）和乳腺癌无复发生存期（BCFI）。单药比较包括随机分配至他莫昔芬或来曲唑单药治疗 5 年的患者。在来曲唑与他莫昔芬相比显示出无病生存获益后，2005 年，方案修正案便于让仍单独接受他莫昔芬治疗的患者转为来曲唑治疗；使用逆概率 censoring 加权（IPCW）的 Cox 模型和 Kaplan-Meier 估计来计算（n=619）他莫昔芬组中选择性转为来曲唑的患者。与来曲唑单药治疗相比，序贯治疗的比较包括随机分配至来曲唑治疗 5 年、来曲唑治疗 2 年联合他莫昔芬治疗 3 年或他莫昔芬治疗 2 年联合来曲唑治疗 3 年的患者。所有患者的治疗均已结束，关于治疗 5 年内发生的不良事件的详细安全性结果已在其他地方报告。对于参加四臂方案的患者，随访仍在继续。BIG 1-98 在 clinicaltrials.gov 上注册（NCT00004205）。

发现

8010 例患者入组该试验，中位随访 8.1 年（范围 0-12.4）。2459 例患者随机分配至他莫昔芬单药治疗 5 年，2463 例患者随机分配至来曲唑单药治疗 5 年。在试验的四臂方案中，1546 例患者随机分配至来曲唑治疗 5 年，1548 例患者随机分配至他莫昔芬治疗 5 年，1540 例患者随机分配至来曲唑治疗 2 年联合他莫昔芬治疗 3 年，1548 例患者随机分配至他莫昔芬治疗 2 年联合来曲唑治疗 3 年。从随机分组起，中位随访时间为 8.7 年（范围 0-12.4），来曲唑单药治疗显著优于他莫昔芬，无论采用 IPCW 还是意向治疗分析（IPCW 无病生存 HR 0.82 [95% CI 0.74-0.92]，总生存 HR 0.79 [0.69-0.90]，DRFI HR 0.79 [0.68-0.92]，BCFI HR 0.80 [0.70-0.92]；意向治疗无病生存 HR 0.86 [0.78-0.96]，总生存 HR 0.87 [0.77-0.999]，DRFI HR 0.86 [0.74-0.998]，BCFI HR 0.86 [0.76-0.98]）。从随机分组起，中位随访时间为 8.0 年（范围 0-11.2），与来曲唑单药治疗相比，序贯组的四个终点均无统计学显著差异。来曲唑单药、来曲唑序贯他莫昔芬和他莫昔芬序贯来曲唑的 8 年意向治疗估计值（每个 SE≤1.1%）分别为无病生存 78.6%、77.8%、77.3%；总生存 87.5%、87.7%、85.9%；DRFI 89.9%、88.7%、88.1%；BCFI 86.1%、85.3%、84.3%。