National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA, USA.
Lancet Oncol. 2012 Jul;13(7):734-42. doi: 10.1016/S1470-2045(12)70226-7. Epub 2012 Jun 14.
Bisphosphonates are thought to act through the osteoclast by changing bone microenvironment. Previous findings of adjuvant clodronate trials in different populations with operable breast cancer have been mixed. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-34 aims to ascertain whether oral clodronate can improve outcomes in women with primary breast cancer.
NSABP B-34 is a multicentre, randomised, double-blind, placebo-controlled study in 3323 women with stage 1-3 breast cancer. After surgery to remove the tumour, patients were stratified by age, axillary nodes, and oestrogen and progesterone receptor status and randomly assigned in a 1:1 ratio to either oral clodronate 1600 mg daily for 3 years (n=1662) or placebo (1661). The primary endpoint was disease-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00009945.
Median follow-up was 90·7 months (IQR 82·7-100·0) and 3311 patients had data for this period. Disease-free survival did not differ between groups (286 events in the clodronate group vs 312 in the placebo group; hazard ratio 0·91, 95% CI 0·78-1·07; p=0·27). Moreover, no differences were recorded for overall survival (0·84, 0·67-1·05; p=0·13), recurrence-free interval (0·83, 0·67-1·04; p=0·10), or bone metastasis-free interval (0·77, 0·55-1·07; p=0·12). Non-bone metastasis-free interval was slightly increased with clodronate (0·74, 0·55-1·00; p=0·047). Analyses in women age 50 years or older on study entry showed benefits of clodronate for recurrence-free interval (0·75, 0·57-0·99; p=0·045), bone metastasis-free interval (0·62, 0·40-0·95; p=0·027), and non-bone metastasis-free interval (0·63, 0·43-0·91; p=0·014), but not for overall survival (0·80, 0·61-1·04, p=0·094). Adherence to treatment at 3 years was 56% for the clodronate group and 60% for the placebo group. Grade 3 or higher liver dysfunction was noted in 23 of 1612 patients in the clodronate group and 12 of 1623 patients in the placebo group; grade 3-4 diarrhoea was noted in 28 patients in the clodronate group and in ten in the placebo group. There was one possible case of osteonecrosis of the jaw in the clodronate group.
Findings of NSABP B-34 suggest that bisphosphonates might have anticancer benefits for older postmenopausal women. A meta-analysis of adjuvant bisphosphonate trials is suggested before recommendations for use in non-osteoporotic postmenopausal women with primary breast cancer are made.
National Cancer Institute, Bayer Oy (formerly Schering Oy).
双膦酸盐被认为通过改变骨微环境来作用于破骨细胞。先前在不同人群中进行的可手术乳腺癌辅助氯膦酸盐试验的结果参差不齐。国家外科辅助乳腺和肠道项目（NSABP）B-34 方案旨在确定口服氯膦酸盐是否可以改善原发性乳腺癌患者的结局。
NSABP B-34 是一项针对 3323 名 1-3 期乳腺癌女性的多中心、随机、双盲、安慰剂对照研究。在手术切除肿瘤后，根据年龄、腋窝淋巴结和雌激素和孕激素受体状态对患者进行分层，并按 1:1 的比例随机分配至口服氯膦酸盐 1600mg 每日 1 次（n=1662）或安慰剂（1661）。主要终点是无病生存，采用意向治疗进行分析。该试验在 ClinicalTrials.gov 注册，编号为 NCT00009945。
中位随访时间为 90.7 个月（IQR 82.7-100.0），3311 名患者在此期间有数据。两组无病生存无差异（氯膦酸盐组 286 例事件，安慰剂组 312 例事件；风险比 0.91，95%CI 0.78-1.07；p=0.27）。此外，总生存（0.84，0.67-1.05；p=0.13）、无复发间隔（0.83，0.67-1.04；p=0.10）或骨转移无间隔（0.77，0.55-1.07；p=0.12）也无差异。氯膦酸盐组无骨转移无间隔略有增加（0.74，0.55-1.00；p=0.047）。在研究入组时年龄为 50 岁或以上的女性分析中，氯膦酸盐对无复发间隔（0.75，0.57-0.99；p=0.045）、骨转移无间隔（0.62，0.40-0.95；p=0.027）和无骨转移无间隔（0.63，0.43-0.91；p=0.014）有获益，但对总生存无获益（0.80，0.61-1.04，p=0.094）。氯膦酸盐组在 3 年内的治疗依从性为 56%，安慰剂组为 60%。氯膦酸盐组有 23 名患者（1612 名患者中的 1.4%）和安慰剂组有 12 名患者（1623 名患者中的 0.7%）出现 3 级或更高级别的肝功能障碍；氯膦酸盐组有 28 名患者（1612 名患者中的 1.7%）和安慰剂组有 10 名患者（1623 名患者中的 0.6%）出现 3-4 级腹泻。氯膦酸盐组有 1 例可能发生颌骨坏死。
NSABP B-34 的结果表明，双膦酸盐可能对老年绝经后妇女具有抗癌益处。建议在向非骨质疏松性原发性乳腺癌绝经后妇女推荐使用之前，对辅助双膦酸盐试验进行荟萃分析。
美国国立癌症研究所，拜耳制药公司（前身为先灵葆雅制药公司）。
