Background

Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population.

Methods

In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990.

Findings

Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43–0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39–0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34–0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31–0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43–0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously.

Interpretation

The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results.

Funding

Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.

中文翻译：

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使用阿司匹林预防遗传性结直肠癌（林奇综合征）的癌症，CAPP2 研究中的 10 年随访和基于登记的 20 年数据：一项双盲、随机、安慰剂对照试验。

背景

林奇综合征与结直肠癌和更广泛的癌症（尤其是子宫内膜癌）风险增加有关。2011 年，我们小组报告了林奇综合征参与者的长期癌症结果（平均随访 55·7 个月 [SD 31·4]），这些参与者参加了每日阿司匹林与安慰剂的随机试验。该报告完成了计划的 10 年随访，以便对这一高危人群定期服用阿司匹林的效果进行长期评估。

方法

在双盲、随机 CAPP2 试验中，来自全球 43 个国际中心的 861 名患者（707 名 [82%] 来自欧洲，112 名 [13%] 来自澳大利亚，38 名 [4%] 来自非洲，4 名 [<1%] 来自澳大利亚美洲）患有林奇综合征的患者被随机分配每天服用 600 毫克阿司匹林或安慰剂。自招募起，癌症结果被监测至少 10 年，其中英国、芬兰和威尔士参与者的监测时间长达 20 年。主要终点是结直肠癌的发生。分析是按照意向治疗并按照方案进行的。该试验已在 ISRCTN 登记处注册，编号 ISRCTN59521990。

发现

1999年1月至2005年3月期间，937名平均年龄为45岁的林奇综合征患者开始接受治疗，其中861人同意被随机分配到阿司匹林组或安慰剂组；427 名 (50%) 参与者服用阿司匹林，434 名 (50%) 参与者服用安慰剂。参与者平均随访 10 年，约 8500 人年。接受阿司匹林治疗的 427 名参与者中有 40 名（9%）患上结直肠癌，而接受安慰剂的 434 名参与者中有 58 名（13%）患上结直肠癌。意向治疗 Cox 比例风险分析显示，与安慰剂相比，阿司匹林的风险比 (HR) 显着降低为 0·65（95% CI 0·43–0·97；p=0·035）。考虑多个主要事件的负二项式回归得出的发病率为 0·58 (0·39–0·87；p=0·0085)。根据方案分析仅限于 509 名实现 2 年干预的人，HR 为 0·56 (0·34–0·91；p=0·019)，发病率为 0·50 (0·31–0 ·82；p=0·0057)。据报道，接受阿司匹林治疗的 36 名参与者和接受安慰剂治疗的 36 名参与者患有非结直肠林奇综合征癌症。意向治疗和符合方案分析显示没有效果。对于所有林奇综合征癌症的总和，意向治疗分析并未达到显着性，但按方案分析显示阿司匹林组的总体风险显着降低（HR=0·63、0·43–0·92；p=0 ·018）。阿司匹林组和安慰剂组在干预阶段的不良事件相似，对于具有完整干预阶段数据的参与者，干预组之间的依从性没有显着差异；之前报道过详细信息。

解释

我们的结果支持了在林奇综合征中使用阿司匹林预防结直肠癌的案例。

资金

英国癌症研究中心、欧盟、MRC、NIHR、拜耳制药公司、巴伯基金会。