Background

The only established treatment for preventing colorectal cancer in patients with familial adenomatous polyposis (FAP) is colectomy, which greatly reduces patient quality of life. Thus, an alternative method is warranted. In this trial, we aimed to clarify the individual and joint effects of low-dose aspirin and mesalazine on the recurrence of colorectal polyps in Japanese patients with FAP.

Methods

This was a randomised, double-blind, placebo-controlled, multicentre trial with a two-by-two factorial design done in 11 centres in Japan. Eligible patients were aged 16–70 years and had a history of more than 100 adenomatous polyps in the large intestine, without a history of colectomy. Before the study, patients underwent endoscopic removal of all colorectal polyps of at least 5·0 mm in diameter. Randomisation was done with a minimisation method with a random component to balance the groups with respect to the adjustment factors of sex, age (<30 years vs ≥30 years), or smoking status at the time of entry. Patients and researchers were masked to the treatment group. There were four groups: aspirin (100 mg per day) plus mesalazine (2 g per day), aspirin (100 mg per day) plus mesalazine placebo, aspirin placebo plus mesalazine (2 g per day), or aspirin placebo plus mesalazine placebo. Treatment was continued until 1 week before 8 month colonoscopy. The primary endpoint was the incidence of colorectal polyps of at least 5·0 mm at 8 months and was assessed in the intention-to-treat population. Safety was assessed in the ITT population. We also did a per-protocol analysis including only patients who took at least 70% of the allocated study drug. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000018736, and is complete.

Findings

Between Sept 25, 2015, and March 13, 2017, 104 patients were randomly assigned to receive either aspirin or aspirin placebo (n=52) or mesalazine or mesalazine placebo (n=52). Two patients withdrew from the aspirin plus mesalazine placebo group. 26 (50%) of 52 patients who received no aspirin had colorectal polyps of at least 5·0 mm at 8 months, as did 15 (30%) of the 50 patients who received any aspirin, 21 (42%) of the 50 patients who received no mesalazine, and 20 (38%) of the 52 patients who received any mesalazine. The adjusted odds ratio for polyp recurrence was 0·37 (95% CI 0·16–0·86) in the patients who received any aspirin and 0·87 (95% CI 0·38–2·00) in any who received mesalazine. The most common adverse events were grade 1–2 upper gastrointestinal symptoms in three (12%) of 26 patients who received aspirin plus mesalazine, one (4%) of 24 patients who received aspirin plus mesalazine placebo, and one (4%) of 26 patients who received mesalazine plus aspirin placebo. There was one grade 4 event in the mesalazine plus aspirin placebo group, but not related to the treatment.

Interpretation

Low-dose aspirin safely suppressed the recurrence of colorectal polyps larger than 5·0 mm in patients with FAP. These results suggest an effect of low-dose aspirin for FAP and could be an alternative method for preventing colorectal cancer in FAP.

Funding

Japan Agency for Medical Research and Development.

中文翻译：

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在未接受结肠切除术的家族性腺瘤性息肉病患者中，低剂量阿司匹林，美沙拉嗪或两者联合进行化学预防（J-FAPP研究IV）：一项多中心，双盲，随机，二乘二因子设计试验

背景

结肠切除术是预防家族性腺瘤性息肉病（FAP）患者结肠直肠癌的唯一有效方法，这大大降低了患者的生活质量。因此，需要一种替代方法。在该试验中，我们旨在阐明小剂量阿司匹林和美沙拉嗪对日本FAP患者结直肠息肉复发的个体和联合作用。

方法

这是一项随机，双盲，安慰剂对照的多中心试验，在日本的11个中心进行了二乘二因子设计。符合条件的患者年龄在16-70岁之间，在大肠内有100多个腺瘤性息肉病史，没有结肠切除术史。在研究之前，患者需在内窥镜下切除所有直径至少为5·0 mm的大肠息肉。随机分组采用最小化方法进行，并采用随机成分来平衡性别，年龄（<30岁与≥30岁），或进入时吸烟。患者和研究人员被掩盖在治疗组中。分为四组：阿司匹林（每天100 mg）加美沙拉嗪（每天2 g），阿司匹林（每天100 mg）加美沙拉嗪安慰剂，阿司匹林安慰剂加美沙拉嗪（每天2 g）或阿司匹林安慰剂加美沙拉嗪安慰剂。治疗一直持续到结肠镜检查8个月前的1周。主要终点是大肠息肉在8个月时至少5·0 mm的发生率，并在意向性治疗人群中进行了评估。在ITT人群中评估了安全性。我们还按方案进行了分析，仅包括服用至少70％分配的研究药物的患者。该试验已在UMIN临床试验注册中心注册，编号为UMIN000018736，并且已经完成。

发现

在2015年9月25日至2017年3月13日期间，随机分配104例患者接受阿司匹林或阿司匹林安慰剂（n = 52）或美沙拉嗪或美沙拉嗪安慰剂（n = 52）。两名患者退出了阿司匹林加美沙拉嗪安慰剂组。52例未接受阿司匹林的患者中有26例（50％）在8个月时大肠息肉至少为5·0 mm，50例接受阿司匹林的患者中有15例（30％），50例中有21例（42％）没有接受美沙拉嗪治疗的患者，52名接受美沙拉嗪治疗的患者中有20名（38％）。接受阿司匹林治疗的患者息肉复发的校正比值比为0·37（95％CI 0·16–0·86），接受阿司匹林的患者息肉复发的校正后优势比为0·87（95％CI 0·38-2·00）。美沙拉嗪。最常见的不良事件是接受阿司匹林加美沙拉嗪的26例患者中有3例（12％）出现1-2级上消化道症状，接受阿司匹林加美沙拉嗪安慰剂的24名患者中有1名（4％），接受美沙拉嗪加阿司匹林安慰剂的26名患者中有1名（4％）。美沙拉嗪加阿司匹林安慰剂组发生了1次4级事件，但与治疗无关。

解释

小剂量阿司匹林可安全抑制FAP患者大于5·0 mm的大肠息肉复发。这些结果表明小剂量阿司匹林对FAP有疗效，并且可能是在FAP中预防结直肠癌的另一种方法。

资金

日本医学研究与发展局。