Taking at least 75 mg of aspirin daily for several years reduces significantly the long-term risks of developing colorectal cancer and of dying from the disease, according to an analysis of five randomized trials involving more than 14,000 patients.

The 20-year incidence of colon cancer was reduced by 24% (hazard ratio 0.76) and 20-year mortality by 35% (HR 0.65) in patients who took aspirin and were compared with a control group in pooled data from four of the trials, reported Dr. Peter M. Rothwell, a professor of clinical neurology and founder of the stroke prevention research unit at the University of Oxford, U.K, and his colleagues.

Allocation to aspirin in those trials did not, however, reduce the overall risk of developing rectal cancer (HR 0.90), according to findings published online in the Oct. 22 issue of The Lancet.

All of the trials were designed to look at prevention of vascular events, not colorectal cancer specifically. The four pooled trials compared aspirin with either placebo or no treatment. The new analysis shows that 391 of 14,033 patients (2.8%) developed colon cancer after a median of 6 years of scheduled treatment and at a median follow-up of 18.3 years.

Of note was a finding that in studies for which data were available, patients allocated to receive aspirin had a significantly reduced risk of cancer of the proximal colon (HR 0.45), but not the distal colon (HR 1.10). Similarly, patients on aspirin had a significantly reduced risk of fatal proximal colon cancers (HR 0.34), but not fatal distal colon cancers (HR 1.21), the investigators said (Lancet 2010 Oct. 22 [doi:10.1016/S0140-6736(10)61543-7]).

The risk reduction increased with scheduled duration of treatment; patients allocated to take aspirin for at least 5 years had a highly significant reduction of about 70% in the risk of proximal colon cancer (HR 0.35). They also had a significantly reduced incidence of rectal cancer but not distal colon cancer.

Furthermore, no increase in benefit was seen with doses above 75 mg daily, according to an analysis of data from the fifth study and one of the four controlled studies, both of which compared various doses of aspirin. An absolute reduction of 1.76% in 20-year risk of any fatal colorectal cancer was seen with doses ranging from 75 mg daily to 300 mg daily; it persisted when the analysis was limited to patients allocated to 75 mg daily. In one study, which compared a 30 mg and 283 mg daily dose, however, mortality was significantly higher with the 30 mg dose (odds ratio 2.02).

In a previous report of data from two of the trials in the current analysis, the investigators showed that the 20-year incidence of colorectal cancer was reduced by 30% in patients who used high-dose aspirin for 5 years. The current findings are important in that they show a similar effect with doses as low as 75 mg daily, they said.

The study has some potential limitations, including the possibility that trial participants had more investigations because adverse treatment effects, and therefore may have had an earlier diagnosis of colorectal adenoma or cancer than they would have had otherwise. Also, the number of cancers in the study that compared 30-mg and 283-mg doses was small, which limits the certainty of the effect.

Nonetheless, the finding of an approximately 1.5% reduction in absolute long-term risk of colorectal cancer does have implications for clinical practice, the investigators said. “In patients with an established indication for long-term antiplatelet treatment, such as in secondary prevention of vascular disease, this additional benefit will favor treatment with aspirin over other antiplatelet drugs, assuming that other drugs do not afford similar benefit,” they wrote.

Also, in light of the recently “finely balanced” risk-benefit debate over long-term benefits vs. major bleeding risk with aspirin therapy to reduce the risk of ischemic vascular events, the current findings might “tip the balance” back to favoring treatment, they argued.

“The five trials we studied all predated endoscopic screening for adenomas, which also reduced colorectal cancer incidence and mortality, and might therefore reduce the absolute benefit of aspirin. However, the suggestion of a particular effect of aspirin on more aggressive and rapidly growing tumors might allow less frequent screening, and the prevention of proximal colonic cancer by aspirin, which would not be identified by sigmoidoscopy screening and for which colonoscopy screening is only partly effective, is clearly important,” they wrote.

Since the “very substantial” reduction in proximal colon cancers in patients on aspirin therapy in this study might be a result of an effect on aggressive non-polypoid or de novo cancers, which are often flat and can be easily missed on colonoscopy, it is probable that screening and aspirin therapy for preventing colorectal cancer will be synergistic, they concluded.

In an accompanying editorial, Dr. Robert Benamouzig and Dr. Bernard Uzzan said that these findings, along with others showing the benefits of aspirin use for reducing the risk of cancer-specific and overall mortality, could incite clinicians to use aspirin for primary prevention of colorectal cancer, particularly in high-risk populations.

Although the current study has several important limitations, the authors do provide an extremely long follow-up, and they present a number of original findings, not the least of which is the finding of a predominant and significant effect of aspirin on proximal colonic lesions.

“If confirmed, this original finding might present a strong argument for the addition of aspirin chemoprevention to screening sigmoidoscopy,” they wrote (Lancet 2010 Oct. 22 [doi:10.1016/S0140-6736(10)1509-7]).

As such, guidelines for aspirin chemoprevention are needed and would be the next logical step, they concluded.

Dr. Rothwell and coauthor, Dr. Bo Norrving, reported receiving honoraria for giving talks and serving on advisory boards and clinical trial committees for AstraZeneca, Bayer, Boehringer Ingelheim, Sanofi-BMS, and Servier – all of which have an interest in antiplatelet agents. Dr. Ale Agra reported receiving honoraria for serving on advisory boards and research funding from Boehringer Ingelheim. The remaining study authors reported having no disclosures.

Dr. Benamouzig and Dr. Uzzan are with the departments of gastroenterology and pharmacology, respectively, of Avicenne Hospital, Bobigny, France. They declared no conflicts of interest.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

据10月22日在线发表在《柳叶刀》杂志上的一项对包括14,000例患者的5项随机临床研究进行的分析发现，每日服用至少75 mg阿司匹林且持续数年可显著降低罹患结直肠癌并死于该病的长期风险。

 

英国牛津大学临床神经病学教授和卒中预防研究所创始人Peter M. Rothwell博士及其同事对来自上述4项研究的汇总数据分析发现，与对照组相比，服用阿司匹林的患者20年结肠癌的发生率下降了24%(危险比0.76)，而因结肠癌死亡率降低了35%(危险比0.65)。应用阿司匹林并未降低发生直肠癌的总体风险(危险比0.90)。

 

汇总的四项研究将阿司匹林与安慰剂或未治疗相比。最新发析发现，14,033例患者在中位时间为6年的计划治疗后在中位时间为18.3个月的随访期间391例(2.8%)发生了结肠癌。值得注意的是，在可获得相关数据的研究中，被分配接受阿司匹林治疗的患者发生近端结肠癌的风险显著降低(危险比0.45)，而远端结肠癌的发生风险却未降低(危险比1.10)。同样，接受阿司匹林治疗的患者因近端结肠癌死亡的风险亦有显著下降(危险比0.34)，而因远端结肠癌死亡的风险却未降低(危险比1.21)[Lancet 2010 Oct. 22 (doi:10.1016/S0140-6736(10)61543-7)]。

 

另外，据对不同剂量阿司匹林进行对比的第五项研究和另外一项对照研究的数据发现，阿司匹林剂量超过75 mg时其益处并未增加。然而，在一项对30 mg和283 mg剂量阿司匹林进行对比的研究中，30 mg剂量组的死亡率却显著较高(比值比2.02)。此分析入选的5项研究中的2项研究之前报告，应用大剂量阿司匹林达5年的患者其20年结直肠癌的发生风险下降30%，而分析发现阿司匹林剂量低至每日75 mg即可有上述大剂量的效果。

 

该研究存在一些潜在局限，包括因治疗不良反应受试者可能接受了更多研究，他们可能之前被诊断过结直肠腺瘤或癌，而不是用药后才患病。另外，比较30 mg和283 mg剂量阿司匹林效果的研究受试者较少，这限制了其效果的确定性。

 

研究者表示，结直肠癌长期发生的绝对风险下降近1.5%的结果对于临床实践颇具意义；应用阿司匹林预防近端结肠癌显然非常重要。

 

在文后发表的评论中， Robert Benamouzig博士和Bernard Uzzan博士表示，这些发现连同其他显示阿司匹林应用可降低癌症特异性和总体病死率益处的研究可能促使临床医生将阿司匹林用于预防结直肠癌，尤其在那些高危人群。“如果以上结果得以确认，这些新的发现将可能为乙状结肠镜筛查加用阿司匹林化学预防提供有力证据。照这样，需要制定阿司匹林化学预防方面的临床指南，这也是合乎逻辑的下一步工作。”[Lancet 2010 Oct. 22 (doi:10.1016/S0140-6736(10)1509-7)]

 

研究者声明接受多家医药公司经济资助。

 

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