| 肠癌专题 >> Aspirin仅预防COX-2阳性大肠直肠癌
Aspirin仅预防COX-2阳性大肠直肠癌
一项新研究结果显示，aspirin（乙醯水杨酸）於预防大肠直肠癌的效果仅限於COX-2阳性病患。根据研究者於5月24日新英格兰医学期刊发表的文章结论，服用aspirin显著地降低COX-2阳性大肠直肠癌的风险。
　　
　　主要作者波士顿麻州综合医院与哈佛医学院Andrew Chan医师在访谈中向Medscape表示，我们的研究显示，aspirin主要可以预防COX-2阳性的大肠直肠癌，但是目前我们并没有哪些病患会得到这种肿瘤的良好预测因子；这些因素是否会影响将会得到COX-2阳性肿瘤的病患、以及是否有检验可以找出这些病患，这些将是未来研究的关键问题。
　　
　　Chan医师进一步表示，其中一方面需要在不久的将来进行研究，即aspirin是否可以预防已经罹患大肠直肠癌、且為COX-2阳性病患以及有大肠憩肉且為COX-2阳性病患再发；他指出，这样的病患人数是眾多的，50岁以上的群眾，有30~40%病患会发生憩肉，如果我们可以提供这群病患资讯，这将会是向前的一大步。
　　
　　这些研究给我们的其他讯息包括这提供了COX-2讯息传递途径是癌症生成的一个重要途径，且这条途径会受到药物，就像aspirin的破坏；未来的研究最终将研究出新药物作為化学预防，具有aspirin的好处，而没有其缺点（例如肠胃道出血）。
　　
　　【Aspirin并不建议作為化学预防用药】
　　Chan医师向Medscape表示，目前為止，aspirin并不建议作為一般大眾化学预防使用，因為其副作用，以及aspirin并没有完全排除罹患癌症的风险；有许多医师可能决定使用於部分可能会有效的病患身上，但是我们目前没有相关数据，截至目前仍是临床判断。
　　
　　然而，他表示，以公共卫生的角度来看，要建议使用aspirin於预防大肠直肠癌仍然太早；医师面对问到这个问题的病患时，必须强调大肠直肠癌筛检的好处，通常使用大肠直肠内视镜，但是仍有其他的选择；另外一个癥结点是生活型态，我们知道维持正常体重、均衡饮食，别吃太多红肉、以及运动都有助於降低癌症风险；但是aspirin作為一个化学预防药物是否能做到像上述这些降低风险措施那样的程度，目前仍不清楚。
　　
　　Chan医师也於两项最近在英国进行之大型aspirin研究发表的主篇评论中提出同样的观点，他表示，这些研究提供aspirin确实能够预防大肠直肠癌「令人信服」的证据（Flossman E et al. Lancet. 2007;369:1603-1613; Chan A. Lancet. 2007: 369: 1577-1578），Medscape也有相关报导。
　　
　　这些显示aspirin的预防效果仅出现於表现COX-2的大肠直肠癌上的最新研究结果，这些结果来自於两项在美国进行的大型研究，其中一个為护士健康研究，於1976年开始，共纳入了121,701位女性；另外一项為健康照护者追踪研究，於1986年开始，共纳入51,529位受试者；综合起来看，这些研究提供了2,446,4431每人每年的后续追踪资料。
　　
　　Chan医师与其同事确认出636个大肠直肠癌案例，且其中二分之三有COX-2的表现资料（423个肿瘤，67%）呈阳性，剩下的三分之一（213个肿瘤，33%）為COX-2阴性。
　　
　　研究者接著估计使用aspirin与年龄标準化后整各族群的大肠直肠癌发生率，结果发现：
　　* COX-2阳性肿瘤中，每100,000每年每位规律使用aspirin的人有37件大肠直肠癌事件，相较於未使用aspirin者则是為56件（多变项相对风险為0.64，95%信赖区间為0.52-0.78）。
　　* COX-2阴性肿瘤中，每100,000每年每位规律使用aspirin的人有27件大肠直肠癌事件，相较於未使用aspirin者则是28件（多变项销对风险為0.96，95%信赖区间為0.73-1.26）。
　　
　　研究者指出，COX-2阳性肿瘤，使用与未使用aspirin之间有显著差异，但COX-2阴性肿瘤则没有这样的情形；他们表示，综合这两项研究，aspirin可以有效降低大肠直肠癌的风险，但是风险下降几乎全都是因為规律服用aspirin使COX-2阳性肿瘤数目下降所致。
　　
　　【前方还有许多挑战】
　　在他们的文章中，研究者表示，这些结果显示COX-2可以作為有大肠直肠癌病史病患是否使用aspirin作為化学治疗药物的指标；但随后的主篇评论则指出，这样的「个体化医疗」面对许多挑战。
　　
　　俄亥俄州克里夫兰Case Western Reserve大学的Case Western Reserve医师表示，首先，必须要拿找出最能受益的一群病患；接著，必须要能证实部分病患的独立腺瘤或癌症，因為基因及环境的影响，会一再地是高度表现COX-2的；第三，Chan医师与其同事的研究，需要透过aspirin或是COX-2抑制剂可以预防大肠腺瘤的作用，也牵涉到阻断COX-2表现病灶的生成。
　　
　　主编对於Chan医师与其同事发现的结论是，他们提供了COX-2作為大肠癌发展中扮演重要角色的证据，且现在提出须研究高度或是低度表现COX-2的大肠癌之间其生化与临床差异的问题。

Aspirin Prevents Only C0X-2-Positive Colorectal Cancer

— The effect of aspirin (acetylsalicylic acid) in preventing colorectal cancer is restricted only to tumors that are COX-2-postive, a new analysis concludes. Taking aspirin significantly reduced the risk of developing COX-2-positive colorectal cancer, but not COX-1-positive colorectal cancer, researchers conclude in the May 24 issue of the New England Journal of Medicine.

\"Our research suggest that aspirin is effective primarily against colorectal cancer that has COX-2 expression, but at this point in time we don\'t have any real good predictors as to which type of patients will develop these tumors,\" lead researcher Andrew Chan, MD, from Massachusetts General Hospital and Harvard Medical School, in Boston, told Medscape in an interview. \"That is a key question for future research — are there factors that will influence who will develop a COX-2-positive tumor, and are there any tests that we can use to identify these patients?\"

One aspect of this that needs investigation in the near future, Dr. Chan continued, is whether aspirin can prevent a recurrence in patients who have already had colorectal cancer that is COX-2-positive and in individuals who have had polyps that were COX-2-positive. That is a substantial number of people, he pointed out, as between 30% and 40% of people over the age of 50 years of age develop polyps. \"If we could provide information for this subset of people, that would be a huge step forward,\" he said.

\"The other take-home message from our study is that it provides proof of principle that the COX-2 pathway is the critical pathway for cancer progression and that this pathway can be interrupted by medication like aspirin,\" Dr. Chan told Medscape. Further research may eventually lead to new drugs for cancer chemoprevention that have the benefits of aspirin without the drawbacks (eg, gastrointestinal bleeding).

Aspirin Cannot Be Recommended for Chemoprevention

At present, aspirin cannot be recommended for colorectal cancer prevention for the general public because of its adverse-effect profile and because aspirin does not entirely eliminate the risk for colorectal cancer, Dr. Chan told Medscape. There may be individual cases in which a physician may decide that for a particular patient it may be useful, but \"as we don\'t have firm data at this point, it will be more of a judgment.\"

From a public health point of view, however, it is too premature to make any recommendation on the use of aspirin in colorectal cancer prevention, he said. Physicians who are faced with patients who are asking about this should emphasize the effectiveness of screening for colorectal cancer, usually with colonoscopy, but there are also other options, Dr. Chan continued. \"The other point to raise is lifestyle issues — we know that maintaining a good body weight, eating a balanced diet with not too much red meat, and exercise are all important in reducing the risk for cancer. Where aspirin as a chemopreventive agent fits in to all of this is not clear yet.\"

These same points were laid out by Dr. Chan recently in a Lancet editorial that accompanied a new analysis of data from 2 large aspirin trials from the United Kingdom, which he said provided \"convincing evidence\" that aspirin does prevent colorectal cancer (Flossman E et al. Lancet. 2007;369:1603-1613; Chan A. Lancet. 2007: 369: 1577-1578), as reported by Medscape.

The latest results, which show that the preventive effect is confined only to colorectal cancer expressing COX-2, comes from a new analysis of data from 2 large aspirin studies conducted in the United States. One was the Nurses Health Study, which began in 1976 and involved 121,701 females; the other was the Health Professionals Follow-up Study, established in 1986 with 51,529 male participants. Together, these studies provided 2,446,4431 person-years of follow-up.

Dr. Chan and colleagues identified 636 incident cases of colorectal cancer that were available for COX-2 expression and found that about two thirds (423 tumors, 67%) were COX-2 positive, while the remaining third (213 tumors, 33%) were COX-2 negative.

The researchers then estimated the age-standardized incidence rate of colorectal cancer in relation to aspirin use for the entire cohort and found it to be:


Thirty-seven per 100,000 person-years for regular aspirin users vs 56 per 100,000 person-years for nonusers for COX-2–positive tumors (multivariate relative risk, 0.64; 95% CI, 0.52 – 0.78).
Twenty-seven per 100,000 person years for regular aspirin users vs 28 per 100,000 for nonusers for COX-2–negative tumors (multivariate relative risk, 0.96; 95% CI, 0.73 – 1.26).

The difference between aspirin users and nonusers was significant for COX-2-positive tumors, but not for COX-1-negative tumors, the researchers point out. In total in the 2 studies, aspirin had a significant effect in reducing the risk for colorectal cancer, but this reduction in risk \"was due almost entirely to a reduction in the number of COX-2–positive colorectal cancers in regular aspirin users,\" they comment.

Several Challenges Ahead

In their paper, the researchers say these results suggest that COX-2 could be used as a molecular marker to tailor the use of aspirin as a chemopreventive agent in patients with a history of colorectal cancer. However, such an \"individualized-medicine\" approach poses several challenges, comments an accompanying editorial.

First, the individuals who would be most likely to benefit need to be identified, writes editorialist Sanford Markowitz, MD, PhD, from Case Western Reserve University, in Cleveland, Ohio. Then, it needs to be shown that certain persons reproducibly demonstrate high COX-2 expression in independent adenomas or cancers, because of genetic predisposition or environmental exposures. And third, the work of Dr. Chan and colleagues needs to be extended by demonstrating that prevention of colon adenomas by aspirin or COX-2 inhibitors also involves blocking the development of the highest COX-2–expressing lesions, he says.

The editorial concludes that the findings of Dr. Chan and colleagues \"provide powerful support for the role of COX-2 as a key mediator in the development of colon cancer and now pose important questions about the biologic basis and clinical implications of discovering differences between colon cancers that express high or low levels of COX-2.\"

发布时间：2007年06月06日
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