结直肠癌筛查有助降低远期死亡率

《新英格兰医学杂志》9月19日在线发表的两项研究显示，进行内镜或大便隐血试验筛查的患者的远期结直肠癌发生率低于未进行筛查的患者，即使筛查是在数十年前进行的，结果也是如此。重要的是，筛查患者的结直肠相关死亡率也相应低于未筛查的患者。两项研究的研究者表示，识别并切除结直肠息肉具有显著益处，可延长30年的寿命。

在第一项研究中，丹娜-法伯癌症研究所和哈佛医学院的Reiko Nishihara博士及其同事在2个前瞻性随访22年的大型美国队列中评估了下消化道内镜对偶发性结直肠癌远期风险的影响。护士健康研究入组1976年基线年龄30~55岁的121,700例女性护士，医务人员随访研究入组1986年基线年龄40~75岁的51,529例男性卫生专业人员。研究者对22年随访期间发生1,815起偶发性结直肠癌的57,166例女性受试者和31,736例男性受试者的病历数据进行二次分析。

研究者确定，至1998年(随访中点)，14,287例男性和31,423例女性未进行下消化道内镜筛查；3,578例男性和3,957例女性进行了内镜筛查且结果为阴性；8,091例男性和16,748例女性进行了乙状结肠镜筛查且结果为阴性；1,259例男性和1,481例女性进行了下消化道内镜筛查和息肉切除术。

随访结束时，进行任何这些筛查的男性和女性的结直肠癌发生率显著低于未进行任何筛查者。内镜+切除腺瘤性息肉(息肉切除术)后的结直肠癌多因素风险比为0.57，阴性乙状结肠镜筛查后的结直肠癌多因素风险比为0.60，阴性结肠镜筛查后的结直肠癌多因素风险比为0.44。

研究者估计，如果所有入组的受试者进行结肠镜筛查的话，将可预防随访期间发生的40%的结直肠癌(包括61%的远端结直肠癌和22%的近端结肠癌) (N. Engl. J. Med. 2013 Sept. 19 [doi:10.1056/NEJMoa1301969])。

在就诊时处于所有各种疾病分期的男性和女性中均观察到这一结直肠癌降低的情况，不管受试者年龄、体重指数、吸烟状态如何及是否预防性使用阿司匹林。

阴性结肠镜筛查与较低的远端结直肠癌和近端结肠癌发生率相关，而阴性乙状结肠镜筛查和结肠镜筛查+息肉切除术主要与较低的远端结直肠癌发生率相关。

值得注意的是，与无内镜筛查相比，乙状结肠镜和结肠镜筛查与较低的结直肠癌特异性死亡率相关。阴性结肠镜筛查与结直肠癌发生率显著降低之间的关联持续至筛查后15年。因此，该研究结果支持现行指南对结肠镜筛查阴性的中危个体提出的间隔10年检查1次的建议。该研究表明，甚至是单次的阴性结肠镜筛查也与非常低的远期结直肠癌风险相关。

在存在腺瘤的受试者中，结直肠癌发生率降低的情况持续至筛查后5年。因此，该研究既支持对有结直肠癌家族史的个体进行间隔更频繁的筛查，也支持现行监测指南。

研究者还从62例内镜筛查后5年内发生结直肠癌的患者采集肿瘤样本，检查了样本中的DNA。与其他癌症相比，这一时间间隔的癌症更可能存在CpG岛甲基子表型(CIMP)、微卫星不稳定性和高水平LINE-1甲基化，所有这些都是肿瘤侵袭性增加的征象。

研究者表示，此类病变可能特别难以通过内镜检出或被充分切除。目前尚不清楚通过改善内镜技术(包括更仔细的检查或改善肠道清洁)是否可解决这些生物学差异引起的问题。

在第二项研究中，明尼阿波利斯退伍军人卫生保健系统和明尼苏达大学明尼阿波利斯分校的Aasma Shaukat医生及其同事发现，在使用大便隐血试验(FOBT)进行结直肠癌筛查的成人中，结直肠癌相关死亡率降低32%并且效果持续至此后30年。这一关联在男性中较在女性中更强烈。

研究者对明尼苏达结肠癌控制研究的数据进行二次分析。在该研究中，1975年~1978年基线年龄50~80岁的46,551例健康男性和女性随机进行每年1次、2年1次或无FOBT筛查直至1993年。

研究者在2011年试图确定尽可能多的受试者的死亡状态和死亡原因，他们发现33,020例死亡，占整个研究人群的71%。共732例死亡的原因为结直肠癌。

每年1次和2年1次FOBT筛查均使结直肠癌特异性死亡率降低1/3并且效果持续至筛查后30年。与无FOBT组相比，每年1次FOBT组结直肠癌死亡相对风险为0.68，2年1次FOBT组为0.78。总体而言，与无FOBT组相比，任何FOBT筛查组的死亡相对风险为0.73。这一降低的情况与切除进展至癌症和死亡的腺瘤产生的效果一致(N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1300720])。

男性的结直肠癌特异性死亡率降幅大于女性。研究者表示，以粪便为基础的筛查方法具有可及性和可接受性高的特点，对于提高公众的筛查率具有重大意义，但这种筛查方法的检查频率大于灵活的乙状结肠镜或结肠镜筛查。

Nishihara博士的研究获美国国立卫生研究院等机构支持。Nishihara博士声明与药企无联系；其一名同事声明与拜耳等多家药企存在联系。Shaukat医生的研究获退伍军人事务部绩效评审奖励计划等机构支持。Shaukat医生及其同事声明无经济利益冲突。

随刊述评：筛查有效且指南适当

Kaiser Permanente医疗中心的Theodore R. Levin医生和Douglas A. Corley医生表示，这两项研究证实结肠镜和FOBT是有效的结直肠癌筛查方法，并且再次确认现行筛查指南是适当的。然而，这两项研究一项为随机研究，另一项为志愿者观察性研究，两者不同且研究人群不具有可比性，因此对它们进行比较是错误的。并且自这两项研究开展后，结肠镜和FOBT技术都有了改进。目前正在进行的随机研究将可弄清以下问题：结肠镜相对于FOBT的价值、间期癌症的生物学特征以及结直肠癌筛查项目的总体有效性。Levin医生和Corley医生均声明无相关经济利益冲突(N. Engl. J. Med. 2013;369:1164-6)。

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By: MARY ANN MOON, Internal Medicine News Digital Network

The long-term incidence of colorectal cancer was lower in patients who underwent screening by either endoscopy or fecal occult-blood testing than in those who did not, even if that screening took place decades earlier, according to two separate reports published online Sept. 19 in the New England Journal of Medicine.

Importantly, colorectal cancer–related mortality also was correspondingly lower in screened patients.

Identifying and removing colorectal polyps yields far-reaching benefits, saving lives for up to 30 years afterward, researchers involved in both studies said.

In the first study, Reiko Nishihara, Ph.D., of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, and her associates assessed lower-GI endoscopy’s effect on the long-term risk of incident colorectal cancer in two large U.S. cohorts that were prospectively followed for 22 years. The Nurses’ Health Study involved 121,700 female nurses aged 30-55 years at baseline in 1976, and the Health Professionals Follow-Up Study involved 51,529 male health professionals aged 40-75 years at baseline in 1986.

For their secondary analysis of data from these cohorts, Dr. Nishihara and her colleagues examined the records of 57,166 female subjects and 31,736 male subjects who developed 1,815 incident colorectal cancers during 22 years of follow-up. "We were able to directly compare actual incidences of cancer among persons after polypectomy with the incidences among persons from the same background population who did not undergo endoscopy, while adjusting for potential confounders."

At their own discretion, 14,287 of the men and 31,423 of the women had undergone no lower endoscopy at all by 1998, the midpoint of follow-up; 3,578 men and 3,957 women had undergone colonoscopy with negative results; 8,091 men and 16,748 women had undergone sigmoidoscopy with negative results; and 1,259 men and 1,481 women had undergone lower endoscopy with polypectomy.

At the end of follow-up, the incidence of colorectal cancer was significantly lower among the men and women who had undergone any of these screening methods than among those who had not had any screening. The multivariate hazard ratios for colorectal cancer were 0.57 after endoscopy plus removal of adenomatous polyps (polypectomy), 0.60 after negative sigmoidoscopy, and 0.44 after negative colonoscopy.

"We estimated that 40% of colorectal cancers (including 61% of distal colorectal cancers and 22% of proximal colon cancers) that developed during follow-up would have been prevented if all the participants in our study had undergone colonoscopy," the investigators said (N. Engl. J. Med. 2013 Sept. 19 [doi:10.1056/NEJMoa1301969]).

This decrease in colorectal cancer occurred in both men and women, across all stages of disease at presentation, and regardless of subject age, body mass index, smoking status, or use of aspirin prophylaxis.

"Negative colonoscopy was associated with a lower incidence of both distal colorectal cancer and proximal colon cancer, whereas negative sigmoidoscopy and colonoscopy with polypectomy were associated primarily with a lower incidence of distal colorectal cancer," they said.

Notably, screening sigmoidoscopy and screening colonoscopy were associated with lower colorectal cancer–specific mortality, compared with no endoscopy.

The association between a negative colonoscopy and a significantly reduced incidence of colorectal cancer persisted for up to 15 years after the procedure. Thus, "our findings support the 10-year examination interval recommended by existing guidelines for persons at average risk who have a negative colonoscopy. Our study suggests that even a single negative colonoscopy is associated with a very low long-term risk of colorectal cancer," Dr. Nishihara and her associates said.

Among study subjects who were found to have adenomas, the reduced incidence of colorectal cancer persisted for up to 5 years after the procedure. Thus, "our data support screening at more frequent intervals for persons with a family history of colorectal cancer, which [also] supports current surveillance guidelines."

The researchers also examined DNA from stored specimens of tumors from 62 patients who developed colorectal cancer within 5 years of "passing" an endoscopy. Compared with other cancers, these interval cancers were much more likely to have CpG island methylator phenotype (CIMP), microsatellite instability, and high levels of LINE-1 methylation – all indicators of increased tumor aggressiveness.

It is possible that such lesions are particularly difficult to detect endoscopically or to remove adequately. "It remains unclear whether any of the challenges posed by these biological differences can be addressed by improvements in colonoscopic technique, including more meticulous inspection or improved bowel cleaning," the researchers said.

In the second study, a different research group found that adults who were screened for colorectal cancer using fecal occult blood testing (FOBT) had a 32% decrease in colorectal cancer–related mortality for up to 30 years afterward.

This association appeared to be stronger for men than for women, said Dr. Aasma Shaukat of the Minneapolis Veterans Affairs Health Care System and the University of Minnesota, Minneapolis, and her associates.

They performed a secondary analysis of data from the Minnesota Colon Cancer Control Study, in which 46,551 healthy men and women aged 50-80 years at baseline in 1975 through 1978 were randomly assigned to undergo annual, biennial, or no FOBT screening until 1993. Dr. Shaukat and her colleagues attempted to identify the mortality status and cause of death for as many of these study subjects as possible in 2011.

They identified 33,020 deaths, which represents 71% of the entire study population. A total of 732 deaths were from colorectal cancer.

Both annual and biennial FOBT screening reduced colorectal-cancer-specific mortality by approximately one-third for up to 30 years. The relative risk of death from colorectal cancer was 0.68 with annual FOBT and 0.78 with biennial FOBT, compared with no FOBT. Overall, the relative risk of death with any FOBT screening was 0.73, compared with no FOBT.

This reduction "is consistent with the effect of removing adenomas that would have progressed to cancer and death,\" Dr. Shaukat and her associates said (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1300720]).

The decline in colorectal cancer-specific mortality was greater for men than for women.

"The high accessibility and acceptability of stool-based tests have major public health implications for improving screening rates, although this approach to screening involves more frequent testing than does screening with flexible sigmoidoscopy or colonoscopy," the investigators noted.

Dr. Nishihara’s study was supported by the National Institutes of Health, the Bennett Family Foundation, and the Entertainment Industry Foundation. Dr. Nishihara reported no ties to industry sources; one of her associates reported ties to Bayer Healthcare, Pfizer, Millenium Pharmaceuticals, and Pozen. Dr. Shaukat’s study was supported by the Veterans Affairs Merit Review Reward Program, the National Institutes of Health, and the National Cancer Institute. Dr. Shaukat and her associates reported no financial conflicts of interest.

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Screening is effective and guidelines are appropriate

These two studies confirm that both colonoscopy and FOBT are effective for colorectal cancer screening, and reaffirm that current screening guidelines are appropriate, said Dr. Theodore R. Levin and Dr. Douglas A. Corley.

However, the two studies are different and have study populations that are not comparable, so it would be a mistake to compare them with each other. "One was a randomized trial, the other an observational study of volunteers, and both [screening] tests have undergone improvements since the studies were performed," they noted.

Randomized trials that are currently underway will clarify remaining questions about the relative value of colonoscopy vs. FOBT, the biologic features of interval cancers, and the overall effectiveness of colorectal-cancer screening programs, Drs. Levin and Corley said.

Dr. Theodore R. Levin and Dr. Douglas A. Corley are at the Kaiser Permanente Medical Centers in Walnut Creek, Antioch, and San Francisco, CA. They reported no relevant financial conflicts of interest. These remarks were taken from their editorial accompanying the reports by Dr. Nishihara and Dr. Shaukat (N. Engl. J. Med. 2013;369:1164-6).