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Colonoscopy is the recommended screening method for colorectal cancer in clinical guidelines, but evidence has previously been limited to cohort study data
.
Cohort studies may overestimate the real-world effects
of colonoscopy due to the inability to adjust for bias factors such as adherence and the greater willingness of healthier people to undergo screening.
The NordICC trial, published online October 9 in the New England Journal of Medicine (NEJM), fills this evidence gap
.
This effective randomized trial involving nearly 85,000 people in three European countries divided participants into two groups in a 1:2 ratio, invited (invited group) or uninvited (routine group) for colonoscopy screening
.
After 10 years of follow-up, the risk of colorectal cancer in the invited group and the conventional group were 0.
98% and 1.
20%, respectively, and the risk was reduced by 18%, but there was no significant difference in
the risk of colorectal cancer death between the two groups.
An editorial distributed by NEJM called the study iconic
.
The small reduction in the risk of colorectal cancer and the lack of reduction in the risk of death were both surprising and disappointing
.
The editorial authors suggest that the results may be mainly related to the following reasons: first, screening is only effective if colonoscopy is actually done; In this trial, only 42% of the invited group were screened
.
Conformity protocol analysis showed that colonoscopy screening reduced colorectal cancer incidence by 31% and associated mortality by 50%.
Second, the benefits of colonoscopy screening take a long time to become apparent, and the study plans to analyze
them again at 15 years.
Third, colonoscopy is highly dependent on endoscopists, and adenoma detection rates are low
in this trial.
The editorial believes that if the test results reflect the true effect of colonoscopy screening in the population, then in the case of simpler and less invasive screening strategies such as sigmoidoscopy and immunological fecal occult blood test (FIT), colonoscopy is not reasonable
depending on the risk and cost.
However, as screening participation and quality improve, colorectal cancer incidence and mortality are expected to decline
even more substantially.
We invited Professor Wei Wenqiang of the National Cancer Center, who has been engaged in tumor epidemiology for a long time, to interpret the study
.
The results of the world's first colonoscopy multi-center randomized clinical trial were announced, and the screening effect controversy Wei
Wenqiang National Cancer Center/National Cancer Clinical Research Center/Cancer Registry Office
, Cancer Hospital of the Chinese Academy of Medical Sciences, colorectal cancer is the third most common cancer in the world, It is also the second leading cause of cancer death [1].
Colorectal cancer is one of the most suitable cancers for population screening because the early symptoms are not obvious, the natural history of
the disease is clear, the intervention window is long, and the survival benefits of early intervention are good.
At present, the screening techniques consistently recommended by domestic and foreign guidelines include colonoscopy, sigmoidoscopy, colon CT imaging technology, fecal occult blood screening (gFOBT and FIT) [2], but there is still a lack of high-quality evidence
for the best screening strategy.
Fecal occult blood screening includes guaiac fecal occult blood (gFOBT) and immunological fecal occult blood test (FIT).
Results from randomized clinical trials have shown that fecal occult blood screening can reduce the relative risk of death from colorectal cancer by approximately 15% compared with no screening, but has a limited effect on the risk of morbidity2
.
Endoscopic methods use optical means to directly examine the rectum and colon, including sigmoidoscopy and colonoscopy
.
Because most colorectal cancers develop from benign polyps that can be found and removed during endoscopy, colonoscopy is both an initial screening tool and a follow-up test for people who test positive for other screening methods
.
In a pooled analysis of three randomized trials, those invited for sigmoidoscopy had a 25 percent reduction in the incidence of colorectal cancer after 10 to 12 years of follow-up compared with the non-screening group [3].
Because colonoscopy can provide a complete view of the entire colorectal and is generally more effective than sigmoidoscopy, colonoscopy has replaced sigmoidoscopy as the primary colorectal cancer screening method in developed countries such as the United States, and it is recommended that appropriate people have a test
every 10 years.
Large randomized clinical trials of screening for sigmoidoscopy have demonstrated its effectiveness in preventing colorectal morbidity and mortality, but there are no randomized
clinical trials of colonoscopy screening.
Nevertheless, numerous observational studies have shown that the relative risk of morbidity and mortality in sigmoidoscopy or colonoscopy recipients is significantly lower than in the control group
.
The latest meta-analysis of observational studies estimates that colonoscopy reduces morbidity and mortality by nearly 70 percent, while sigmoidoscopy reduces morbidity and mortality by nearly 50 percent [4].
On October 9, 2022, the New England Journal of Medicine (NEJM) published online the results of the world's first published randomized clinical trial (NordICC) for colonoscopy screening, which found that colonoscopy screening only reduced the risk of colorectal disease by 18%, but not colorectal cancer death [5]
.
The NordICC trial is a large, multicenter randomized clinical trial to evaluate the effect
of population-based colonoscopy screening on the risk of colorectal cancer and associated mortality after 10 years.
The study included participants aged 55 to 64 years from Poland, Norway, Sweden, and the Netherlands between 2009 and 2014, and was randomly assigned to either an invited group (invited to participate in a colonoscopy screening) or a routine group (no invitation to screening)
in a 1:2 ratio.
The primary endpoint was risk of colorectal cancer and associated mortality, and the secondary endpoint was all-cause mortality
.
A total of 84,585 participants (excluding the Dutch sample, which is prohibited by regulation), 28,220 in the invited group and 56,365 in the regular group; Among the invited groups, 11,843 cases (42.
0%) were screened
.
The intention-to-treat analysis showed that the 10-year incidence of colorectal cancer in the invited group and the regular group was 0.
98% and 1.
20%, respectively, and the risk of incidence in the invited group was reduced by 18%.
The risk of colorectal cancer-related death in the invited group and the conventional group was 0.
28% and 0.
31%, and the risk of all-cause death was 11.
03% and 11.
04%, respectively, with no statistically significant difference, suggesting that colonoscopy could not reduce the risk of colorectal cancer-related death and all-cause mortality in the invited group
.
Figure 1.
10-year risk of colorectal cancer in an intention-to-treat analysis
Figure 2 10-year risk of colorectal cancer death in an intention-to-treat analysis
Once the paper was published, it caused controversy
such as "the gold standard status of colonoscopy is shaken" and "the screening effect is overestimated".
But a closer look at the study revealed otherwise
.
Overall, low adherence to screening, short follow-up, and no observed reduction in mortality were the main reasons for the
controversial results.
Adherence refers to the proportion of people invited to the
screening who actually participate in the screening.
In previous sigmoidoscopy screening trials (PLCO [6] in the US, SCORE [7] and NORCCAP [8] in Europe), adherence ranged from 58%~87%, compared with only 42%
in this study.
The authors found through adjusted protocol-based analysis that if all participants randomized to the screening group were actually screened, the risk of colorectal cancer would decrease by 0.
84% from 1.
22%
after 10 years.
In addition, the risk of dying from colorectal cancer in the screening group was 0.
15%, compared with 0.
30% in the conventional group, and screening could reduce the risk of colorectal cancer by 31% (hazard ratio [RR], 0.
50; 95% CI, 0.
27~077) and 50% of the risk of colorectal cancer death (RR, 0.
69; 95% CI, 0.
55~0.
83).
Shorter follow-up periods directly affected the number
of deaths that occurred.
Due to the nature of colorectal cancer, colonoscopy, as a preventive screening program, can detect and treat polyps in advance, thereby directly reducing the risk of colorectal cancer; A reduction in the risk of morbidity can be observed earlier than a reduction
in the risk of mortality.
In addition, in the early follow-up period, the number of colorectal cancer cases is expected to be higher than the related number of deaths, and as the follow-up period is extended and more deaths occur, the preventive effect of colonoscopy screening to reduce the risk of colorectal cancer death can be reflected
.
Finally, due to the improvement of colorectal cancer treatment options in the past 10 years, the colorectal cancer-related mortality rate of both groups of participants in the paper was low, and the effect
of screening could only be better evaluated through long-term follow-up and the accumulation of more cases.
We look forward to the results
of the 15-year follow-up in this study program.
Bowel cancer screening should consider benefits, risks and cost-effectiveness
.
Based on current evidence, the preventive effect of colonoscopy screening is clear
.
However, it should also be noted that the high cost of colonoscopy screening technology, the high requirements for professional and technical personnel, the long technical mastery time, more invasive than stool examination and sigmoidoscopy, poor public compliance, lack of grassroots professional and technical personnel and capacity, and multi-source financing mechanism for screening costs have affected its large-scale continuous promotion and implementation
。 Therefore, the screening technology scheme of colorectal cancer still needs to be further studied from the aspects of comparison of the effects of different technologies, the selection of initial screening technology, the determination of screening interval, and the early warning and prediction of positive cases, so as to obtain more evidence from large-scale randomized clinical trials, so as to provide evidence-based basis
for optimizing the current screening guidelines with colonoscopy as the core and determining the best screening technology protocol.
References
1.
Sung H, Ferlay J, Siegel RL, et al.
Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
CA Cancer J Clin 2021; 71:209-249.
Lauby-Secretan B, Vilahur N, Bianchini F, et al.
The IARC perspective on colorectal cancer screening.
N Engl J Med 2018; 378:1734-1740.
3.
Holme Ø, Schoen RE, Senore C, et al.
Effectiveness of flexible sigmoidoscopy screening in men and women and different age groups: pooled analysis of randomised trials.
BMJ 2017; 356:i6673.
4.
Brenner H, Stock C, Hoffmeister M.
Effect of screening sigmoidoscopy and screening colonoscopy on colorectal cancer incidence and mortality: systematic review and meta-analysis of randomised controlled trials and observational studies.
BMJ 2014; 348:g2467.
5.
Bretthauer M, Løberg M, Wieszczy P, et al.
Effect of colonoscopy screening on risks of colorectal cancer and related death.
N Engl J Med 2022 October 9 (Epub ahead of print).
6.
Schoen RE, Pinsky PF, Weissfeld JL, et al.
PLCO Project Team.
Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy.
N Engl J Med 2012; 356:2345-2357.
7.
Segnan N, Armaroli P, Bonelli L, et al.
SCORE Working Group.
Once-only sigmoidoscopy in colorectal cancer screening: follow-up findings of the Italian Randomized Controlled Trial-SCORE.
J Natl Cancer Inst 2011; 356:1310-13228.
Holme Ø, Løberg M, Kalager M, et al.
Effect of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality: a randomized clinical trial.
JAMA 2014; 356:606-615.
About the author
Wei Wenqiang, Ph.
D.
, researcher, doctoral supervisor
.
He has long been engaged in tumor epidemiology and comprehensive prevention and treatment of
high-discovery populations of gastrointestinal tumors.
He has presided over more than ten scientific research projects such as the National Key R&D Program, the Prime Minister's Fund, the National Natural and Health Industry Special Project, and international cooperation; He has participated in the research and preparation of
policy documents such as strategic research on national medium- and long-term science and technology development plans, medium- and long-term plans for chronic disease prevention and control, national cancer prevention and control plans, plans, and cancer prevention and control implementation plans.
He has won 13 awards and honors at or above the national, provincial and ministerial levels, and was selected as a national talent project and a special allowance expert
of the State Council.
He has published more than 200 academic papers in domestic and foreign professional journals such as JCO, NG, Gut, Lancet series, AJG, Gastroenterology and China series, and edited or participated in dozens of monographs
.
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.
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.
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