Screening and prevention of colorectal cancer

[Pages:15]STATE OF THE ART REVIEW

BMJ: first published as 10.1136/bmj.n1855 on 15 September 2021. Downloaded from on 7 April 2022 by guest. Protected by copyright.

Screening and prevention of colorectal cancer

Priyanka Kanth,1,2 John M Inadomi3

1Division of Gastroenterology, University of Utah, Salt Lake City, UT, USA 2Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA 3Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA

Correspondence to: P Kanth priyanka.kanth@hsc.utah.edu

Cite this as: BMJ 2021;374:n1855

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors.

ABSTRACT

Mortality from colorectal cancer is reduced through screening and early detection; moreover, removal of neoplastic lesions can reduce cancer incidence. While understanding of the risk factors, pathogenesis, and precursor lesions of colorectal cancer has advanced, the cause of the recent increase in cancer among young adults is largely unknown. Multiple invasive, semi- and non-invasive screening modalities have emerged over the past decade. The current emphasis on quality of colonoscopy has improved the effectiveness of screening and prevention, and the role of new technologies in detection of neoplasia, such as artificial intelligence, is rapidly emerging. The overall screening rates in the US, however, are suboptimal, and few interventions have been shown to increase screening uptake. This review provides an overview of colorectal cancer, the current status of screening efforts, and the tools available to reduce mortality from colorectal cancer.

Introduction Colorectal cancer (CRC) remains a major health burden with high mortality throughout the world. Globally, there were 1.8 million cases and 880792 deaths from CRC in 2018.1 An increase in rates of CRC in individuals under 50 has been recently described. Most cases of CRC are sporadic, whereas 20-30% are familial. Inherited causes (with known genetic mutation) contribute up to 6-10% of all cases.2 3 CRC mortality is preventable and the goal of this review is to provide a comprehensive understanding of the screening and prevention efforts in controlling CRC incidence and mortality. The review provides an overview of the worldwide prevalence, risk factors, precursor lesions, and pathways of CRC development, followed by discussion of available screening modalities, colonoscopy quality metrics, and chemoprevention of CRC.

Methods We identified literature through a search of PubMed, Medline, and Embase from 1980 to 2021. Key words searched included "colon cancer", "colorectal cancer", "screening", "prevention", "FIT", "FOBT", and "colonoscopy". We selected articles published in peer review journals with high impact factor, and by reputed societies. Whenever possible we chose large randomized controlled trials (RCTs) published in high impact and peer review journals over retrospective studies. If no RCTs were available then similar criteria were used for observational studies.

National and international clinical guidelines were included as indicated.

Epidemiology of colorectal cancer In the US, an estimated 149500 new cases of CRC occurred in 2021, and 52980 deaths.4 5 It is the

third and fourth most common cancer diagnosed in the US and the UK, respectively, and is the second leading cause of cancer related deaths in both men and women in both the countries.6 7 While the incidence and mortality of CRC have been declining in some countries in North America, Australia, and northern Europe, an opposing trend of increases is seen in parts of Asia and South America.8-10 Figures 1 and 2 depict the incidence of CRC and mortality among men in selected countries since 2000.11 CRC incidence appears to increase with a rise in the human development index of a country, and as less developed countries adopt a more western lifestyle.12

The incidence rate of CRC varies around the world. The age standardized incidence rate (ASRi) is 38.7 per 100000 persons in the US (2012-16) and it ranges from 20 to 40 per 100000 persons in Europe (2015).14 13 The ASRi for Asia varies widely and is as low as 4.4 (India) to as high as 44.5 (Korea). The overall ASRi for African countries and Latin America is around 8.0 and 16.8 per 100000 persons, respectively.1 14 In general, CRC remains a major health and socioeconomic burden in the developed world. Screening for CRC is largely opportunistic in the US, compared with many European countries which have implemented an organized approach. Opportunistic systems mostly comprise an ad hoc or fee based service, while population based organized approaches requires measurement and reporting of screening quality at every step of the process.13

Both organized and opportunistic CRC screening have contributed to the declining trend in the incidence and mortality in many countries. Stool based screening modalities such as the fecal occult blood test (FOBT) were recommended by the US Preventive Services Task Force (USPSTF) in 1996.15 Screening colonoscopy was introduced in the US in

thebmj|BMJ 2021;374:n1855 | doi: 10.1136/bmj.n1855

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STATE OF THE ART REVIEW

BMJ: first published as 10.1136/bmj.n1855 on 15 September 2021. Downloaded from on 7 April 2022 by guest. Protected by copyright.

USA, SEER (9 registries) India, Chennai Korea (5 registries) Thailand (4 registries) 40

Netherlands Slovakia UK, England

Rate per 100 000

30

20

10

0 2000

2002

2004

2006

2008

2010

Fig 1 | CRC incidence in men from selected countries (2000-12)

2012 Year

1997, and has been a benefit covered by the Center for Medicare and Medicaid Services since 2001. CRC incidence and mortality has declined in the US since these recommendations (fig 1). Modeling studies suggest around a 50% decline in CRC incidence and mortality can be attributed to implementation of screening.16 17 Increased uptake of organized screening was associated with a notable decline in CRC incidence and mortality in a large community based study from the US.18 A modeling study from the Netherlands calculated that the introduction of organized screening could lead to a clinically significant decrease in the incidence and mortality of CRC over 20 to 30 years.19

Early onset colorectal cancer One of the most alarming current healthcare issues is the rise in CRC incidence in individuals aged 2049.20-25 Data from the North American Association of Central Cancer Registries from 2012 to 2016 show a 1.8% increase in the annual incidence in individuals under 50.4 26 27 Conversely, incidence of CRC among individuals over 50 has declined during the same period (fig 3). However, it is important to note that the absolute CRC rate for individuals younger than 50 remains low overall (increased from 7.29 to 8.36 per 100000) compared with those 50 and older

Slovakia

Thailand

UK

South Africa

Netherlands

USA

40

Rate per 100 000

30

20

10

0 2000 2002 2004 2006 2008 2010 2012 2014 2016

Year Fig 2 | CRC mortality in men from selected countries (2000-17)

(declined from 123.00 to 111.61 per 100000) from 2013 to 2017 (fig 3). The rise in rates of CRC in the younger population is not limited to the western hemisphere, but is a worldwide phenomenon.9 10 22 24

CRC tends to occur mostly in the distal colon (splenic flexure to the rectum) in younger people.28 29 Certain risk factors include male sex, and Black or Asian race; however, the cause of the rise of young onset cancer is not completely understood.30-32 A minority of these cancers originates from underlying genetic conditions such as Lynch syndrome and other less common genetic mutations.31 33 34 A study of 430 individuals under 50 diagnosed with CRC showed that one in five people carried a known germline mutation associated with CRC. The authors recommended the use of a multigene panel to screen individuals for the presence of these pathogenic mutations in this cohort.35

Most early onset cancers do not have an identifiable genetic cause and are not caused by Lynch syndrome or other hereditary conditions. A major concern is that CRC in many younger individuals is diagnosed at a late stage and follows an aggressive course.29 36 The National Comprehensive Cancer Network (NCCN) recommends swift endoscopic evaluation for alarming signs and symptoms such as rectal bleeding, anemia, or change in bowel habits in younger individuals.37 Earlier diagnosis is of utmost importance as shown by a study projecting a statistically significant reduction in mortality from cancer by detecting CRC at an earlier stage.38 NCCN recommends genetic risk counseling evaluation for all individuals younger than 50 who have a CRC diagnosis.39

Precursor lesions and neoplasia pathways Most CRCs arise from two pre-cancerous polyp subtypes; adenomatous polyps or sessile serrated lesions (previously termed sessile serrated adenoma/ polyps).40 41 Sessile serrated lesions (SSLs) have been included in the World Health Organization classification of tumors since 2010.42 Pre-cancerous polyps typically have distinct features identifiable by colonoscopy. Adenomatous polyps are usually well demarcated with an elevated appearance and may have a stalk or pedicle, while sessile serrated lesions are flat (non-pedunculated) and typically have a "mucus cap" with indistinct polyp margins43 (figs 4a, 4b, 4c). Because of these features, the likelihood of missing sessile serrated lesions on colonoscopy is higher than with adenomatous polyps. Sessile serrated lesions also have histological features that overlap with features of benign hyperplastic polyps. Many studies have shown high interobserver variability and poor consensus among pathologists in the accurate classification of sessile serrated lesions44 45 that can lead to errors in the recommendations for post-polypectomy surveillance.

These different polyp subtypes lead to cancer development through distinct neoplasia pathways. The adenoma-carcinoma pathway contributes up to 60-70% of all CRCs, while the serrated neoplasia

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doi: 10.1136/bmj.n1855|BMJ 2021;374:n1855 | thebmj

STATE OF THE ART REVIEW

BMJ: first published as 10.1136/bmj.n1855 on 15 September 2021. Downloaded from on 7 April 2022 by guest. Protected by copyright.

Rate per 100 000

125

100 Age (years)

85%.115 118 119 Multiple randomized clinical trials have shown the benefit of using fecal based screening in reducing CRC mortality.73 74 120 121 The Minnesota colon cancer control study has shown a sustained reduction in CRC mortality for individuals undergoing fecal based screening.72 122 These

clinical trials show the effectiveness of programmatic

screening using annual or biennial screening.

FIT directly measures human hemoglobin in

the stool with greater sensitivity and specificity

than gFOBT. Most guidelines recommend annual

fecal testing for the detection of CRC, although

the American College of Physicians recommends

gFOBT or FIT every two years instead of annually.

This is based on a study that compared annual and

biennialFOBT with no difference in mortality in the screening cohort.80 122 FIT has several advantages

over FOBT including the recommendation to use one

instead of three stool samples, and absence of dietary

restrictions before the test. Several studies have compared FIT with gFOBT and colonoscopy.123-129

A meta-analysis of 19 studies from 1996 to 2013 in

the screening population showed an overall pooled

sensitivity and specificity of 79% and 94% for FIT in the detection of CRC.130 Many qualitative and

quantitative FIT kits are available worldwide with

variable threshold values of hemoglobin in feces for the detection of CRC.115 The sensitivity to detect

CRC varies considerably based on the threshold value used.113 115 131 132 Most FIT brands have >20

?g Hb/g feces as threshold value with sensitivity ranging from around 50% to 88%.115 133 134 Greater

than 87% sensitivity was noted for different brands when a threshold of 10 ?g/g was used.127 135 136 A

study comparing nine quantitative FIT brands with

a threshold from 2 to 15 ?g/g showed a sensitivity

ranging from 56% to 81% and specificity up to 97% in detecting CRC.113 A study from Taiwan compared

two FIT brands with the same threshold of 20 ?g/g

in more than 900000 individuals undergoing

Table 3 | Clinical criteria for diagnosis of Lynch syndrome (LS)

Criteria

Components

Amsterdam II Resvised Bethesda

Proband affected by LS associated cancer and three relatives with LS associated cancers should meet the following family criteria: a) One relative should be a FDR of the other two b) At least two successive generations should be affected c) At least one LS associated cancer should be diagnosed before age 50

Tumors from individuals should be tested for MSI in the following situations: a) CRC diagnosed in patient ................
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