- Email: [email protected]
Colorectal cancer: prevention and early diagnosis
COLORECTAL CANCER
Colorectal cancer: prevention and early diagnosis
What’s new? C
Shivaram K Bhat C
James E East C
Abstract Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. This article examines strategies for the prevention and early diagnosis of CRC, and reviews the aetiology and risk factors for CRC. Preventative strategies involve improving modifiable risk factors through public health awareness. Patients known to be at higher risk of CRC development, such as those with a genetic predisposition or long-standing inflammatory bowel disease, should undergo endoscopic surveillance in order to detect early cancer or polyps. Population screening for CRC is now strongly established as an effective method for the early detection of CRC and prevention through polypectomy. Screening has been shown to improve the stage of disease at diagnosis and CRC-specific mortality. This article will highlight recent developments in the understanding of the serrated pathway for CRC development and discuss the clinical relevance of this in terms of cancer prevention, as well as exploring future directions for research into the prevention and early diagnosis of CRC.
C
promotion, surveillance of patients deemed at high risk, and screening of the population.
Aetiology and risk factors Colorectal cancer may develop over a number of years, with dysplastic adenomas the most common precursor lesion. CRC is thought to develop through the ‘adenoma e carcinoma sequence’, the term used to describe the stepwise progression from adenomatous polyp to cancer. A series of genetic mutations in oncogenes (e.g. KRAS and c-myc), tumour suppressor genes (e.g. APC and p53) and DNA repair genes occur over time resulting in neoplastic progression from polyp to cancer. Our understanding of the genetics of CRC has come about largely through studying familial cases of CRC. Hereditary non-polyposis colorectal cancer (HNPCC; Lynch syndrome) and familial adenomatous polyposis (FAP) are the most common familial CRC syndromes, but together account for less than 5% of all CRC cases.3 In recent years the ‘serrated pathway’ for development of CRC has become better understood. Colorectal polyps were previously broadly categorized into two groups, adenomatous polyps, which were thought to be the sole precursor to CRC, and hyperplastic polyps, which were thought to be benign. However, over time it has become clear that another pathway involving hyperplastic polyps and related lesions such as sessile serrated adenomas could result in progression to CRC.4 It is now thought that 20e30% of CRC cases arise through this ‘serrated pathway’. A number of risk factors for the development of CRC have been established through epidemiological studies (Table 1). Increased age, male sex, family history of CRC, smoking, obesity and dietary factors are all known to play a role. Modifiable risk factors such as diet and smoking can be tackled through public health promotion campaigns. Non-modifiable risk factors allow categorization of patients at higher risk, who can then be selected for surveillance programmes.
Keywords Colonoscopy; colorectal cancer; colorectal polyps; screening; surveillance
Introduction Colorectal cancer (CRC) is the fourth most common cancer in the UK and the second most common cause of cancer death.1 The incidence of CRC increases with age; the median age at diagnosis is 70 years.2 The lifetime risk in the UK is approximately 6%. CRC is more common in men than in women with a male:female ratio of 13:10. When detected early CRC is highly treatable, with survival rates of over 90% at 5 years for patients with early stage (stage I) disease (localized to the bowel wall). Patients with regional spread (stage III) have a worse prognosis with approximately 65% surviving at 5 years. However, only a minority of symptomatic patients are detected with early stage disease, so strategies for the prevention and early detection of CRC are vitally important to improve survival from CRC. The prevention of CRC involves tackling modifiable risk factors through health
Shivaram K Bhat PhD MRCP is a Specialty Registrar in Gastroenterology at Antrim Area Hospital, Antrim, UK. Research interest: Gastrointestinal endoscopy, cancer epidemiology. Competing interests: none declared. James E East MD (Res) FRCP is Consultant Gastroenterologist and Endoscopist at Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. Research interest: Gastrointestinal endoscopy, early detection of colorectal cancer. Competing interests: Research Funding: Olympus, Cosmo technologies; Speaker: Olympus, Abbvie.
MEDICINE 43:6
Improved understanding of the serrated pathway in the development of colorectal cancer The importance of high-quality endoscopic examination to detect and remove adenomas and sessile serrated polyps in the colon Research continues into the optimal population screening strategy between colonoscopy, flexible sigmoidoscopy, and stool blood and DNA testing A large, population-based, randomized UK trial has demonstrated that once-only flexible sigmoidoscopy between the ages of 55 and 64 years reduces colorectal cancer incidence and mortality
Diet, lifestyle and colorectal cancer The relationship between diet and development of CRC has been examined in a number of studies and is complex. The European
295
Ó 2015 Elsevier Ltd. All rights reserved.
COLORECTAL CANCER
previous colorectal cancer may be offered surveillance in an attempt to identify tumour recurrence or adenomas, but the evidence of clear clinical benefit from these strategies is weak.11
Factors associated with colorectal cancer
Modifiable
Non-modifiable
Increased risk
Decreased risk
Smoking Excess alcohol Obesity Red meat Increased age Male sex Family history/known genetic risk Inflammatory bowel disease Acromegaly
Dietary fibre Large bowel endoscopy Aspirin Physical activity
Surveillance following adenoma removal Patients with previously detected adenomas are at risk of developing further adenomas, and are usually offered endoscopic surveillance between every 1 and 5 years based on the size and number of polyps detected (Figure 1). The practice of endoscopic removal of polyps in an effort to prevent future CRC is supported by evidence from several studies. In the US National Polyp Study polypectomy was shown to reduce both the incidence of subsequent CRC and CRC mortality.12 More recent studies have shown that the quality of endoscopic examination is likely to be of importance, measured by adenoma detection rate. In a US study, increased adenoma detection rate was inversely associated with the risk of subsequent development of CRC.13 Advanced polypectomy removal techniques such as endoscopic mucosal resection (EMR) now allow very large polyps several centimetres in size, which would otherwise have required surgical resection (with a high risk of operative mortality), to be safely removed endoscopically.14
Table 1
prospective investigation into cancer and nutrition (EPIC) study is one of the largest cohort studies conducted worldwide. It reported a linear decrease in the risk of colorectal cancer with increasing fibre intake, a finding confirmed by meta-analyses.5 Increased red meat consumption has previously been associated with an increased risk of CRC, but meta-analyses have suggested weak associations between red meat consumption and CRC risk.6 Increased fish consumption (80 g or more) has been shown to be protective. Obesity has been shown in epidemiological studies to be associated with increased risk of CRC. The mechanisms are poorly understood but the metabolic syndrome, insulin resistance and modifications in concentrations of adipocytokines are thought to play a role.7 Conversely, increased physical activity has been shown to be protective against CRC. Proposed mechanisms include the increase in gut motility, decreasing insulin and insulin-like growth factor concentrations, decreasing obesity, and altered prostaglandin concentrations.8 As in other cancers, smoking has been shown to be a risk factor for the development of CRC. In the EPIC study the risk of CRC was increased in both ‘ever smokers’ and former smokers compared with ‘never smokers’. The study also showed that smokers who had not smoked for at least 20 years had a similar risk of developing CRC to that of ‘never smokers’.9 Research into diet, smoking and lifestyle has assisted in guiding public health messages for the primary prevention of CRC in the population.
Population-based screening for CRC has begun relatively recently in many countries worldwide with the UK Bowel Cancer screening programme beginning in England in 2006. The aim of screening is to identify CRC at an earlier, more treatable stage to improve clinical outcome. Screening can also identify and remove colorectal polyps, the precursors to cancer, thereby reducing the risk of CRC development in screened patients. The evidence supporting screening has accumulated over time, with several large trials showing a reduction in CRC mortality with initial screening using faecal occult blood (FOB) testing.15 Patients with a positive FOB test are subsequently offered colonoscopy. A systematic review showed an approximate 25% relative risk reduction in colorectal cancer mortality in screened patients compared to unscreened.15 In England, screening using FOB testing is offered to men and women in the general population every 2 years between the ages of 60 and 74 (Figure 2); other UK nations have variations in entry criteria. Research has shown that in the screened population CRC is detected at a significantly earlier stage than in a non-screened population.16
Surveillance of high-risk groups
Methods of screening
Colonoscopic surveillance is recommended in groups of patients known to be at higher risk of development of CRC.10 Guidelines currently recommend surveillance in patients with a known inherited genetic predisposition, such as HNPCC or FAP, or a strong family history of CRC, and in patients with long-standing colitis.11 Surveillance intervals vary according to risk, with patients deemed to be at higher risk of CRC development being surveyed more frequently. For example, in patients with longstanding colitis, surveillance colonoscopy is initially offered after 10 years, with subsequent surveillance between every 1e5 years dependent on the severity and extent of the colitis. Patients with
Debate exists as to the optimal test to use for CRC screening. The advantages of initial FOB testing are its relatively low cost and the clinical trials supporting its use. However, FOB testing has lower sensitivity compared to other more expensive faecal tests such as the faecal immunochemical test (FIT). In addition, the principle behind FOB testing is the detection of blood in the stool and not all colonic lesions will bleed. There is an argument for the initial use of structural screening tests, such as colonoscopy or flexible sigmoidoscopy, which allow the detection and removal of polyps that may not always bleed.17 A large multicentre study performed in the UK suggested that a once-only
MEDICINE 43:6
Prevention of colorectal cancer through screening
296
Ó 2015 Elsevier Ltd. All rights reserved.
COLORECTAL CANCER
Surveillance following adenoma removal Baseline colonoscopy
Low risk
Intermediate risk
High risk
1–2 adenomas AND both small (<1 cm)
3–4 small adenomas OR at least one ≥1 cm
≥5 small adenomas OR ≥3 at least one ≥1 cm
A
B
C
No surveillance or 5 yr*
3 yr
1 yr
Findings at follow up
Findings at follow up
Findings at follow up
No adenomas
Cease follow-up
1 negative exam
B
Low risk adenomas
A
2 consecutive negative exams
Cease follow-up*
Intermediate risk adenomas
B
Low or intermediate risk adenomas
B
High risk adenomas
C
High risk adenomas
C
Negative, low or intermediate risk adenomas
B
High risk adenomas
C
*Other considerations: Age, comorbidity, family history, accuracy and completeness of examination
Reproduced from Atkin WS, Saunders BP. Surveillance guidelines after removal of colorectal adenomatous polyps. Gut 2002;51(Suppl V):v6–v9 with permission from BMJ Publishing Group Ltd.
Figure 1
that followed up the outcomes of four trials of the use of lowdose aspirin for vascular events over a 20-year period, aspirin was found to reduce both the incidence and mortality from colorectal cancer.20 Aspirin is not currently routinely recommended for the chemoprevention of sporadic CRC.
flexible sigmoidoscopy performed in men and women between the ages of 55 and 64 was effective at reducing CRC incidence and mortality.18 The rationale for this approach is that approximately two-thirds of colorectal cancers are located in the rectum or sigmoid colon, which can be accessed by flexible sigmoidoscopy. The flexible sigmoidoscopic screening programme ‘bowel scope’ is now being rolled out across England as a single examination at age 55 in addition to biennial FOB for ages 60e74. A detailed review of the relative advantages and disadvantages of each screening test is beyond the scope of this article.
Prevention and early diagnosis e the future Future research into improving CRC outcomes will undoubtedly concentrate on prevention and early diagnosis. Uncertainty remains about the modification of which specific aspects of diet, nutrition and lifestyle in the population might result in further reduction of CRC incidence. Population screening has already improved detection of early-stage disease and mortality from CRC, but further improvements in screening technique, target population selection and uptake of screening are possible. Research into blood-based or other stool-based screening methods, such as blood-based DNA methylation or stool methylation, may further improve both the uptake of screening and the sensitivity of testing.21 Better understanding of the serrated pathway for CRC development has led to greater efforts to identify and remove serrated lesions at endoscopy. Advances in endoscopic equipment and technique have led to improved adenoma detection rates and
Chemoprevention Chemoprevention refers to the use of oral medication to reduce the risk of colorectal cancer development. Aspirin and other nonsteroidal anti-inflammatory drugs have been studied most widely. These drugs inhibit the enzymes, cyclo-oxygenase-1 and cyclo-oxygenase-2, which are thought to play a role in the development of adenomatous polyps.19 Studies have suggested that long-term use of high-dose aspirin may be of benefit at reducing colorectal cancer occurrence, but the greater risk of bleeding and the short follow-up time within the trials has limited its use in the primary prevention of CRC. In a larger study
MEDICINE 43:6
297
Ó 2015 Elsevier Ltd. All rights reserved.
COLORECTAL CANCER
7 Bardou M, Barkun AN, Martel M. Obesity and colorectal cancer. Gut 2013 Jun; 62: 933e47. 8 Slattery ML. Physical activity and colorectal cancer. Sports Med Auckl NZ 2004; 34: 239e52. 9 Leufkens AM, Van Duijnhoven FJ, Siersema PD, et al. Cigarette smoking and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition study. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 2011 Feb; 9: 137e44. 10 National Institute for Health and Care Excellence. Colonoscopic surveillance for prevention of colorectal cancer in people with ulcerative colitis, Crohn’s disease or adenomasjGuidance and guidelinesjNICE [Internet]. [cited 2014 Nov 16]. Available from: http://www.nice.org. uk/guidance/CG118. 11 Cairns SR, Scholefield JH, Steele RJ, et al. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut 2010 May 1; 59: 666e89. 12 Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 2012 Feb 22; 366: 687e96. 13 Corley DA, Jensen CD, Marks AR, et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med 2014 Apr 2; 370: 1298e306. 14 Moss A, Bourke MJ, Williams SJ, et al. Endoscopic mucosal resection outcomes and prediction of submucosal cancer from advanced colonic mucosal neoplasia. Gastroenterology 2011 Jun 1; 140: 1909e18. 15 Hewitson P, Glasziou P, Watson E, Towler B, Irwig L. Cochrane systematic review of colorectal cancer screening using the fecal occult blood test (hemoccult): an update. Am J Gastroenterol 2008 Jun; 103: 1541e9. 16 Ellul P, Fogden E, Simpson CL, et al. Downstaging of colorectal cancer by the National Bowel Cancer Screening programme in England: first round data from the first centre. Colorectal Dis Off J Assoc Coloproctology G B Irel 2010 May; 12: 420e2. 17 Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology134: 1570e95. 18 Atkin WS, Edwards R, Kralj-Hans I, et al. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 2010 May; 375: 1624e33. 19 J€anne PA, Mayer RJ. Chemoprevention of colorectal cancer. N Engl J Med 2000; 342: 1960e8. 20 Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010 Nov 20; 376: 1741e50. 21 Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 2014 Apr 3; 370: 1287e97. 22 Ignjatovic A, East JE, Suzuki N, Vance M, Guenther T, Saunders BP. Optical diagnosis of small colorectal polyps at routine colonoscopy (Detect InSpect ChAracterise Resect and Discard; DISCARD trial): a prospective cohort study. Lancet Oncol 2009 Dec; 10: 1171e8.
Expected outcomes in the UK bowel cancer screening programme 3 Invitation for faecal occult blood testing to 60 to 74 year-olds
Uptake: 60%
Negative result: 98%
Re-enter programme, repeat test at 2 years
Positive result: 2%
Colonoscopy
Colorectal cancer: 10%
Polyps: 40%
Normal or benign disease: 50%
Local guidelines
National guidelines
Re-enter programme
Adapted from Ballinger AB, Anggiansah C. Colorectal cancer. BMJ 335, 715–718 (2007) with permission from BMJ Publishing Group Ltd.
Figure 2
the possibility of in vivo polyp characterization (‘optical biopsy’).22 These techniques require further research before they can be recommended for routine use. A REFERENCES 1 Cancer Research UK. Bowel cancer incidence statistics [Internet]. 2014 [cited 2014 Nov 16]. Available from: http://www. cancerresearchuk.org/cancer-info/cancerstats/types/bowel/incidence/. 2 Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 2012 Aug; 62: 220e41. 3 Ballinger AB, Anggiansah C. Colorectal cancer. BMJ 2007 Oct 6; 335: 715e8. 4 East JE, Saunders BP, Jass JR. Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: classification, molecular genetics, natural history, and clinical management. Gastroenterol Clin North Am 2008 Mar; 37: 25e46, v. 5 Aune D, Chan DS, Lau R, et al. Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies. BMJ 2011; 343. d6617ed6617. 6 Alexander DD, Weed DL, Cushing CA, Lowe KA. Meta-analysis of prospective studies of red meat consumption and colorectal cancer. Eur J Cancer Prev Off J Eur Cancer Prev Organ ECP 2011 Jul; 20: 293e307.
MEDICINE 43:6
298
Ó 2015 Elsevier Ltd. All rights reserved.
Colorectal cancer: prevention and early diagnosis
What’s new? C
Shivaram K Bhat C
James E East C
Abstract Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. This article examines strategies for the prevention and early diagnosis of CRC, and reviews the aetiology and risk factors for CRC. Preventative strategies involve improving modifiable risk factors through public health awareness. Patients known to be at higher risk of CRC development, such as those with a genetic predisposition or long-standing inflammatory bowel disease, should undergo endoscopic surveillance in order to detect early cancer or polyps. Population screening for CRC is now strongly established as an effective method for the early detection of CRC and prevention through polypectomy. Screening has been shown to improve the stage of disease at diagnosis and CRC-specific mortality. This article will highlight recent developments in the understanding of the serrated pathway for CRC development and discuss the clinical relevance of this in terms of cancer prevention, as well as exploring future directions for research into the prevention and early diagnosis of CRC.
C
promotion, surveillance of patients deemed at high risk, and screening of the population.
Aetiology and risk factors Colorectal cancer may develop over a number of years, with dysplastic adenomas the most common precursor lesion. CRC is thought to develop through the ‘adenoma e carcinoma sequence’, the term used to describe the stepwise progression from adenomatous polyp to cancer. A series of genetic mutations in oncogenes (e.g. KRAS and c-myc), tumour suppressor genes (e.g. APC and p53) and DNA repair genes occur over time resulting in neoplastic progression from polyp to cancer. Our understanding of the genetics of CRC has come about largely through studying familial cases of CRC. Hereditary non-polyposis colorectal cancer (HNPCC; Lynch syndrome) and familial adenomatous polyposis (FAP) are the most common familial CRC syndromes, but together account for less than 5% of all CRC cases.3 In recent years the ‘serrated pathway’ for development of CRC has become better understood. Colorectal polyps were previously broadly categorized into two groups, adenomatous polyps, which were thought to be the sole precursor to CRC, and hyperplastic polyps, which were thought to be benign. However, over time it has become clear that another pathway involving hyperplastic polyps and related lesions such as sessile serrated adenomas could result in progression to CRC.4 It is now thought that 20e30% of CRC cases arise through this ‘serrated pathway’. A number of risk factors for the development of CRC have been established through epidemiological studies (Table 1). Increased age, male sex, family history of CRC, smoking, obesity and dietary factors are all known to play a role. Modifiable risk factors such as diet and smoking can be tackled through public health promotion campaigns. Non-modifiable risk factors allow categorization of patients at higher risk, who can then be selected for surveillance programmes.
Keywords Colonoscopy; colorectal cancer; colorectal polyps; screening; surveillance
Introduction Colorectal cancer (CRC) is the fourth most common cancer in the UK and the second most common cause of cancer death.1 The incidence of CRC increases with age; the median age at diagnosis is 70 years.2 The lifetime risk in the UK is approximately 6%. CRC is more common in men than in women with a male:female ratio of 13:10. When detected early CRC is highly treatable, with survival rates of over 90% at 5 years for patients with early stage (stage I) disease (localized to the bowel wall). Patients with regional spread (stage III) have a worse prognosis with approximately 65% surviving at 5 years. However, only a minority of symptomatic patients are detected with early stage disease, so strategies for the prevention and early detection of CRC are vitally important to improve survival from CRC. The prevention of CRC involves tackling modifiable risk factors through health
Shivaram K Bhat PhD MRCP is a Specialty Registrar in Gastroenterology at Antrim Area Hospital, Antrim, UK. Research interest: Gastrointestinal endoscopy, cancer epidemiology. Competing interests: none declared. James E East MD (Res) FRCP is Consultant Gastroenterologist and Endoscopist at Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. Research interest: Gastrointestinal endoscopy, early detection of colorectal cancer. Competing interests: Research Funding: Olympus, Cosmo technologies; Speaker: Olympus, Abbvie.
MEDICINE 43:6
Improved understanding of the serrated pathway in the development of colorectal cancer The importance of high-quality endoscopic examination to detect and remove adenomas and sessile serrated polyps in the colon Research continues into the optimal population screening strategy between colonoscopy, flexible sigmoidoscopy, and stool blood and DNA testing A large, population-based, randomized UK trial has demonstrated that once-only flexible sigmoidoscopy between the ages of 55 and 64 years reduces colorectal cancer incidence and mortality
Diet, lifestyle and colorectal cancer The relationship between diet and development of CRC has been examined in a number of studies and is complex. The European
295
Ó 2015 Elsevier Ltd. All rights reserved.
COLORECTAL CANCER
previous colorectal cancer may be offered surveillance in an attempt to identify tumour recurrence or adenomas, but the evidence of clear clinical benefit from these strategies is weak.11
Factors associated with colorectal cancer
Modifiable
Non-modifiable
Increased risk
Decreased risk
Smoking Excess alcohol Obesity Red meat Increased age Male sex Family history/known genetic risk Inflammatory bowel disease Acromegaly
Dietary fibre Large bowel endoscopy Aspirin Physical activity
Surveillance following adenoma removal Patients with previously detected adenomas are at risk of developing further adenomas, and are usually offered endoscopic surveillance between every 1 and 5 years based on the size and number of polyps detected (Figure 1). The practice of endoscopic removal of polyps in an effort to prevent future CRC is supported by evidence from several studies. In the US National Polyp Study polypectomy was shown to reduce both the incidence of subsequent CRC and CRC mortality.12 More recent studies have shown that the quality of endoscopic examination is likely to be of importance, measured by adenoma detection rate. In a US study, increased adenoma detection rate was inversely associated with the risk of subsequent development of CRC.13 Advanced polypectomy removal techniques such as endoscopic mucosal resection (EMR) now allow very large polyps several centimetres in size, which would otherwise have required surgical resection (with a high risk of operative mortality), to be safely removed endoscopically.14
Table 1
prospective investigation into cancer and nutrition (EPIC) study is one of the largest cohort studies conducted worldwide. It reported a linear decrease in the risk of colorectal cancer with increasing fibre intake, a finding confirmed by meta-analyses.5 Increased red meat consumption has previously been associated with an increased risk of CRC, but meta-analyses have suggested weak associations between red meat consumption and CRC risk.6 Increased fish consumption (80 g or more) has been shown to be protective. Obesity has been shown in epidemiological studies to be associated with increased risk of CRC. The mechanisms are poorly understood but the metabolic syndrome, insulin resistance and modifications in concentrations of adipocytokines are thought to play a role.7 Conversely, increased physical activity has been shown to be protective against CRC. Proposed mechanisms include the increase in gut motility, decreasing insulin and insulin-like growth factor concentrations, decreasing obesity, and altered prostaglandin concentrations.8 As in other cancers, smoking has been shown to be a risk factor for the development of CRC. In the EPIC study the risk of CRC was increased in both ‘ever smokers’ and former smokers compared with ‘never smokers’. The study also showed that smokers who had not smoked for at least 20 years had a similar risk of developing CRC to that of ‘never smokers’.9 Research into diet, smoking and lifestyle has assisted in guiding public health messages for the primary prevention of CRC in the population.
Population-based screening for CRC has begun relatively recently in many countries worldwide with the UK Bowel Cancer screening programme beginning in England in 2006. The aim of screening is to identify CRC at an earlier, more treatable stage to improve clinical outcome. Screening can also identify and remove colorectal polyps, the precursors to cancer, thereby reducing the risk of CRC development in screened patients. The evidence supporting screening has accumulated over time, with several large trials showing a reduction in CRC mortality with initial screening using faecal occult blood (FOB) testing.15 Patients with a positive FOB test are subsequently offered colonoscopy. A systematic review showed an approximate 25% relative risk reduction in colorectal cancer mortality in screened patients compared to unscreened.15 In England, screening using FOB testing is offered to men and women in the general population every 2 years between the ages of 60 and 74 (Figure 2); other UK nations have variations in entry criteria. Research has shown that in the screened population CRC is detected at a significantly earlier stage than in a non-screened population.16
Surveillance of high-risk groups
Methods of screening
Colonoscopic surveillance is recommended in groups of patients known to be at higher risk of development of CRC.10 Guidelines currently recommend surveillance in patients with a known inherited genetic predisposition, such as HNPCC or FAP, or a strong family history of CRC, and in patients with long-standing colitis.11 Surveillance intervals vary according to risk, with patients deemed to be at higher risk of CRC development being surveyed more frequently. For example, in patients with longstanding colitis, surveillance colonoscopy is initially offered after 10 years, with subsequent surveillance between every 1e5 years dependent on the severity and extent of the colitis. Patients with
Debate exists as to the optimal test to use for CRC screening. The advantages of initial FOB testing are its relatively low cost and the clinical trials supporting its use. However, FOB testing has lower sensitivity compared to other more expensive faecal tests such as the faecal immunochemical test (FIT). In addition, the principle behind FOB testing is the detection of blood in the stool and not all colonic lesions will bleed. There is an argument for the initial use of structural screening tests, such as colonoscopy or flexible sigmoidoscopy, which allow the detection and removal of polyps that may not always bleed.17 A large multicentre study performed in the UK suggested that a once-only
MEDICINE 43:6
Prevention of colorectal cancer through screening
296
Ó 2015 Elsevier Ltd. All rights reserved.
COLORECTAL CANCER
Surveillance following adenoma removal Baseline colonoscopy
Low risk
Intermediate risk
High risk
1–2 adenomas AND both small (<1 cm)
3–4 small adenomas OR at least one ≥1 cm
≥5 small adenomas OR ≥3 at least one ≥1 cm
A
B
C
No surveillance or 5 yr*
3 yr
1 yr
Findings at follow up
Findings at follow up
Findings at follow up
No adenomas
Cease follow-up
1 negative exam
B
Low risk adenomas
A
2 consecutive negative exams
Cease follow-up*
Intermediate risk adenomas
B
Low or intermediate risk adenomas
B
High risk adenomas
C
High risk adenomas
C
Negative, low or intermediate risk adenomas
B
High risk adenomas
C
*Other considerations: Age, comorbidity, family history, accuracy and completeness of examination
Reproduced from Atkin WS, Saunders BP. Surveillance guidelines after removal of colorectal adenomatous polyps. Gut 2002;51(Suppl V):v6–v9 with permission from BMJ Publishing Group Ltd.
Figure 1
that followed up the outcomes of four trials of the use of lowdose aspirin for vascular events over a 20-year period, aspirin was found to reduce both the incidence and mortality from colorectal cancer.20 Aspirin is not currently routinely recommended for the chemoprevention of sporadic CRC.
flexible sigmoidoscopy performed in men and women between the ages of 55 and 64 was effective at reducing CRC incidence and mortality.18 The rationale for this approach is that approximately two-thirds of colorectal cancers are located in the rectum or sigmoid colon, which can be accessed by flexible sigmoidoscopy. The flexible sigmoidoscopic screening programme ‘bowel scope’ is now being rolled out across England as a single examination at age 55 in addition to biennial FOB for ages 60e74. A detailed review of the relative advantages and disadvantages of each screening test is beyond the scope of this article.
Prevention and early diagnosis e the future Future research into improving CRC outcomes will undoubtedly concentrate on prevention and early diagnosis. Uncertainty remains about the modification of which specific aspects of diet, nutrition and lifestyle in the population might result in further reduction of CRC incidence. Population screening has already improved detection of early-stage disease and mortality from CRC, but further improvements in screening technique, target population selection and uptake of screening are possible. Research into blood-based or other stool-based screening methods, such as blood-based DNA methylation or stool methylation, may further improve both the uptake of screening and the sensitivity of testing.21 Better understanding of the serrated pathway for CRC development has led to greater efforts to identify and remove serrated lesions at endoscopy. Advances in endoscopic equipment and technique have led to improved adenoma detection rates and
Chemoprevention Chemoprevention refers to the use of oral medication to reduce the risk of colorectal cancer development. Aspirin and other nonsteroidal anti-inflammatory drugs have been studied most widely. These drugs inhibit the enzymes, cyclo-oxygenase-1 and cyclo-oxygenase-2, which are thought to play a role in the development of adenomatous polyps.19 Studies have suggested that long-term use of high-dose aspirin may be of benefit at reducing colorectal cancer occurrence, but the greater risk of bleeding and the short follow-up time within the trials has limited its use in the primary prevention of CRC. In a larger study
MEDICINE 43:6
297
Ó 2015 Elsevier Ltd. All rights reserved.
COLORECTAL CANCER
7 Bardou M, Barkun AN, Martel M. Obesity and colorectal cancer. Gut 2013 Jun; 62: 933e47. 8 Slattery ML. Physical activity and colorectal cancer. Sports Med Auckl NZ 2004; 34: 239e52. 9 Leufkens AM, Van Duijnhoven FJ, Siersema PD, et al. Cigarette smoking and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition study. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 2011 Feb; 9: 137e44. 10 National Institute for Health and Care Excellence. Colonoscopic surveillance for prevention of colorectal cancer in people with ulcerative colitis, Crohn’s disease or adenomasjGuidance and guidelinesjNICE [Internet]. [cited 2014 Nov 16]. Available from: http://www.nice.org. uk/guidance/CG118. 11 Cairns SR, Scholefield JH, Steele RJ, et al. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut 2010 May 1; 59: 666e89. 12 Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 2012 Feb 22; 366: 687e96. 13 Corley DA, Jensen CD, Marks AR, et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med 2014 Apr 2; 370: 1298e306. 14 Moss A, Bourke MJ, Williams SJ, et al. Endoscopic mucosal resection outcomes and prediction of submucosal cancer from advanced colonic mucosal neoplasia. Gastroenterology 2011 Jun 1; 140: 1909e18. 15 Hewitson P, Glasziou P, Watson E, Towler B, Irwig L. Cochrane systematic review of colorectal cancer screening using the fecal occult blood test (hemoccult): an update. Am J Gastroenterol 2008 Jun; 103: 1541e9. 16 Ellul P, Fogden E, Simpson CL, et al. Downstaging of colorectal cancer by the National Bowel Cancer Screening programme in England: first round data from the first centre. Colorectal Dis Off J Assoc Coloproctology G B Irel 2010 May; 12: 420e2. 17 Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology134: 1570e95. 18 Atkin WS, Edwards R, Kralj-Hans I, et al. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 2010 May; 375: 1624e33. 19 J€anne PA, Mayer RJ. Chemoprevention of colorectal cancer. N Engl J Med 2000; 342: 1960e8. 20 Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010 Nov 20; 376: 1741e50. 21 Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 2014 Apr 3; 370: 1287e97. 22 Ignjatovic A, East JE, Suzuki N, Vance M, Guenther T, Saunders BP. Optical diagnosis of small colorectal polyps at routine colonoscopy (Detect InSpect ChAracterise Resect and Discard; DISCARD trial): a prospective cohort study. Lancet Oncol 2009 Dec; 10: 1171e8.
Expected outcomes in the UK bowel cancer screening programme 3 Invitation for faecal occult blood testing to 60 to 74 year-olds
Uptake: 60%
Negative result: 98%
Re-enter programme, repeat test at 2 years
Positive result: 2%
Colonoscopy
Colorectal cancer: 10%
Polyps: 40%
Normal or benign disease: 50%
Local guidelines
National guidelines
Re-enter programme
Adapted from Ballinger AB, Anggiansah C. Colorectal cancer. BMJ 335, 715–718 (2007) with permission from BMJ Publishing Group Ltd.
Figure 2
the possibility of in vivo polyp characterization (‘optical biopsy’).22 These techniques require further research before they can be recommended for routine use. A REFERENCES 1 Cancer Research UK. Bowel cancer incidence statistics [Internet]. 2014 [cited 2014 Nov 16]. Available from: http://www. cancerresearchuk.org/cancer-info/cancerstats/types/bowel/incidence/. 2 Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 2012 Aug; 62: 220e41. 3 Ballinger AB, Anggiansah C. Colorectal cancer. BMJ 2007 Oct 6; 335: 715e8. 4 East JE, Saunders BP, Jass JR. Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: classification, molecular genetics, natural history, and clinical management. Gastroenterol Clin North Am 2008 Mar; 37: 25e46, v. 5 Aune D, Chan DS, Lau R, et al. Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies. BMJ 2011; 343. d6617ed6617. 6 Alexander DD, Weed DL, Cushing CA, Lowe KA. Meta-analysis of prospective studies of red meat consumption and colorectal cancer. Eur J Cancer Prev Off J Eur Cancer Prev Organ ECP 2011 Jul; 20: 293e307.
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