Colorectal cancer screening

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Chapter 18 COLORECTAL CANCER SCREENING

KEY POINTS

• Colorectal (CRC) screening can reduce incidence and mortality from CRC by up to 90%.
• All average subjects aged 50 years and older should be screened.
• Colonoscopy is the best screening modality.
• The most prominent obstacle for CRC screening is the low compliance rate.
• Each of the current screening modalities is better than no screening and is effective in reducing mortality from CRC in the average risk population.
• Colonoscopy is the preferred screening tool for symptomatic patients and for moderate and high-risk groups.
• Recently developed screening modalities and technologies may replace current screening modalities.

BACKGROUND

The third millennium is witnessing the emergence of preventive medicine as a cornerstone in our concept of health. Colorectal cancer (CRC) is a major health concern (Chapter 17), and one that fits the criteria of a preventable disease. Approximately two-thirds of the cases involve average-risk men and women, with a sharp increase of its incidence starting from the fifth decade of life.

Detection and removal of colonic adenomas, the non-invasive neoplasm that are the precursors of CRC, could prevent up to 90% of CRC cases. The transition process between adenomas to carcinoma is estimated as 5–10 years and that of normal mucosa thorough adenoma to adenocarcinoma as 15–20 years. This interval provides a unique window of opportunity for screening and effective interventions to reduce CRC-associated mortality. The respective curative benefits that can be gained by detecting CRC at early stages, e.g. node-negative stages I and II, are as high as 90% and 75%, respectively, with surgery alone, while the 5-year survival rate is close to zero for metastatic CRC.

Most medical societies strongly recommend mass screening of the average-risk adult population starting at age 50 and earlier for individuals at higher risk due to family history or other predisposing factors. Several screening tests are available and are in common use.

FAECAL OCCULT BLOOD TESTING

Faecal occult blood test (FOBT) is a low-cost, non-invasive periodic procedure that detects faecal haemoglobin and does not require cathartic bowel preparation. Currently available approaches include a guaiac test, based on the peroxidase-like activity of haemoglobin, or immunochemical analysis. In the guaiac-based assay, accuracy of FOBT may be affected by stool re-hydration (which increases sensitivity but decreases specificity), haem degradation (reduced sensitivity), medications (false positives with non-steroidal antiinflammatory drugs [NSAIDS] and false negatives with vitamin C) and interfering dietary ingredients (such as peroxidases and meat haem). Recent professional guidelines have suggested that re-hydration is not recommended since the readability of the test is unpredictable, and the false positive rate is substantially increased. Newer guaiac-based and immunochemical tests are now available with improved sensitivity.

Support for the ability of annual FOBT to reduce the mortality from CRC emerged from several large prospective randomised trials. Mortality was reduced by 15%–33% if the test was done yearly, and when positive results were followed by colonoscopy. A meta-analysis that pooled the results of these studies estimated a 16%–23% reduction in CRC mortality. The estimated FOBT sensitivity for cancer ranges between 30% and 90% depending upon the test used. The major limitation of FOBT is its low sensitivity as a screening test, since some carcinomas and most adenomas do not bleed. Only 24% of advanced neoplasia cases had a positive FOBT result on the three consecutive days’ samples obtained prior to bowel preparation. Proper FOBT testing requires examining three different bowel movements. Prerequisite compliance is difficult to achieve from both patients and physicians. In addition, the test gives an indirect result; hence, individuals who test positive have to undergo colonoscopy to confirm the presence of polyps, cancer or other pathology. Survival benefit may therefore reflect the benefit of colonoscopy, for detecting incidental lesions including those of subjects with false positive FOBT results. Lastly, upper gastrointestinal (GI) tract sources of occult bleeding, NSAID use or false positive results due to dietary ingredients may lead to unnecessary colonoscopies. There is often a low referral rate of patients with positive FOBT screening findings.

FOBT testing has no merit as a single test. It should definitely not be done when a patient has overt rectal bleeding (see Chapter 20) or any alarm symptoms. In such cases colonoscopy must be performed.

SIGMOIDOSCOPY

This method provides direct endoscopic visualisation of the distal part of the colon, preferably up to the splenic flexure, and enables biopsies to be taken and polyps resected. Sigmoidoscopy is considered less invasive than colonoscopy and requires a simple bowel preparation of only two fleet enemas, one hour prior to the procedure. It usually does not require sedation and can be performed by trained nurses. A finding of a neoplastic/dysplastic lesion mandates full evaluation of the entire large intestine by colonoscopy although, according to some guidelines, this decision should be individualised and be performed in high-risk subjects (e.g. age ≥65 years, villous histology in the large adenoma ≥1 cm or multiple adenomas). The currently published data on reducing CRC mortality by screening sigmoidoscopy are derived from non-prospective case-controlled trials which report that screening sigmoidoscopy can reduce the incidence and death rates of distal CRC by 59%–80% and lower overall CRC mortality by up to 40%–50%.

The main drawback of sigmoidoscopy is the limit of its extension, which is up to the splenic flexure at best. Unfortunately, the distance is often significantly shorter. Sensitivity actually depends on the varied experience of the examiners, and on patient discomfort, two factors that have a major impact on the depth of insertion and adequacy of mucosal inspection. Even in the hands of expert endoscopists, the sigmoidoscope was found to traverse the sigmoid colon in only 66% of cases. For more than 50% of proximal advanced lesions (i.e. advanced adenoma or carcinoma) there were no lesions in the distal colon, so those would have been missed by sigmoidoscopy. Sigmoidoscopy is even less rewarding in subjects aged 65–75 years, as a proximal shift of neoplasia in this age group is suggested.

COMBINED FOBT AND SIGMOIDOSCOPY

There is a lack of prospective data regarding the value of a combined approach of 5-year sigmoidoscopy and annual FOBT. Some evidence suggests that it may possess some advantage, as sigmoidoscopy is intended to screen the distal colon, and FOBT is more effective in detecting proximal lesions. Supporting data from case-control studies report that screening FOBT and sigmoidoscopy are individually associated with reduced CRC mortality after controlling for the other test. When both tests are to be done, the FOBT should be performed first because a positive result is an indication for colonoscopy, obviating the need for sigmoidoscopy. This combination may improve the relative efficacy of each test alone, and has been suggested as an alternative strategy for screening colonoscopy. The limitation of this combined approach is exposing individuals to inconvenience, cost and complications of both FOBT and sigmoidoscopy with an uncertain gain in efficacy.

COLONOSCOPY

Colonoscopy is the gold standard procedure to identify colorectal neoplasia. Skilled gastroenterologists perform the examination after a cathartic bowel preparation. Using back-to-back colonoscopies, it was shown that the sensitivity of a single colonoscopy is about 90%–95% for cancers and large adenomas and 75% for polyps <1 cm. The detection rates for adenomas ≥10 mm, 5–10 mm and 1–5 mm were found to be 98%, 87% and 74%, respectively. Colonoscopy miss rates are related to the skills of the endoscopist, withdrawal technique and, in particular, withdrawal time that reflects the time spent to inspect the colon. Although there are no published prospective studies on direct reduction of CRC mortality by primary screening colonoscopy, there is a large body of evidence to support it. The National Polyp Study has demonstrated a 76%–90% decrease in the incidence of CRC at 6 years after the index colonoscopy and polypectomy, compared with several appropriately selected control groups. A prospective 13-year follow-up demonstrated a relative risk of 0.2 for CRC in subjects who underwent colonoscopy with polyp removal compared with the control group. The prevalence of CRC in asymptomatic patients being screened aged 50–75 years in the USA is approximately 1%. Overall, the findings support the use of colonoscopy rather than sigmoidoscopy for screening in this age group.

The bowel preparation is inconvenient and poses a major obstacle. The myths of the discomfort of colonoscopy may be unjustified, since the examination is performed under conscious sedation and discomfort is rare. Indeed, patients who have undergone both endoscopic examinations report that non-sedated sigmoidoscopy is associated with a significantly higher recalled level of discomfort compared with conscious sedated colonoscopy. Studies on colonoscopy in the setting of ambulatory screening examinations have shown a considerably low risk of morbidity (0.1%–0.3%) with no procedure-related deaths. Colonoscopy costs more than FOBT and sigmoidoscopy. The true calculations, however, should be based on the long-term costs for a life-year saved. In a realistic model of a <50% compliance rate, the estimated cost per death prevented was similar for FOBT and endoscopy. Furthermore, if colonoscopy costs are below $750, once-in-a-life-time colonoscopy was found to be more cost effective than any other screening modality at every level of compliance.

Double-contrast barium enema

Double-contrast barium enema (DCBE) is not a viable contemporary screening modality for colorectal neoplasia because of its low sensitivity and specificity compared with other screening modalities.

RISK STRATIFICATION AND CURRENT SCREENING RECOMMENDATIONS

Screening for colonic neoplasia is important for individuals who are free of any signs or symptoms suggestive of CRC. A full colonoscopy is absolutely indicated in the presence of alarm symptoms. A key element for tailoring the most appropriate screening programme relies on the individual’s level of risk, which is based primarily on age, as well as on personal, family and medical history. This risk status determines when screening should be initiated, at what frequency and by which modality. Risk stratification can be determined by asking pertinent questions aimed at uncovering the risk factors for CRC (Table 18.1):

• Is there any personal or familial history of colon cancer, any familial polyposis syndrome or colonic polyps?
• Is there any personal history of inflammatory bowel disease?
• Is there any history of acromegaly or other cancers?

TABLE 18.1 Risk factors for colorectal cancer that mandate colonoscopy as the screening tool

Genetic disorders
• Familial adenomatous polyposis
• Hereditary non-polyposis colorectal cancer
• Peutz-Jegher syndrome
• Hyperplastic polyposis-Juvenile polyposis
• Cowden’s syndrome

Personal history of colorectal cancer or adenoma   Family history of colorectal cancer or adenoma First-degree relative diagnosed <60 years, or two first-degree relatives diagnosed at any age Inflammatory bowel disease After 8 years with pancolitis and 12 years with left-sided colitis Endocrine disorders Acromegaly Other neoplasm Breast cancer?

Asymptomatic individuals with any risk factors for CRC are then re-classified into ‘moderate-risk’ (personal and/or family history of CRC or adenoma), or ‘high risk’ for CRC (e.g. familial neoplastic syndromes or inflammatory bowel disease). Current CRC screening recommendations (based on recent professional guidelines) are shown in Figure 18.1.

image

FIGURE 18.1 Colorectal cancer screening recommendations.

Based on Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale—Update based on new evidence. Gastroenterology 2003; 124:544–60.

CRC screening in average-risk populations

Men and women at average risk should be offered screening with one of the following options beginning at the age of 50 years:

• Annual FOBT, with two samples from each of three consecutive stools examined without re-hydration
• Sigmoidoscopy every 5 years
• Colonoscopy every 10 years.

The rationale for presenting multiple options is that no single test is of unequivocal superiority and giving patients a choice may increase compliance. The strategies are different in terms of the evidence they provide and their specific degree of effectiveness, risk and costs. Clinicians should present the different features of each modality to their patients to enable them to make an informed choice about screening options.

CRC screening in moderate-risk populations

This subpopulation is defined by a personal or family history of adenoma/CRC. Professional guidelines recommend the following guidelines (Table 18.2):

• Colonoscopy (should be done every 5 years) starting at age 40 years or 10 years younger than the earliest diagnosis when the first-degree relative (parent, sibling or child) had CRC or adenomatous polyps diagnosed at age <60 years or if two first-degree relatives have been diagnosed with CRC at any age.
• Screening as for average-risk persons, but beginning at age 40 years when the first-degree relative with CRC or adenomatous polyp was diagnosed at age >60 years or if two second-degree relatives were diagnosed with CRC at any age.
• Screening as for average-risk persons when one second-degree relative (grandparent, aunt or uncle) with CRC or a third-degree relative (great-grandparent or cousin) has been diagnosed with CRC.

TABLE 18.2 Guidelines for colorectal cancer (CRC) screening in a moderate-risk group

Colonoscopy* starting at age 40 years or 10 years younger than the earliest diagnosis if:

• A first-degree relative (parent, sibling or child) with colorectal cancer (CRC) or adenomatous polyps diagnosed at age <60 years
• Two first-degree relatives diagnosed with CRC at any age

Screening as for average risk persons, but beginning at age 40 years, if:

• A first-degree relative with CRC or adenomatous polyp diagnosed at age >60 years
• Two second-degree relatives with CRC of any age
Screening as for average risk persons if:

• One second-degree relative (grandparent, aunt or uncle) with CRC
• One third-degree relative (great-grandparent or cousin) with CRC

* Colonoscopy should be done every 5 years.

The rationale for beginning screening at age 40 years in persons with an affected first-degree relative is that the incidence of CRC for them parallels the risk in persons with no family history but precedes it by about 10 years.

High-risk groups for CRC screening

This group should undergo more intensive surveillance with colonoscopy only (see Table 18.1). These guidelines do not include screening for cancers outside the colon and, for the genetic syndromes, recommendations are based on phenotype only (Table 18.3).

• Familial adenomatous polyposis (FAP): annual sigmoidoscopy, beginning at age 10–12 years.
• Hereditary non-polyposis colon cancer (HNPCC): colonoscopy every 1–2 years beginning at age 20–25 years, or 10 years earlier than the youngest age of cancer associated with HNPCC (gastric, ovarian, uterine, small intestine) in relatives.
• Inflammatory bowel disease (IBD): colonoscopy every 1–2 years after 8 years of disease in patients with pancolitis or after 12–15 years in left-sided colitis. Biopsies should be taken every 10 cm in all four quadrants with additional sampling of strictures or any mucosal irregularities. This applies to both ulcerative colitis and Crohn’s disease, since the cancer risk is similar in both diseases.
• Genetic testing for FAP or HNPCC should be offered to first-degree relatives of persons with a known inherited gene mutation. It should also be offered when the family mutation is not already known, but the clinical suspicion is high.

TABLE 18.3 Guidelines for colorectal cancer (CRC) screening in high-risk groups

Familial adenomatous polyposis Annual sigmoidoscopy, beginning at age 10–12 years*
Hereditary non-polyposis colon cancer Colonoscopy every 1–2 years beginning at age 20–25 years, or 10 years earlier than the youngest age of cancer associated with HNPCC (gastric, ovarian, uterine, small intestine)
Inflammatory bowel disease Colonoscopy every 1–2 years after 8 years of disease in patients with pancolitis or after 12–15 years in left-sided colitis. Biopsies should be taken every 10 cm in all four quadrants with additional sampling of strictures or any mucosal irregularities

* This recommendation holds true based on phenotype only (without a definite genetic mutation).

SURVEILLANCE OF INDIVIDUALS AT INCREASED RISK

Patients who have had numerous adenomas, adenoma with invasive cancer, a large sessile adenoma or an incomplete colonoscopy should have a short-interval follow-up colonoscopy based on clinical judgment. Patients who have advanced or multiple adenomas (>3) should have their first follow-up colonoscopy in 3 years. Patients who have one or two small (<1 cm) tubular adenomas should have their first follow-up colonoscopy at 5 years. Patients with a CRC that has been resected with curative intent should have had a colonoscopy around the time of initial diagnosis to rule out synchronous neoplasm. If the colon is obstructed preoperatively, colonoscopy can be performed approximately 3 months after surgery. If this or a complete preoperative examination is normal, subsequent colonoscopy should be considered after 3 years, and then, if normal, every 5 years.

Emerging screening modalities

There are several newly developed screening tests for CRC, which have shown substantial promise, but none has been sufficiently developed or investigated to be offered as a routine.

Virtual colonoscopy (VC)

The approach involves performing an abdominal computerised tomographic (CT) examination that is analysed by a computer to render an image resembling the one seen at optical colonoscopy. As in colonoscopy, the examination requires cathartic bowel preparation and air insufflations for intestinal distension, and the patients are not sedated. It is considered a minimally invasive procedure, although colonic perforation has been recognised as an associated complication. VC has the additional advantages of an abdominal CT scan, supplying information on tumour invasion, lymph node involvement and metastasis. In cases of suspected lesions, the examination should be followed by conventional colonoscopy. The sensitivity of VC for lesions ≥10 mm reportedly ranges from 81%–94%. The detection rate of polyps ≥6 mm ranges widely (39%–94%). Prepless VC using faecal tags to distinguish stool from true lesions is under evaluation.

Faecal DNA test

A stool-based molecular analysis of DNA markers in exfoliated colonocytes that are regularly shed in the stool. The rationale of the examination is that normal colonocytes are sparse and apoptotic (e.g. contain ‘short’ DNA fragments), while neoplastic colonocytes are abundant and harbour high molecular weight DNA (‘long DNA’). Since CRC is a disease of mutations that occur as tissue evolves from normal to adenoma to carcinoma, these mutations can be detectable in the stool. Advantages of this test over the other screening modalities are their non-invasive nature and lack of bowel preparation or any dedicated procedural time. Testing can be performed on mailed-in specimens, whereby geographic access to stool screening is essentially unimpeded. Initial studies based on either single mutation or panels of genetic markers had a sensitivity of 91% and 82% for CRC and large adenomas, respectively, but controlled studies demonstrated less favourable results. Long DNA was the most frequent neoplastic marker in the stool. The most prevalent genetic alterations were mutations in K-ras and p53 genes, followed by microsatellite instability (MSI) and adenomatous polyposis coli (APC) gene mutations. The test seems promising with considerably higher sensitivity and specificity than FOBT, but has not yet been validated as a screening tool in large-scale prospective trials. At present, the high cost of faecal DNA testing is a major obstacle that reduces its cost-effectiveness. There is a promising future for this approach if sensitivity could be increased by additional markers (e.g. methylation) and if cost could be reduced.

Magnification high-resolution endoscopy

A development in endoscopy design. The new electronic videoendoscopes are equipped with charged couple device (CCD) chips of 100 K to 300 K pixels. The recent generation of videoendoscopes was introduced with 850 K-pixel density and referred to as high resolution endoscopes. In addition, some endoscopes, including the high-resolution types, are equipped with an optical zoom facility, which can provide a magnified image. The combination of both high resolution and magnification may become an important supplementary tool in CRC screening. High resolution can increase the detection rate of small and flat lesions while magnification can enhance details in the suspected lesions, thereby making endoscopic diagnosis more accurate.

Chromoendoscopy

A technique that consists of staining the mucosal surface of the GI tract in order to enhance the diagnostic yield of endoscopy. The main purpose is to screen for neoplastic or preneoplastic lesions (in particular flat or depressed lesions) and to direct endoscopic biopsies. Indigo carmine is a contrast stain that accumulates in pits and valleys between cells highlighting the mucosal architecture that becomes even more apparent with the use of magnification and/or high-resolution endoscopy. The technique only requires a special spraying catheter, making it simple and relatively inexpensive. Its only disadvantage is that it prolongs the overall procedural time. Currently, chromoendoscopy is reserved for high-risk subjects (i.e. patients with a personal history of neoplasia, inflammatory bowel disease or familial neoplastic syndromes).

New technologies on the horizon

The following new technologies are future screening approaches for CRC that have not yet been confirmed by large scale clinical trials.

Assisted colonoscopy

The FDA recently approved a device known as the ColonoSight® (Striker, USA). ColonoSight is ergonomically similar to currently existing colonoscopes. The device is covered by a disposable sleeve and the physician’s hands remain clean. All channels within the device (insufflations, irrigation, suction/working) are completely disposable and no fibre-optics are necessary due to an incorporated LED light source. The air used for sleeve deployment adds a small amount of additional forward force just below the scope tip, which enhances device navigation and forward motion. Pilot studies are available with a mean examination time of 12.4 ± 10.8 minutes with a mean insertion length of 117 ± 26 cm.

Self-propelling self-navigating skill-independent colonoscopy

(The Aer-O-Scope™ GI View, Israel) This new disposable colonoscope is a skill-independent, anaesthesia-free, self-propelling, self-navigating miniaturised endoscopic device that moves along the entire length of the colon, transmitting video pictures of the colonic mucosa. This disposable product is based on a miniaturised self-propelling, self-navigating locomotion mechanism that contains a digital camera. The device is supplied with electricity, air, water and suction via a thin supply cable, which it drags behind it. The device has a novel optical system enabling a 360° view, and hence may decrease the polyp miss rate, particularly behind folds. So far the device has proven safe, without any complications in more than 60 subjects.

The PillCam™ COLON

(Given Imaging, Israel). This capsule is very similar to the oesophageal and small intestine camera capsules. It is slightly bigger (11 mm by 32 mm), has dual cameras, a wide field of view, automatic light control, four frames per second and a battery life of 10 hours. A meticulous preparation is absolutely necessary. The overall sensitivity for significant lesions was around 75%, specificity 70%, and positive and negative predictive values of 65% and 85%, respectively. False positive results were recorded in one-third of study cases.

SUMMARY

CRC is a major health concern and a largely preventable disease. A majority of CRC cases are preventable with screening. Early detection enables either detection of adenomas or diagnosis of CRC at an early stage, which carries a significantly better prognosis than advanced CRC. Screening modalities have developed substantially in recent years. Available modalities include FOBT, sigmoidoscopy, combination of FOBT and sigmoidoscopy and colonoscopy.

Each modality has its own pros and cons, though colonoscopy is the gold standard and is the mandatory screening modality for high-risk populations. There is now a consensus that any screening modality is better than nothing, and that each modality of screening is effective in reducing the mortality from CRC.

Emerging screening modalities include virtual colonoscopy, faecal DNA testing and advanced endoscopic techniques. The choice of screening modality depends upon the risk stratification of the patient. The age at which screening should start in the average risk population is 50 years of age. Higher-risk groups require earlier screening. The most prominent obstacle is low patient compliance rates.

FURTHER READING

Bernstein CN. Ulcerative colitis and low-grade dysplasia. Gastroenterology. 2004;127:950-956.

Levine JS, Ahmen DJ. Clinical Practice. Adenomatous polyps of the colon. N Engl J Med. 2006;355:2551-2557.

Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA. 2006;296:1507-1517.

Rex DK. Maximizing detection of adenomas and cancers during colonoscopy. Am J Gastroenterol. 2006;101:2866-2877.

Schoen RE, Weissfeld JL, Pinsky PF, et al. Yield of advanced adenoma and cancer based on polyp size detected at screening flexible sigmoidoscopy. Gastroenterology. 2006;131:1683-1689.

Walsh JM, Terdiman TP. Colorectal cancer screening; scientific review. JAMA. 2003;289:1288-1296.

Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale—Update based on new evidence. Gastroenterology. 2003;124:544-560.

Winawer S, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology. 2006;130:1872-1885.

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