Screening for Colorectal Cancer

Published on 09/04/2015 by admin

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Screening for Colorectal Cancer

Jin He, MD ^a, Jonathan E. Efron, MD ^b^,^*

^a Department of Surgery, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287, USA

^b Department of Surgery, Division of Colorectal Surgery, 600 North Wolfe Street, Blalock 656, Baltimore, MD 21087, USA

^* Corresponding author.

E-mail address: Jefron1@jhmi.edu

Colorectal cancer (CRC) is a leading cause of death from cancer in the United States. In 2010 there are 143,000 new cases of CRC expected with more than 51,000 people dying from the disease. More than a million individuals worldwide are diagnosed with CRC every year and half a million die of CRC in the same time period [1].

CRC is a preventable disease and effective CRC screening may reduce CRC incidence, mortality, and the cost associated with CRC treatment. The goal of screening is to select those patients who need a colonoscopy for the resection of significant polyps at risk for following the adenoma to carcinoma sequence while avoiding unnecessary colonoscopy in patients with normal findings. With the current financial constraints on health care, cost-effectiveness is an essential component of any screening modality.

Screening rates for colorectal cancer have steadily increased in the past 10 years. This increase is accompanied with decreasing trends in distal CRC rates since 1985. Currently, 55% of insured individuals in the United States aged older than 50 years are screened. The remaining 45% of eligible individuals are not screened by any method. Twenty-two million people aged 50 to 75 years are not screened for CRC. This compliance rate is even worse for those patients without insurance coverage, where only 24% of eligible patients are screened for CRC [2]. The focus of this review is to discuss the current techniques available for CRC screening and their relative effectiveness at early detection and prevention.

Endoscopy

Endoscopy has both screening and therapeutic value. It enables inspection and detection of precancerous and cancerous lesions, with immediate resection of reasonably sized lesions by polypectomy. The two most important outcomes when examining a screening procedure for CRC are mortality reduction by early detection and cancer prevention by identification and removal of advanced adenomas. Sigmoidoscopy and colonoscopy are two widely used screening examinations for CRC. Choice of screening procedure is patient and physician dependent. A successful endoscopy requires an excellent bowel preparation, identification, and possible removal of adenomas with minimal morbidity. Colonoscopy has a higher perforation rate, greater need for sedation, requires increased time and commitment by patients, and has an overall increased cost when compared to sigmoidoscopy. Which screening endoscopic procedure patients undergo depends on their access to specialists, their insurance coverage, potential difficulties in performing the test, and their experience with the test [3].

Numerous studies underscore the cost-effectiveness of every colorectal screening test (at an estimated cost of less than $20,000 per year of life saved), including colonoscopy. Though colonoscopy is the most expensive test, it may ultimately cost less than other alternatives because it prevents more cancers and does not need to be performed frequently [4,5]. Rabeneck and colleagues [6] examined a database of 2,412,077 persons aged 50 to 90 years who underwent colonoscopy. They showed that for every 1% increase in utilization of colonoscopy, there was a 3% reduction in colon cancer death.

Even though colonoscopy and sigmoidoscopy are equally acceptable options in guidelines from the US Preventive Services Task Force (USPSTF) and the US Multisociety Task Force, colonoscopy was granted preferred status in guidelines published by the American College of Gastroenterology [7]. Colonoscopy has achieved a predominant role in colon cancer screening since Medicare initiated reimbursement in 2001. Although colonoscopy is considered the gold standard for colon cancer screening by most physicians, its superiority has been challenged by several recent publications. In a case-control study from Canada, colonoscopy was associated with a reduction in colorectal cancer mortality (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.57–0.69), but this reduction was limited to left-sided cancers (OR, 0.33; 95% CI, 0.28–0.39) with no reduction in right-sided cancers (OR, 0.99; 95% CI, 0.86–1.14) [8]. In two other observational studies, the association between colonoscopy and reduced colorectal cancer risk was limited to the distal colon [9,10]. These two studies suggest that the colon cancer prevention benefit for colonoscopy is primarily for the left colon and not the right. Both of these case-control studies and other randomized trials establish that sigmoidoscopy was also associated with a reduced incidence and mortality from distal CRC [11–14]. Based on these recent data it appears colonoscopy does not provide added screening benefit over sigmoidoscopy. Sigmoidoscopy seems to be as accurate as colonoscopy in detecting distal CRC for average-risk individuals and is more cost-effective [15].

Distal CRC rates in the United States have been steadily decreasing since 1985, whereas rates for proximal colon cancers have remained largely unchanged [6,8,16]. Whether this trend is caused by increased incidence of right colon cancer or missed diagnosis of right colon cancer is still under debate [17]. There are several potential explanations for the high miss rate of right-sided lesions in patients undergoing colonoscopy. It could be the biology of cancers in the right side of the colon, especially tumors characterized by inactivation of a mismatch repair gene, which makes right-sided cancers grow more rapidly than left-sided ones. This biological difference, and hard-to-detect flat lesions, may explain the difference in cancer reduction observed between the right and left side of the colon in patients undergoing programmatic colonoscopy screening every 10 years [18].

The technical challenge and quality of colonoscopy may also account for missed right-sided lesions. Studies have shown that gastroenterologists do much better as far as colon cancer prevention than primary care physicians. Having the colonoscopy done by a low-volume endoscopist was independently associated with colonoscopy-related bleeding and perforation [19]. When colonoscopy is performed by a properly trained endoscopist, the risk of serious adverse events is 3 to 5 events per 1000 colonoscopies. These serious complications include perforation, bleeding, diverticulitis, and postpolypectomy syndrome. In a retrospective cohort study from Kaiser Permanente, 82 serious complications occurred (5.0 per 1000 colonoscopies [95% CI, 4.0–6.2 per 1000 colonoscopies]) in 16,318 patients aged 40 years older undergoing colonoscopy between January 1994 and July 2002 [20]. In another retrospective cohort study, using the California Medicaid program claims database, the investigators showed a total of 228 perforations after 277,434 colonoscopies, which corresponded to a cumulative 7-day incidence of 0.082%. On multivariate analysis, when comparing the group that had a perforation after a colonoscopy (n = 216) with those who did not (n = 269,496), increasing age, significant patient comorbidity, obstruction as an indication for the colonoscopy, and performance of invasive interventions during colonoscopy were significant positive predictors of complications [21]. Similar results were demonstrated using the Surveillance, Epidemiology, and End Results database [22]. In fact, the chance of death from colon cancer was 10 to 12 times higher in the patients who underwent examinations by those endoscopists who had low adenoma detection rates (defined as less than 20% detection of adenomas in screening colonoscopies), in contrast to endoscopists who were achieving an adenoma detection rate of more than 20% [23]. These data demonstrate that quality is important. Evidence suggests that the number of qualified endoscopists may be inadequate to provide colonoscopy (or even sigmoidoscopy) to all eligible US citizens [24]. In such a situation, unqualified examiners could absorb the colonoscopy overflow. This potential increased inaccuracy and higher complication rate may negate the small incremental benefit that colonoscopies might offer over other tests [25].

To improve the technical limitation of current endoscopy, several strategies, including high-definition magnification, imaging enhancers, narrow band imaging, and chromoendoscopy, are being investigated. Limited data are available on these techniques as adjunct screening tools for the general population.

Alternative to colonoscopy

Blood markers

Blood sampling may be more convenient and acceptable for patients. In addition to the obvious displeasure patients have with obtaining stool samples, blood samples provide the added benefit of not having bacteria present, which degrade the potential biomarkers or hamper analysis. The sample processing for blood is also easier than for stool. Biomarkers in blood include carbohydrate antigens, proteins, cytologic markers, DNA, and mRNA markers.

Carbohydrate antigens, including CA 19-9, CA 195, CA M26, CA M29, CA50, CA72-4, CA M43, and CA 242, have been investigated for CRC screening [26–31]. Most have specificity greater than 90% and low sensitivity rates, ranging from 18% to 65%.

The protein marker carcinoembryonic antigen (CEA) was the first blood marker proposed in connection with CRC [32]. In most studies, an elevated CEA level has specificity greater than 90%, with its sensitivity increasing with increasing tumor stage. It therefore varies between 43% and 69% [33,34]. The sensitivity and specificity of insulinlike growth factor-binding protein-2 for diagnosing CRC were 80.2% and 64.0%, respectively [35]. Promising results were also observed for cancer procoagulant [36], serum CD26 [37], fibrin degradation products [38,39], and prolactin [40]. Other protein markers, such as Sialylated Lewis antigen and CO 29.11, showed sensitivity less than 50% [41]. Vascular endothelial growth factor [42,43], insulinlike growth factor II [44], and interleukins-3 [45] also have low sensitivity in detecting CRC. Circulating autoantibodies have also been studied for the detection of CRC. Although their specificity was close to 100%, the sensitivity of these autoantibodies was less than 30% [46–48].

Evidence is suggesting that primary CRC may shed neoplastic cells in the circulation at an early stage. In a study from Taiwan, a high-sensitivity colorimetric membrane-array method has been devised to detect circulating tumor cells in the peripheral blood of patients with CRC. Eighty-eight subjects with CRC and 50 healthy subjects were compared. The sensitivity and specificity of membrane-arrays for the detection of CRCs were 94.3% (95% CI, 86.4%–102.2%) and 94% (95% CI, 85.9%–102.1%), respectively [49,50]. This promising technique requires further examination in the general population.

Both genetic and epigenetic alterations of genes have been investigated for detection of CRC. No current genomic alteration showed adequate sensitivity [51,52]. However, mRNA in circulating tumor cells may be detected by reverse transcriptase-polymerase chain reaction and are showing some promise. Numerous mRNA molecules coding for CEA [53], human telomerase reverse transcriptase [54], guanylyl cyclase C (GCC), carcinoembryonic gene member 2 [55], melanoma-associated antigen family A [56], tumor-associated antigen L6, and thymidylate synthase [57] have also been analyzed for CRC detection. Only GCC mRNA [58] and L6 mRNA [59] showed sensitivity greater than 80% and specificity greater than 95%.

A significant limitation of studies investigating blood markers as a screening tool for CRC is the small sample size of those studies. Large-scale screening studies examining blood markers are missing from the published literature. Cost and practical issues, such as standardized sample collection or processing and storage, need to be considered before a population-based screening program is implemented [60].

Stool markers

Developing alternative, less expensive, and accurate tests to endoscopy is thought to be necessary to decrease screening costs and improve compliance. Alternative tests, such as fecal occult blood test (FOBT), are available and can target those in the population most likely to harbor advanced neoplasm, therefore, identifying those who would most likely benefit from colonoscopy. FOBT complies well with the World Health Organization’s criteria of a screening tool: “A screening test should be inexpensive, rapid, and simple, and is not intended to be diagnostic; those with positive tests require further evaluation [61].” FOBT is rapid and inexpensive, but lacks sensitivity and specificity.

There are two types of fecal occult-blood tests. The standard guaiac FOBT detects pseudoperoxidase activity of heme or hemoglobin and is not specific for human blood. One-time testing with a standard guaiac test has sensitivity for detecting cancer of only 33% to 50%, whereas a more sensitive guaiac test (Hemoccult SENSA; Beckman Coulter, Brea, CA, USA) has sensitivity for detecting cancer of 50% to 75%. Three separate stool samples per test have superior sensitivity, as compared with one or two samples. One must make sure the patients have stopped taking all supplements containing iron and limit their red meat intake during the time of testing to improve sensitivity. Although these tests are rapid and have improved compliance, they are poor detectors of precancerous lesions.

Most CRC screening programs are based on the FOBT or colonoscopy. Although FOBT is poorly accepted and has a low sensitivity, the use of either annual or biennial FOBT significantly reduces the incidence and mortality of CRC [62,63]. FOBT is the only test shown in randomized trials to lower mortality from CRC [64–66] and the mortality benefits of FOBT were similar for right- and left-sided colon lesions (Table 1) [67]. By one estimate, 1173 persons must undergo fecal occult-blood screening to prevent 1 death in 10 years (a 0.09% probability of preventing death for the individual patient) [25].

Table 1 Prospective trials demonstrating the reduction in mortality from fecal occult blood tests