Colorectal Cancer Screening: Old Obstacles, New Tests

Colorectal cancer (CRC) is highly preventable; however, it remains a significant cause of morbidity and mortality in Western countries. CRC develops in more than 125,000 Americans each year, and about 50,000 die of it.¹ Screening and early intervention significantly reduce morbidity and mortality, and a number of organizations have published screening recommendations (Table). Nevertheless, only 1 of every 3 eligible adults elects to be screened.²

In 2002, the US Preventive Services Task Force reviewed its CRC screening guidelines and recommended that 2 new approaches-fecal DNA testing and virtual colonoscopy-undergo evaluation in screening populations.³ Both of these procedures are likely to be more acceptable to patients-and thus may be more widely used-than current tests; they may also decrease the number of unnecessary "next-step" invasive studies. Results of ongoing clinical trials will determine the effectiveness of these modalities.

Here we outline the potential barriers to CRC screening-and review the benefits and risks of the newer technologies.

OBSTACLES TO CRC SCREENING

To improve screening rates, the obstacles faced by both providers and patients-such as the ones that follow-must be identified and eliminated.

Overestimation of screening rates. Some clinicians think their screening rates are much higher than they actually are. One study found that a group of internal medicine residents dramatically overestimated their rates of flexible sigmoidoscopy and fecal occult blood testing (FOBT): they believed that they were achieving a screening rate of 78% for the former test and 88% for the latter. The actual rates were only 16% and 13%, respectively, which are consistent with national CRC screening rates.⁴ Many primary care clinicians are working under increased time and monetary constraints and thus may feel they do not have the time to perform these tests. Others may feel they do not have the ability to perform them properly. Although Medicare covers CRC screening, reimbursement rates are often inadequate.⁵

Lack of personnel. There is also a dearth of properly trained personnel to perform the estimated 70 million routine screening procedures for eligible patients or the "next-step" invasive examinations necessary for those who have positive screening results. Morbidity associated with colonoscopy is approximately 1 in 300; mortality ranges from 1 in 30,000 to 1 in 3000, depending on the population studied.³ The accuracy of the examination is directly related to the skill level and training of the practitioner.⁶

Patient reluctance. Current guidelines recommend that patients at average risk undergo FOBT or combination flexible sigmoidoscopy and FOBT screening using guaiac- impregnated cards from 3 consecutive stools. Some patients, however, view stool collection as embarrassing or distasteful.⁷ Patients may find the dietary restrictions associated with FOBT guaiac screening difficult to follow, or they may fear the prospect of having to undergo more invasive tests if the results are positive.

Lack of public awareness. CRC screening has not received as much media attention as screening for prostate, breast, and other cancers, and there is less awareness of how important screening is.⁷

Continuous public awareness campaigns, insurance policy changes to offer coverage for screening, appropriate reimbursement to clinicians for screening procedures, better patient education, use of provider- patient decision-making strategies, and provider commitment to increasing the numbers of eligible patients screened may all help increase the rate of screening and decrease the morbidity and mortality associated with CRC. Another key factor is the development of more sensitive and specific noninvasive screening techniques-such as fecal DNA testing and virtual colonoscopy.

FECAL DNA TESTING

Bacterial DNA and colonocytes are shed into the bowel lumen and excreted in the stool; so are neoplastic cells and their mutant DNA, which can now be recovered for analysis from cancer and large adenomas.⁸ Sampling for mutations of specific genes known to play a role in colorectal neoplastic formation should permit greater sensitivity than that available with FOBT. Because the specific targeted mutations are found in only a small number of the millions of normal DNA molecules in stool, it is imperative to be able to isolate the specific genetic mutations responsible for the formation of CRC.⁹

Recent results. The question of which mutation or mutations should be surveyed is critical: not all mutant DNA-based markers are specific for cancer, and these markers may not cover all colorectal neoplasms. For example, one such marker, K-ras, may arise from normal colonic tissue or benign hyperplasia and may be expressed in fewer than half of all known CRC lesions.¹⁰

For this reason, a multiple assay approach is desirable. In one study, several DNA targets-including K-ras, APC, p53 genes, BAT-26 (a microsatellite instability marker), and highly amplifiable DNA-were used to identify colorectal neoplasia.¹⁰ Sensitivity was 91% for cancer and 82% for adenomas 1 cm or larger; specificity was 93%. This compares with sensitivity rates for FOBT of about 50% to 90% (the higher rates are found in programs of repeated testing) and specificity of 98%.¹¹ A further decrease in specificity of 3% to 7% with FOBT was found when patients failed to adhere to the recommended dietary restrictions associated with guaiac testing⁸-or if the sample was rehydrated with distilled water.¹²

Early studies of the multitargeted DNA assay are very promising. Two large multicenter studies, involving 9000 patients, are under way to compare FOBT and stool DNA assays. Results should be available this year. If these studies yield the same results as their smaller precursors, fecal DNA testing may offer a new choice to patients undergoing CRC screening, provided that the technology also proves to be cost-effective for widespread use.

Advantages of DNA screening over FOBT. Patients who use the multitargeted fecal DNA assay test are required to submit only 1 stool sample using a simple collection method.They will not need to adhere to dietary restrictions, stop any of their medications, or undergo bowel preparation. Because of its higher specificity, a multitargeted DNA assay may also help reduce the number of unnecessary invasive procedures.

FOBT is a safe, noninvasive test, but it yields frequent false-positive results. One of every 10 to 20 patients screened with FOBT undergoes an unnecessary colonoscopy.⁸ FOBT also has a high rate of false-negatives, which means that important windows of opportunity for intervention may be missed. One large study noted that FOBT alone had a sensitivity for advanced neoplasia of only 24%.¹³

FOBT relies on the detection of blood in the GI tract, but colorectal neoplasms may bleed intermittently or not at all. Bleeding does not al-ways indicate neoplastic disease, but it always requires invasive follow-up. In contrast, DNA is continuously released into the bowel lumen to be picked up by the stool, thus allowing for a more continuous supply of sample material.¹⁴

VIRTUAL COLONOSCOPY

First introduced in 1994, CT colonography is a helical CT scanning technique that involves continuous imaging. This method provides more information in the craniocaudal axis and yields continuous data; more information is thus obtained with each scan. Commercially available software reconstructs processed data by either of 2 methods¹⁵:

Surface rendering, which is a faster processing system but one that is associated with poor definition, data loss, and threshold artifacts.

Volume rendering, which allows for more accurate images and increased detail but is more time-consuming and expensive.

Thin-section helical CT data can generate both 2- and 3-dimensional images of the colon that simulate navigation through the colon lumen at an interactive computer workstation, as with optical colonoscopy (Figure).¹⁶ Although still in the developmental stage, virtual colonoscopy is being offered in some centers as a screening option.¹⁵

Patient preparation for virtual colonoscopy is similar to that required for optical colonoscopy: dietary restriction 24 hours before the procedure andingestion of cathartics and laxatives. Because optimal visualization of the lumen is essential to both procedures, excellent bowel cleansing is vital. Bowel distention during both procedures is also required for adequate visualization; this is achieved by retrograde insufflation with a small rectal tube to the extent tolerated by the patient.¹⁶ Some centers allow patients to self-inflate, and research is under way to determine whether other gases, such as carbon dioxide, might be more comfortable than room air.

Newer multidetector CT scanners allow for thin collimation (1 mm) and rapid scanning of the abdomen and pelvis of approximately 15 to 20 seconds.¹⁶ Images are obtained in the supine and prone positions both to obtain more views and to redistribute residual fluid and fecal material or improve distention, thus achieving better imaging. Radiologists use both endoluminal interactive reviews and reformatted image review for interpretation.¹⁷

Recent results. In studies conducted several years ago, virtual and optical colonoscopy were equally sensitive in detecting clinically significant polyps (6 mm or larger) in patients at high risk for CRC.^17,18 The sensitivity and specificity of virtual colonoscopy decreased as polyp size decreased. In one study, although no cancers were overlooked, virtual colonoscopy missed a 25-mm adenomatous polyp.¹⁸

In a recent study of 1233 patients at average risk for CRC, virtual and optical colonoscopy were almost identical in their ability to detect clinically significant adenomatous polyps.¹⁹ Moreover, 3-dimensional rendering improved the detection of large polyps with virtual colonoscopy: all polyps 10 mm or larger were identified. One malignant polyp behind the hepatic fold was detected with virtual colonoscopy but missed with optical colonoscopy. As in previous studies, the sensitivity of virtual colonoscopy decreased in the detection of polyps 5 mm or smaller.

In previous studies, radiologists' time for reading and interpretation was approximately 30 minutes.¹⁷ Radiologists in these studies used 2-dimensional images for the primary survey and 3-dimensional imaging selectively. This approach reduces the amount of time needed by the reviewer for interpretation. It is unclear whether this will be the standard protocol for viewing and interpreting images; 3-dimensional primary viewing appears to yield better results.¹⁹

Pros and cons. Authors of these studies recognize the limitations of their techniques and protocols. Patients report greater discomfort with virtual colonoscopy (perhaps because they are not sedated), but few rate it as severe, and most prefer virtual to optical colonoscopy. Three-dimensional virtual colonoscopy is not widely available at this time because of cost and equipment considerations; moreover, special expertise is required for an accurate reading of the images rendered by the scans.Furthermore, the identification of polyps by virtual colonoscopy may result in an additional colonoscopy to remove the polyps, which adds to the cost and, in most cases, requires an additional bowel preparation.

Another serious concern is whether intervention is appropriate for small polyps identified with virtual colonoscopy. There is no consensus about whether 1- to 5-mm polyps are clinically significant and whether only larger polyps should be removed. Although some favor universal polypectomy, this would involve a significant burden: risk and discomfort to the patient, skill and training of physicians needed to perform large numbers of procedures, and cost to the health care system.¹⁸ The policy of removal only of polyps larger than 10 mm would render irrelevant the low rate of small polyp detection with virtual colonoscopy, because many experts agree that small polyps are clinically insignificant and require no further intervention or surveillance.^20,21

The potential pitfalls of bowel preparation are patient intolerance of the large volumes required to achieve cleansing and the disruption of visualization if significant amounts of fluid are retained in the colon. Retained fluid and fecal material are easily removed during optical but not virtual colonoscopy.

On the other hand, virtual colonoscopy offers the following advantages:

It takes far less time than optical colonoscopy, because the procedure uses rapid scanners.¹⁶

No sedation is required.

There is no risk of bowel perforation.

It provides the opportunity to identify extracolonic pathology.

Enhancements that would ensure adequacy of and compliance with bowel preparation, improvements in the quality of imaging, and improvements in the training of radiologists may lead to more widespread use of virtual colonoscopy.

IN THE INTERIM

Technologies currently being developed for CRC screening hold great promise. Until these modalities have been thoroughly perfected and incorporated into practice, current screening tools must be used. The Minnesota Colon Cancer Control Study-one of the largest studies of CRC screening-found that annual FOBT was associated with a 33% decrease in CRC mortality.¹²Although FOBT is far from a perfect screening tool, its usefulness should not be underestimated. Offer FOBT, along with the other available screening modalities, to eligible patients, and discuss the risks and benefits of each. n

References:

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