Conjugating colorectal cancer screening: Past, present, future and perfect

Colorectal cancer (CRC) struck approximately 145,000 Americans during 2005, and most did not know it was coming. Many of the resulting 54,000 deaths could have been prevented as CRC is one of a very few diseases that is susceptible to mortality reduction through means of early detection that are reasonably acceptable and highly effective. Screening strategies have limitations. One is incomplete compliance, and another is choosing among the various options.

The past

In the 1960s, the guaiac test was utilized to detect occult fecal bleeding from CRC, which led to the standardized fecal occult blood test (FOBT). In 1993, the Minnesota trial showed a 33 percent reduction in CRC-specific mortality in patients tested annually. Two subsequent European trials showed that if FOBTs were done every other year, the reduction in mortality fell from 15 percent.

In clinical practice, most patients do not get tested every year, and it is likely that testing less than every two years would result in trivial reductions in CRC mortality. If one uses an FOBT that is more sensitive but less specific, this will make the screening program less efficient and more expensive. As a result, many critics have grown disenchanted with the use of FOBTs, whereas optimists hope that immunochemical tests will improve performance.

The utility of endoscopic screening for CRC was initially suggested by uncontrolled report that annual rigid sigmoidoscopy might prevent invasive rectal cancer. Flexible sigmoidoscopes made this screening procedure more acceptable, and permitted examination further up the colon. Case-control trials of sigmoidoscopy demonstrated -60 percent reductions in distal CRC mortality. In an attempt to improve cancer screening throughout the colon, screening colonoscopy gained wide acceptance prior to the conduct of any prospective controlled trials.

Present

The current "standard of care" for asymptomatic individuals is to begin screening for CRC at age 50. In spite of a dearth of data, colonoscopy is widely used as the first screening exam. Most healthy individuals will have a negative exam, and it is no clear what to do thereafter. There is little logic in adding FOBTs to a colonoscopic screening program, as this would only add cost with little likelihood of added benefit.

A second challenge is how to manage patients who have polyps at their initial exam. Detecting early cancers and removing polyps is the point of screening colonoscopy; however, most patients have a negative exam. The wide variation in management choices for patients in whom neoplasms are detected has led to the development of variable surveillance guidelines, which will not be discussed but is a major source of cost in a screening program.

Fecal-based DNA tests of mutated genes shed from CRCs (or adenomas) have been developed to detect the presence of neoplasms in the gastrointestinal tract. These tests are significantly more sensitive than FOBTs for neoplasia, however the current test detects only -50 percent of cancers, the stool must be sent to a centralized reference laboratory and it is expensive.

This technology is in rapid evolution however, and is likely to become more sensitive and useful in the future. Many individuals will not elect colonoscopy or cannot afford it. Furthermore, there is a small risk of serious complications of colonoscopy and polypectomy, and the screened individual loses a day of work. Thus, less invasive approaches are highly desirable.

CT colonography (virtual colonoscopy) is an abdominal CT scan performed on a prepped, gas-filled colon – the simplicity is appealing. This technique is very insensitive for polyps <6 mm in size, and a true or falsely positive exam requires follow-up colonoscopy. Nonetheless, as expertise grows with this approach, diagnostic sensitivity improves and "prepless" exams are perfected, many are likely to choose this option.

Whereas we have some idea of the risks of colorectal neoplasia after colonoscopy, there are no data indicating how long one is "protected" by a negative CT exam, and the issue of the safety of radiation exposure is an unanswered concern. Perhaps of even greater importance, colonoscopy and CT colonography both miss approximately 10 percent of lesions that are substantial in size. Tandem colonoscopy exams – either by a single or two different endoscopists – have demonstrated this unsettling issue.

Furthermore, the use of "segmental unblinding" in cooperative studies between colonoscopists and radiologists have proven that direct visualization of the colon is not a true gold standard for every polypoid lesion in the colon. There are still challenges ahead in improving the detection rates in our screening tests that would relegate invasive procedures to a therapeutic role, much as has happened in the arena of biliary endoscopy.

Future

Advances in equipment will make colonoscopy more sensitive for small and flat lesions, including magnification techniques and the use of dyes in the lumen to provide additional contrast. Self-propelling colonoscopies that can be passed quickly to the cecum by technicians may be used for initial screening, which might be acceptable to a broader segment of the population, and could improve costs.

Fecal DNA testing will also become more sensitive and useful. The future will provide a broader range of non-invasive screening techniques, and colonoscopy may be reserved only for those patients who have lesions that require biopsy or removal. In the future, we must identify the optimal timing for surveillance Colonoscopy, so that we do not exhaust our resources performing needless examinations. It would be ideal to have a blood test for early colorectal neoplasia, but none is on the immediate horizon.

Perfect

The recognition hat the outcome of CRC is significantly better when one finds an early lesion has prompted the development of a wide range of screening techniques. However, no approach is perfect. Each of the currently used approaches fails to detect some large lesions even in the best of hands. Not everyone is properly "prepped", which limits sensitivity of any imaging approach.

Surveillance intervals have been developed based upon reasonable estimates of the growth rates of colorectal neoplasms; most adenomas grow slowly, but a small proportion may grow very rapidly. It must be understood that no population-based screening strategy will prevent every cancer. However, compared to most other cancers, CRC is perhaps the most amenable to intervention, and it will remain the focus of our attention for years to come.