Colorectal Cancer Screening: Encouraging Compliance Today and Looking to the Future

by Sunni Hosemann

What if there were a way to cut in half the number of deaths due to colorectal cancer each year, but patients were unlikely to ask for it, insurance companies were reluctant to pay for it, and physicians sometimes failed to recommend it?

According to Bernard Levin, M.D., a professor of medicine and vice president of the Division of Cancer Prevention at The University of Texas M. D. Anderson Cancer Center, if the screening methods we have in hand today were fully deployed—if all of the people in recommended populations were screened—the death rate from colorectal cancer would drop by 50%. Of course, the compliance rate for any screening measure will never reach 100%, but prevention researchers at M. D. Anderson are working to make colorectal screening more accurate, more convenient, and more common, even as they study ways to prevent colorectal cancer altogether.

The importance of screening

Colorectal cancers begin as adenomatous polyps. For now, the goal of screening is to detect and remove these precursor lesions, as well as early-stage cancers, when they are curable. “If we can find it early, we can cure it,” said Stanley Hamilton, M.D., a professor and head of M. D. Anderson’s Division of Pathology and Laboratory Medicine.

The biology of colorectal cancer makes it particularly amenable to screening: colorectal cancers are associated with a low probability of metastasis in early-stage disease, and a variety of effective screening tools can be employed to detect polyps and early-stage cancer. “It is therefore frustrating to see patients present with metastatic colorectal cancer who have never been screened,” Dr. Hamilton said.

The screening tools of today

Current recommendations call for colorectal cancer screening in the general population after age 50 using flexible sigmoidoscopy and a fecal occult blood test (FOBT), double-contrast barium enema, or colonoscopy. Medically, all of these tools are very effective, but they are not ideal, and compliance is difficult to achieve.

Colonoscopy has some advantages over other methods because it provides direct visualization of the entire colon, along with the opportunity to sample or remove significant lesions. However, colonoscopy is more expensive and more invasive than many other screening methods, and it carries a higher risk of complications. Moreover, it is not covered by many health insurance plans as a primary screening device. “So, should we be doing it? Yes,” said Dr. Hamilton, “because this is one of the cancers where screening will make a difference in the number of deaths today.”

But the fact is that most people are not eager to undergo any of the colorectal cancer screening procedures currently available. Therefore, in addition to efforts to encourage screening by raising awareness of its benefits, research is under way to find screening tools that will be better accepted and more readily used.

A better FOBT

FOBT is the least invasive of the screening methods, but it must be used in combination with other screening tests. A new type of FOBT—an immunochemical method—employs antibodies to detect hemoglobin in stool and has significant advantages over the traditional guaiac-based method. One advantage is that it does not react with ingested food, vitamins, or drugs to cause false-positive test results. Another is that the specimen is collected from the surface of the stool with a brush and transferred to a card, a much easier collection method than that required for guaiac-based testing. Data from trials in large screening populations are not yet available, but based on the known enhanced sensitivity and specificity and other advantages of this method, the “American Cancer Society Guidelines for the Early Detection of Cancer, 2004” now recommends its use over guaiac-based testing.

New visualization tools

Two new visualization techniques have attracted the attention of the public and the medical community, but neither is ready for use as a large-scale screening test. Computed tomographic (CT) colonography, popularly known as “virtual colonoscopy,” is an imaging procedure in which a series of helical CT scans of the patient’s colon are rendered by computer into slices that can be visualized as still, rotatable images or serially combined to provide a three-dimensional tour of the colon. So far, this technique has been evaluated only in small trials, mostly conducted in diagnostic (rather than screening) settings in higher-risk patients. The results of those studies indicate that CT colonography is comparable to conventional colonoscopy for the detection of neoplasms and polyps larger than 10 mm but may be less effective at detecting smaller polyps.

Although CT colonography may eventually become an important and widely used screening tool, a few obstacles must be overcome first. The amount of irradiation required for CT colonography is a concern, and the technique requires bowel preparation and insufflation (the two factors that account for most of the objections to colonoscopy) but does not allow for removal of polyps during the procedure, as does colonoscopy. In addition, CT colonography requires a radiologist experienced with the technique (and the learning curve is somewhat high), and no standards exist for performing or interpreting the scans. CT colonography is performed at M. D. Anderson as part of research studies, but according to Dr. Levin, it is not ready to be used as standard care. “It is not specific enough in differentiating between significant and nonsignificant lesions inside and outside of the colon and therefore may prompt additional, unnecessary testing,” he said. “Nevertheless, the technique is evolving rapidly and may become much easier to perform and thus more acceptable to the public.”

Capsule video endoscopy—the “camera-in-a-capsule” technique—has also attracted a good deal of attention. When swallowed, the capsule provides approximately eight hours of videography of the digestive tract. To date, the battery life of the device is one of its limiting factors: it usually runs out before the capsule reaches the lower intestinal tract. Nevertheless, it has been shown to be safe and effective in animal and clinical studies. The wider lumen of the colon poses additional challenges in visualization, so major refinements in equipment and technique will be needed before capsule video endoscopy can be considered for the screening or diagnosis of colorectal cancer.

Genetic and proteomic tumor markers

In the near future, testing stool for tumor DNA may prove more effective than testing for occult blood. Tumors bleed intermittently, but they shed DNA constantly, so markers would be present in any stool sample. Researchers are still determining the best set of markers to include in a test to screen the general population. For more than a decade, Dr. Levin has been collaborating with scientists at The Johns Hopkins University to develop a method for molecular testing.

Yet another area of promise and intense research is serum proteomics—the study of protein patterns circulating in the blood. Such patterns can have a high predictive value, and researchers are working to identify these patterns and develop tests that will recognize them as markers of colorectal cancer.

These methods promise to have a dramatic impact on colorectal cancer screening. Identifying genetic and proteomic tumor markers has the potential to yield highly sensitive and specific tests that are also less invasive (with fewer associated risks), more convenient, and less expensive than current screening tools. “This would result in a tremendous improvement in compliance and effective screening,” said Dr. Hamilton, “and would move the more invasive procedures such as colonoscopy to a diagnostic, rather than screening, role.”

Chemoprevention

“One of the challenges in studying any intervention,” said Patrick Lynch, M.D., an associate professor in the Department of Gastrointestinal Medicine and Nutrition, “is to agree upon what it is important to prevent: an endpoint.” In the interest of time and feasibility, most colorectal cancer prevention trials today do not focus on cancer occurrence but rather on the incidence of polyps.

Calcium and aspirin are the most recent significant findings in the search for colorectal cancer chemopreventive agents. Laboratory, clinical, and epidemiological evidence has long suggested that calcium may help prevent colorectal adenomas, and clinical trials showed a moderate—but significant—reduction in the risk of recurrent colorectal adenomas. In recent landmark studies, a multi-institutional group of researchers that included Robert Bresalier, M.D., professor and chair of the Department of Gastrointestinal Medicine and Nutrition at M. D. Anderson, showed that aspirin reduced the incidence of adenomas. Interestingly, in these and subsequent studies, low-dose baby aspirin (81 mg) worked better than adult aspirin (325 mg).

Current chemoprevention trials are studying cyclooxygenase 2 (COX2) inhibitor agents rather than aspirin. Both are nonsteroidal anti-inflammatory drugs (NSAIDs) and have similar attributes; however, COX2 inhibitors have fewer side effects than does aspirin, a nonspecific NSAID that affects both COX1 and COX2 receptors.

Researchers at M. D. Anderson, in collaboration with those at St. Mark’s Hospital and Academic Institute, London, England; the National Cancer Institute; and Pfizer, Inc., conducted a study of patients with familial adenomatous polyposis (FAP) who had dozens to hundreds of polyps. In the study, COX2 inhibitors reduced the number of polyps by 30%. “This didn’t necessarily prevent cancer or obviate the need for surgery, but it served as proof of the principle that this drug can reduce polyps,” said Dr. Lynch.

COX2 inhibitors also are being studied in a pediatric trial of carriers of FAP susceptibility genes to determine whether they can delay onset. “This will not be a cure, and it does not change the need for endoscopic surveillance and frequent screening in these patients,” said Dr. Lynch, “but it may delay surgery for youngsters in whom colectomy is often necessary at a young age.”

Polyp precursors

A new M. D. Anderson prevention trial led by Dr. Bresalier is enrolling patients who are at increased risk for colon or rectal cancer. In the study, aspirin, sulindac, and ursodiol will be evaluated as potential chemopreventive agents. Rather than using cancer or polyps as endpoints, however, this study will look at aberrant crypt foci (ACF), micropolyps that develop before (macro)polyps. Investigators use a special spray dye with illumination that makes these dysplastic spots visible during colonoscopy. The effect is dramatic: in a patient with FAP, for example, there are perhaps five to 15 visible polyps but literally hundreds of precursor spots.

This method takes investigators one step back in the chain of screening markers, from studying polyps as cancer precursors to studying ACF as polyp precursors. “The advantage is that we gain useful information with smaller samples in a shorter period of time,” said Dr. Lynch.

Diet and vitamins

Although there seems to be a relationship between diet and the development of colorectal cancer, such a link has not been proved. “There was disappointing news from clinical trials in the past couple of years that ran contrary to epidemiologic data that suggested that fiber in the diet was associated with low risk,” said Dr. Lynch.

And despite the interest in the role of vitamins and other dietary supplements in the prevention of colorectal cancer, only calcium has been proved effective. Some epidemiologic data suggest that antioxidants found in fruits and vegetables may confer some protection, but thus far, no convincing evidence has been found to support vitamin supplementation for colorectal cancer prevention.

Tomorrow, research may lead to better recommendations about diet, discover more chemopreventive agents, and deliver screening tools that patients and doctors are more willing and able to use. Meanwhile, most experts recommend colorectal cancer prevention strategies that include periodic screening, regular exercise, a diet high in vegetables and fruits, and in individuals at high risk, chemoprevention using agents such as calcium.

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

Other articles in OncoLog, February 2004 issue:

• Despite Its Drawbacks, Mammography Is Still Recommended: Researchers Look for Biomarkers That Would Improve Patient Compliance and Screening Accuracy
• Communication Is Essential When Guiding Patients through the Maze of Genetic Breast Cancer Screening
• House Call: Cancer Epidemiology, Step-by-Step
• DiaLog: On Being a Volunteer

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