Colorectal cancer screening: confusion reigns.

In 2008, it is estimated that 148,810 new cases of colorectal cancer (CRC) will be diagnosed in the United States and that 49,960 people will die from the disease (1); lung cancer is the only cancer that kills more people each year in developed countries than CRC. According to almost universal consensus based largely on indirect evidence from a decade or more ago, effective implementation of screening would substantially reduce CRC morbidity and mortality (Table 1). The population is divided into people at average (f75%) and increased (f25%) risk for CRC. People at average risk for CRC are the topic of the current discussion. The lengthening list of screening test options for average-risk subjects includes guaiac-based fecal occult blood testing (gFOBT), fecal immunochemical testing (FIT), stool DNA, double-contrast barium enema (DCBE), flexible sigmoidoscopy (FSIG), optical colonoscopy (OC), and computed tomographic colonography (CTC), which is colloquially referred to as virtual colonoscopy. The lengthening list of options has just been further complicated by suggested new joint guidelines from the American Cancer Society, the U.S. Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology (Table 2; ref. 2). The U.S. Preventive Services Task Force assigns its strongest grade A category of recommendation ‘‘that clinicians screen men and women 50 years of age or older for colorectal cancer’’ (accessed 7/13/2008). The U.S. Preventive Services Task Force approves the use of FOBT, FSIG, OC, and DCBE but not CTC or stool DNA. Until the latest American Cancer Society revisions, the American Cancer Society and U.S. Preventive Services Task Force guidelines were broadly similar (3). What is the current status of CRC screening in this setting of multiple alternative tests and changing recommendations? In the general population of the United States, FOBT use is in decline and OC is supplanting FSIG (4). According to an analysis of data from the National Health Interview Survey for 2005, CRC screening rates exceeded 50% only in high-income men and women (5). Rates in low-income men and women were 32 and 35%, respectively. Will the new guidelines, summarized in Table 2, aid efforts to increase the uptake of CRC screening and to what extent will the new additions to the list of approved tests increase screening accuracy? The decision to stratify tests into those that ‘‘detect adenomatous polyps and cancer’’ and ‘‘tests that primarily detect cancer’’ is baffling if an important purpose is to promulgate simple instructions for the health care community and general public that will increase CRC screening rates. Advanced colorectal adenomas (CRA), comprising CRAs with a diameter of z10 mm or CRAs of any size with villous histology or high-grade dysplasia (6), are those most likely to progress to CRC. The public health message should unequivocally be that preferred screening methods are those most likely to lead to the diagnosis of advanced CRAs as well as CRCs; CRCs and advanced CRAs are combined in the category of advanced colorectal neoplasms. A strong case can be made for reducing the number of recommended tests. The sensitivity for advanced colorectal neoplasms of a ‘‘one-time’’ (i.e., three test cards and sampling of three bowel movements) gFOBT is only 24% (7). A more sensitive gFOBT and FITs have been developed in attempts to improve on gFOBT performance. The yield of advanced CRAs with the newer tests is not substantially improved but FIT sensitivity for asymptomatic CRCs approaches 66% (8, 9) compared with 26% with traditional gFOBT (10). Reluctance to jettison gFOBT is puzzling given the superior sensitivity of FIT for CRC. The allure of molecular diagnostics has fueled considerable interest in stool DNA detection as a novel method for CRC screening; the concept is that neoplasm-specific DNA from CRA or CRC cells shed into the fecal lumen can be detected in stool. However, the methodology for stool DNA analysis is a work in progress. According to a web announcement on June 5, 2008, LabCorp has stopped offering what was at the time the only commercially available stool DNA test (PreGen-Plus), which required collection and shipping within 24 hours of collection an entire refrigerated stool specimen. In a recent experimental laboratory study comparing two generations of stool DNA tests with gFOBT, the latest stool DNA test detected 46% of advanced CRAs with a diameter of z10 mm compared with 17% with a sensitive gFOBT (11). There are no published studies comparing the sensitivity and specificity of stool DNA and FIT for asymptomatic CRC in a screening setting. Given the evolving nature of the technology and the lack of widespread evaluation of stool DNA testing in a population setting, not to mention the current lack of availability of any commercial stool DNA test, it is surprising, to say the least, that this technology has been recommended by the American Cancer Society and other professional