2015-02-24 03:42:13 UTC


Feb. 17, 2015

Cologuard is a welcome addition to the menu of options for colorectal neoplasia screening, but it is not a replacement for colonoscopy.

Uri Ladabaum, MD, MS

Uri Ladabaum, MD, MS

Professor of Medicine and Director, Gastrointestinal, Cancer Prevention Program, Division of Gastroenterology and Hepatology, Stanford University School of Medicine

Should Cologuard be recommended instead of screening colonoscopy? Not today. But answering where Cologuard fits now in clinical practice is more nuanced.

The principal goal of colorectal neoplasia screening is to decrease CRC-associated mortality. I believe that CRC prevention should also be a primary goal of screening. In determining where Cologuard fits in the current landscape, we must consider evidence on test performance characteristics, one-time versus programmatic performance, clinical outcomes, participation rates, and the balance between benefits and risks. The context for screening (e.g., an organized program versus opportunistic screening) affects the perspective on these variables and also another important factor: cost.

If we focus narrowly on one-time Cologuard versus one-time screening colonoscopy test performance, we have solid evidence for this comparison with colonoscopy as the gold standard.1 In a large prospective study, Cologuard had sensitivities of 92.3 percent (83–97.5 percent) for CRC, and 42.4 percent (38.9–46 percent) for “advanced precancerous lesions,” defined as advanced adenomas and sessile serrated polyps greater than or equal to 1 cm. Thus, as a one-time test, Cologuard found almost all (but not all) the CRCs and a reasonable fraction (but still a minority) of the advanced precancerous lesions detected by colonoscopy. If we take this as the principal basis for comparison, then we must conclude that Cologuard cannot be recommended instead of colonoscopy. However, things are more complicated than that. Although one-time screening has substantial impact on CRC incidence and mortality,2 screening usually consists of a program of repeated testing over time. CMS decided to cover Cologuard every three years. This seems like a reasonable interval, but there is no direct evidence to support it. While a 10-year interval for screening colonoscopy was a similar “educated guess” initially, subsequent evidence has accumulated that a high-quality normal screening colonoscopy predicts a low risk of interval CRC for 10 years. How does Cologuard every three years perform versus colonoscopy every 10 years? We don’t know yet.

Regarding clinical outcomes, the evidence supporting screening colonoscopy’s benefits consists of extrapolating data from randomized controlled trials of sigmoidoscopy,2 and observational studies.3 Randomized controlled trials of colonoscopy versus fecal immunochemical testing (FIT) are ongoing. As would be expected for a new test, comparable data are not yet available for Cologuard. Must we have comparative randomized controlled trials assessing CRC incidence and mortality to make clinical and policy decisions today? I don’t think so. However, the requirements regarding levels of evidence are probably different when making decisions for a single patient versus an organized national or regional screening program. Test performance characteristics (and the clinical outcomes that follow based on them) do not matter if a test is not used in the first place. For both one-time screening and a program of repeated screening over time, participation is a key determinant of yield (detection of early CRCs and advanced precancerous lesions) and outcomes (reduction in CRC incidence and mortality). While it is clear that one-time colonoscopy detects more CRCs and advanced precancerous lesions than one-time FIT, the first interim analysis of the COLONPREV study reported higher participation in the first FIT round versus uptake of colonoscopy (34.2 percent compared with 24.6 percent, p< 0.001), and this was associated with comparable overall CRC detection rates (0.1 percent in each arm).4 Although advanced adenomas were found in 1.9 percent versus 0.9 percent and nonadvanced adenomas in 4.2 percent versus 0.4 percent of subjects in the colonoscopy versus FIT arms,4 biennial FITs are continuing in this study, which is expected to improve the programmatic performance of the FIT arm. What will be the rates of initial uptake and adherence over time for Cologuard? What will be the impact of the Cologuard “compliance program,” which offers support for patients and physicians? We don’t know yet.

Cologuard cannot be recommended instead of colonoscopy.

The principal risks of a colorectal neoplasia screening program are procedure-related complications. Cologuard’s specificity of 86.6 percent (85.9–87.2 percent)1 among participants with nonadvanced or negative findings suggests that most people tested once with Cologuard might avoid the small but non-negligible risk of colonoscopy. However, here too it gets more complicated. What happens over time? How many people with normal colons eventually end up with a colonoscopy anyway? We don’t know this yet either. Before turning to cost, I would ask: is “Cologuard versus colonoscopy” the right question? If we focus instead on screen-eligible, average-risk persons who are unwilling or unable to undergo screening colonoscopy, then the question becomes, “what about Cologuard versus FIT or other alternatives?” The major prospective Cologuard study1 also assessed FIT (OC FIT-CHEK, Polymedco, at a threshold of 100 ng/mL). In that study, the sensitivities of one-time FIT were not as good as those of one-time Cologuard (73.8 percent [61.5–84 percent] for CRC; 23.8 percent [20.8–27 percent] for advanced precancerous lesions; and 5.1 percent for sessile serrated polyps greater than or equal 1 cm versus 42.4 percent [32.6-52.8 percent] with Cologuard), but the specificity of FIT was superior (94.9 percent [94.4–95.3 percent]).1 For Cologuard versus FIT or other alternatives, the questions discussed above also apply — as does the question of cost.

CMS will pay $492.72 for Cologuard, and the self-pay list price is $599. The total payment for colonoscopy can range from approximately $700 to several thousand dollars, depending on site of service, use of anesthesia and other factors, with commercial payments averaging approximately 1.7-fold those of CMS.5 Payments for FIT are $20 to $40.5 How is the “screening dollar” best spent? There is no straightforward answer.

In conclusion, Cologuard is a welcome addition to the menu of options for colorectal neoplasia screening. Today, I don’t think it can replace colonoscopy for those willing and able to be screened by colonoscopy. I look forward to the emergence of data that will refine our understanding of the merits of a Cologuard screening program compared with the alternatives.

Dr. Ladabaum is a consultant for Exact Sciences Corporation and Given Imaging, and he is also a scientific advisor for Mauna Kea Technologies.


1. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 2014;370:1287-97.

2. Atkin WS, Edwards R, Kralj-Hans I, et al. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 2010;375:1624-33.

3. Nishihara R, Wu K, Lochhead P, et al. Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med 2013;369:1095-105.

4. Quintero E, Castells A, Bujanda L, et al. Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening. N Engl J Med 2012;366:697-706.

5. Ladabaum U, Levin Z, Mannalithara A, et al. Colorectal testing utilization and payments in a large cohort of commercially insured US adults. Am J Gastroenterol 2014;109:1513-25.

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