Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM)

Colorectal cancer (CRC) is currently the second most common cause of cancer death in the
United States, and one of the most preventable cancers. It has been shown in several
randomized controlled trials that screening using fecal occult blood testing (FOBT) reduces
CRC mortality by 13-33%. While there is strong consensus amongst experts regarding the value
of CRC screening, the best approach to screening is not clear. Of the widely recommended
modalities, FOBT and colonoscopy are the most commonly used within the United States. FOBT is
inexpensive, non-invasive, and its use as a screening tool is supported by the highest
quality evidence (i.e. randomized controlled trials). Moreover, newer FOBT, such as fecal
immunochemical tests or FITs, have advantages over conventional FOBT in terms of both test
characteristics and ease of use that make them quite attractive as a population-based
screening tool.

While colonoscopy is invasive and has higher up-front risks and costs than FOBT, it does
afford the opportunity to directly assess the colonic mucosa and is widely believed to be the
best test to detect colorectal cancer. In addition, colonoscopy allows for the detection and
removal of colorectal adenomas -a well recognized colorectal cancer precursor. There is
indirect evidence that suggests colonoscopy is effective in reducing colorectal cancer
mortality, but to date, no large clinical trials have been completed to support this
assumption. While colonoscopy use is increasing, data is emerging that colonoscopy may not be
as effective as previously believed. Prior support for colonoscopy as a screening test relied
upon effectiveness estimates that now appear to be overly optimistic. Given the invasive
nature of colonoscopy, the associated small, but real risk of complications, and dramatically
higher costs than other screening tests, it is especially important to determine the true
comparative effectiveness of colonoscopy relative to other proven non-invasive options.

The investigators propose to perform a, large, simple, multicenter, randomized, parallel
group trial directly comparing screening colonoscopy with annual FIT screening in average
risk individuals. The hypothesis is that colonoscopy will be superior to FIT in the
prevention of colorectal cancer mortality measured over 10 years. Individuals will be
enrolled if they are currently eligible for CRC screening (e.g. no colonoscopy in the past 10
years and no FOBT in the past 1 year) and are between 50 and 75 years of age. The
investigators will exclude individuals for whom colonoscopy is indicated (e.g. signs or
symptoms of CRC, first degree family member with CRC, personal history of colorectal
neoplasia or inflammatory bowel disease).

All participants will complete baseline demographic, medication, and lifestyle questionnaires
(e.g. diet, non-steroidal anti-inflammatory use, frequency of exercise) prior to
randomization in a 1:1 ratio to either screening colonoscopy or annual FIT screening (Figure
1). Those testing positive by FIT will undergo evaluation to determine appropriateness for
colonoscopy. Screening will be performed in a manner consistent with the currently accepted
standard of care in order to determine the comparative effectiveness of the two screening
strategies. Participants will be surveyed annually to determine if they have undergone
colonoscopy or been diagnosed with CRC.

The primary study endpoint will be CRC mortality within 10 years of enrollment. The secondary
endpoints are (1) the incidence of CRC within 10 years of enrollment and (2) major
complications of colonoscopy. Mortality will be determined through queries of the VA Vital
Status File. Cause of death will be determined primarily using death certificates from the
National Death Index-Plus database, augmented by adjudication of medical records for known
CRC cases where CRC is not listed as a cause of death on the death certificate. The
investigators postulate that screening colonoscopy will result in a 40% reduction in CRC
mortality over 10 years relative to annual FIT screening. Using a log-rank test with a
2-sided test of significance, =0.05, a sample size of 50,000 participants will be required to
test the primary hypothesis with 82% power, assuming a 1% annual rate of crossover from FIT
to colonoscopy and a 0.5% annual rate of loss to follow-up. The planned study duration is
12.5 years with 2.5 years of recruitment and 10 years of follow-up for all enrolled
participants.