Back to the future of screening colonoscopy

It is difficult not to appreciate the intrinsic qualities of colonoscopy as a screening modality for colorectal cancer (CRC). As a structural test, it allows direct visualization of the entire colon, it targets and allows removal of precancerous polyps, it can detect CRC at early and curable stages, it can risk-stratify patients and help determine appropriate surveillance intervals according to baseline colonoscopic findings, and it represents the final common pathway for all other screening options, including fecal tests and computed tomographic colonography. Given these considerations and other advantages including comfort with adequate sedation and relatively infrequent surveillance requirements, it is not a major surprise that colonoscopy has become the dominant modality for CRC screening in the United States, carried by a wave of public and media support, and endorsed by professional societies and policy makers.

Yet, the available evidence supporting the use of colonoscopy for population-based CRC screening is relatively modest, and rests largely on indirect evidence and observational studies. No randomized controlled trials (RCTs) have been conducted to determine the effect of screening colonoscopy on CRC incidence and mortality. In contrast, CRC screening using fecal occult blood testing (FOBT) [1] [2] [3] and flexible sigmoidoscopy [4] [5] is supported by RCT-quality evidence, which in the case of FOBT was published over 15 years ago. The fact that RCTs examining the effect of colonoscopy on CRC incidence and mortality are only now getting underway is notable and deserves comment.

The National Polyp Study (NPS) reported a 76 % to 90 % reduction in the incidence of CRC in patients with adenomas who underwent colonoscopy and polypectomy, compared with three historical control groups [6]. Recently, long-term follow-up of the original NPS cohort revealed a 53 % reduction in CRC mortality compared with a Surveillance, Epidemiology, and End Results (SEER) reference group, after a median of nearly 16 years after colonoscopy with polypectomy [7]. An Italian prospective adenoma cohort study conducted in routine clinical practice showed findings comparable to the NPS [8]. Population-based case – control studies from Canada and Germany showed that colonoscopy decreased CRC incidence and mortality [9] [10]. A cohort study of average-risk patients undergoing screening colonoscopy also highlighted the protective effect of colonoscopy, showing a 67 % incidence reduction and 65 % mortality reduction compared with SEER, after up to 18 years of follow-up [11]. Observational studies that followed large groups of patients after a negative screening colonoscopy demonstrated marked, and long-lasting, protection against the development of and death from CRC [12] [13]. However, the central role of colonoscopy in the fight against CRC has been questioned, particularly after the publication of several well-publicized studies which have suggested that (i) in adenoma cohorts, the magnitude of protection may not be as high as originally thought [14], and (ii) colonoscopy does not protect against right-sided CRC to the same extent as left-sided CRC [9] [15]. Given that the right side of the colon is where colonoscopy should outperform other modalities, the observed decreased effectiveness has led some to advocate that colonoscopy is no better than flexible sigmoidoscopy [16].

We now know that colonoscopy’s power to protect against CRC is operator-dependent, and many of the observed inconsistencies in the literature may be due to the variable performance of colonoscopy, and the direct impact of performance quality on important patient outcomes [15] [17] [18]. However, it has also become clear that the place of screening colonoscopy in the battle against CRC cannot be clearly and finally defined based on the available evidence. We may have simply reached the limits of the conclusions and extrapolations which can be obtained from indirect and observational studies. Fundamental questions such as the benefits and risks of colonoscopy-based screening in a population setting, compared with other screening modalities or no screening at all, require high quality evidence from randomized controlled trials for adequate and definitive answers. These trials are now underway. Recently, an RCT from Spain (ClinicalTrials.gov number, NCT00906997) comparing CRC mortality after once-only screening colonoscopy with that following biennial fecal immunochemical testing (FIT) reported its preliminary findings [19]. The rate of participation was higher in the FIT group than in the colonoscopy group and the cancer yield was comparable for both modalities; however, more adenomas were identified in the colonoscopy group. The primary endpoint of this RCT, CRC mortality after 10 years, will be determined when the study is completed. In the United States, the CONFIRM (Colonoscopy versus Immunochemical Testing in Reducing Mortality from Colorectal Cancer) trial (ClinicalTrials.gov number, NCT01239082) will compare 10-year CRC mortality in US veterans randomized to screening colonoscopy or annual FIT. The Nordic-European Initiative on Colorectal Cancer (NordICC) RCT promises to be a very important entry in the growing list of ongoing or imminently starting studies of screening colonoscopy. This RCT will enroll men and women aged 55 to 64 from the population registries of Sweden, Norway, Poland, and the Netherlands. A total of 22 800 participants will be randomized to once-only screening colonoscopy compared with 45 600 participants randomized to no screening, which is the standard of care in the trial geographic catchment area. The primary endpoints are intention-to-screen cumulative incidence and mortality after 15 years; however, an interim analysis is planned at 10 years and will allow early termination of the trial with the appropriate statistical adjustments if dictated by the findings. Secondary endpoints include CRC mortality and incidence between the screening group and the control group after adjustment for imperfect uptake, and all-cause mortality. A study such as NordICC would be nearly impossible to conduct today in the United States, as it is unlikely that many patients would accept randomization to the no-screening control arm, and it would potentially face insurmountable regulatory and ethical challenges. However, it does show where screening colonoscopy studies might have started many years ago, as this is the design which will most closely estimate the effect of colonoscopy on CRC incidence and mortality when used in a population-based screening program.

In some ways, we are now back to the future of screening colonoscopy, and rewriting its history. More than 20 years after first publication of feasibility and safety studies of screening colonoscopy [20] [21] and nearly 20 years after the publication of the first FOBT RCT [3], colonoscopy RCTs are just starting. It will be years before the final results of these RCTs are available, and high quality observational studies will – and should – continue to be conducted and published to help refine screening policies, allow judicious allocation of scarce health care resources, and promote universal screening for CRC. However, for those who have been involved in and following the saga of screening colonoscopy and the overarching goal of defeating CRC, it has been a long and exciting journey, and the knowledge we expect from these randomized trials is worth the wait.

• References

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