Colorectal Cancer Screening: Randomized Trials Are Essential to Support Recommendations

Colorectal cancer screening for persons older than 45 or 50 years has been introduced in many countries. The most frequently used methods are endoscopy (today usually colonoscopy but also sigmoidoscopy) and fecal testing (1). The advantage of endoscopic screening versus fecal testing is that endoscopy aims to prevent colorectal cancer by removal of premalignant polyps, whereas fecal testing primarily targets detection of colorectal cancer at an early stage. Also, fecal testing needs to be repeated every year or every other year, whereas endoscopy is recommended with longer time intervals (5 or 10 years) (1). Although colonoscopy screening is recommended as an effective screening test, especially in the United States, no data from randomized trials have quantified its benefits and harms. The assumed effects of colonoscopy screening on population health have been extrapolated from randomized trials of sigmoidoscopy screening, which only examines the rectum and lower portion of the colon. When endoscopic screening for colorectal cancer was first discussed in the early 1990s, colonoscopy was regarded as too invasive, too resource demanding, and too burdensome on patients to be seriously considered as a screening test. Also, consensus existed that tests should not be introduced without assessment of benefits and harms in randomized trials. Thus, between 1993 and 1999, the United States, United Kingdom, Italy, and Norway started large, government-funded randomized trials of population screening with sigmoidoscopy (2–5). In their article, Senore and colleagues report long-term results of the Italian sigmoidoscopy screening trial (6). With this report, all 4 sigmoidoscopy trials have reported primary end points: colorectal cancer incidence and mortality over more than 15 years after screening (2–6). The new Italian report concludes a remarkable, 3-decades long era in colorectal cancer screening and provides an opportunity to summarize and look ahead. The 4 trials together includedmore than 450000 persons randomly assigned to sigmoidoscopy screening or usual care. The Italian, United Kingdom, and Norwegian trials comprised 1 screening sigmoidoscopy, whereas the U.S. trial comprised 2 screening sigmoidoscopies, the second 3 or 5 years after the first (3). In all trials, screening was done as high-turnover outpatient procedures without sedation and with bowel cleansing primarily by enema, thus limiting costs, resources, andpatient's time commitment. In the current report of the Italian trial, colorectal cancer incidence and mortality was 19% lower 15 years and 22% lower 19 years, respectively, after a single screening sigmoidoscopy at around age 60 years compared with control persons (6). These results are consistent with findings from the other 3 trials and establish a long-lasting, almost 20-year benefit of sigmoidoscopy screening. The Italian trial, similar to the United Kingdom and U.S. trials, used a conventional trial design with enrollment after informed consent (2, 3, 5). These 3 trials were not population based because only persons who consented to be in the trial were randomized. In contrast, the Norwegian trial was pragmatic, randomly assigning the whole population of 2 geographic areas in the eligible age range to screening or no screening (4). Consent was obtained from those attending screening. Despite the design differences, the 4 trials showed similar benefits: 18% to 26% reduction in colorectal cancer incidence and 21% to 30% reduction in colorectal cancer mortality (2–6). With the colorectal cancer prevalence seen in the trials (which are representative of many countries in the developed world), this translates to absolute risk reductions with screening of about 6 to 8 per 1000 screened for colorectal cancer incidence and about 3 to 5 per 1000 persons screened for colorectal cancer mortality over 15 to 20 years. Although clearly clinically significant, the reduction in colorectal cancer incidence and mortality in the screening groups of the trials was of moderate magnitude. There are 3 likely explanations. First, effect estimates derive from intention-to-screen analyses, and screening adherence was only 57% to 84% across the trials (2–6). However, even in adjusted per protocol analyses comparing those adherent with screening to the control group, relative risk reductions for colorectal cancer incidence and mortality rarely exceeded 60%. Second, sigmoidoscopy does not examine the entire colon. In the Italian trial, cancer incidence and mortality within reach of the sigmoidoscopy were reduced by 30% and 31%, respectively (6), in line with what has been seen in the other trials (3–5). Even though patients with pathologic findings at sigmoidoscopy were referred to full colonoscopy, screening had little effect on proximal colorectal cancer incidence. Finally, a single screening (or even 2 as applied in the U.S. trial) can obviously not prevent all subsequent cancer. Most guidelines recommend repeating sigmoidoscopy screening every 5 years and colonoscopy every 10 years (1). The new Italian report and the reports from the sister trials establish a benefit of screening far beyond the currently recommended screening intervals. Guideline makers may consider prolonging recommended screening intervals for sigmoidoscopy and colonoscopy. Longer intervals result in lower costs as well as reduced harms and burdens through less exposure to screening and surveillance endoscopy and may not substantially compromise the benefit of screening. This may be especially relevant to persons at the lower end of the screening age where cancer risk is smaller and absolute benefits moremarginal (7). A previous meta-analysis of older data from the Italian, U.S., and Norwegian trials indicated smaller screening benefits for women as compared with men (8). In the new Italian report, screening had similar effects in women and men for colorectal cancer incidence, whereas screening had no significant effect on colorectal cancer mortality in