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Original Investigation
December 17, 2018

Long-term Risk of Colorectal Cancer and Related Deaths After a Colonoscopy With Normal Findings

Author Affiliations
  • 1Department of Gastroenterology, Kaiser Permanente San Francisco, San Francisco, California
  • 2Division of Research, Kaiser Permanente Northern California, Oakland, California
  • 3Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
  • 4Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, California
  • 5Department of Family Medicine and Community Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia
JAMA Intern Med. 2019;179(2):153-160. doi:10.1001/jamainternmed.2018.5565
Key Points

Question  What are the long-term risks of colorectal cancer and related deaths in average-risk patients after a colonoscopy with normal findings (negative colonoscopy results)?

Findings  In this community-based study of 1 251 318 individuals, adjusted annual colorectal cancer risks were reduced by 46% to 95%, and related deaths by 29% to 96%, across more than 12 years of follow-up after negative colonoscopy results compared with average-risk individuals with no screening. Although reductions in risk were attenuated with increasing years of follow-up, there was a 46% lower risk of colorectal cancer and 88% lower risk of related deaths at the guideline-recommended 10-year rescreening interval.

Meaning  A colonoscopy with normal findings in average-risk patients appears to be associated with a lower risk of colorectal cancer deaths and overall, proximal, distal, early-stage, and advanced-stage colorectal cancer for more than 12 years compared with no screening.


Importance  Guidelines recommend a 10-year rescreening interval after a colonoscopy with normal findings (negative colonoscopy results), but evidence supporting this recommendation is limited.

Objective  To examine the long-term risks of colorectal cancer and colorectal cancer deaths after a negative colonoscopy result, in comparison with individuals unscreened, in a large, community-based setting.

Design, Setting, and Participants  A retrospective cohort study was conducted in an integrated health care delivery organization serving more than 4 million members across Northern California. A total of 1 251 318 average-risk screening-eligible patients (age 50-75 years) between January 1, 1998, and December 31, 2015, were included. The study was concluded on December 31, 2016.

Exposures  Screening was examined as a time-varying exposure; all participants contributed person-time unscreened until they were either screened or censored. If the screening received was a negative colonoscopy result, the participants contributed person-time in the negative colonoscopy results group until they were censored.

Main Outcomes and Measures  Using Cox proportional hazards regression models, the hazard ratios (HRs) for colorectal cancer and related deaths were calculated according to time since negative colonoscopy result (or since cohort entry for those unscreened). Hazard ratios were adjusted for age, sex, race/ethnicity, Charlson comorbidity score, and body mass index.

Results  Of the 1 251 318 patients, 613 692 were men (49.0%); mean age was 55.6 (7.0) years. Compared with the unscreened participants, those with a negative colonoscopy result had a reduced risk of colorectal cancer and related deaths throughout the more than 12-year follow-up period, and although reductions in risk were attenuated with increasing years of follow-up, there was a 46% lower risk of colorectal cancer (hazard ratio, 0.54; 95% CI, 0.31-0.94) and 88% lower risk of related deaths (hazard ratio, 0.12; 95% CI, 0.02-0.82) at the current guideline-recommended 10-year rescreening interval.

Conclusions and Relevance  A negative colonoscopy result in average-risk patients was associated with a lower risk of colorectal cancer and related deaths for more than 12 years after examination, compared with unscreened patients. Our study findings may be able to inform guidelines for rescreening after a negative colonoscopy result and future studies to evaluate the costs and benefits of earlier vs later rescreening intervals.

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    1 Comment for this article
    Surveillance interval among asymptomatic individuals with negative index colonoscopy
    Martin CS Wong, MD, MPH | The School of Public Health and Primary Care, Chinese University of Hong Kong
    To the Editor,

    Lee and colleagues are to be congratulated for their important study comparing the long-term risk of colorectal cancer (CRC) and related deaths between screened asymptomatic subjects with negative index colonoscopy and an unscreened population in a community-based setting involving more than 1.2 million individuals [1]. They found that the adjusted yearly CRC risk and its related deaths were significantly lower by up to 46%-95% and 29%-96%, respectively, across more than 12 years of follow-up in subjects with normal baseline colonoscopy. The findings are potentially practice-changing as they imply a 10 year surveillance interval should be
    revisited, when the adjusted CRC incidence rate at >12 years (87.8 per 100,000 person-years, 95% C.I.=32.2-191.1) was lower than that in the unscreened group (224.8, 95% C.I.=202.5-247.0) with a pretty low hazard ratio (0.31, 95% C.I.=0.14-0.68). It should be noted that the CRC mortality rates at >12 years was also much lower in the screened negative group (38.1, 95% C.I.=7.9-68.4) than the unscreened group (192.0, 95% CI=169.7-214.3), although the hazard ratio was not statistically significant (0.40 95% C.I.=0.13-1.24).

    The limitations of the study do not seem to be major – as the authors have rightly highlighted, residual confounders of CRC might exist. Although the researchers excluded subjects diagnosed with CRC 6 months after index colonoscopy, they could be considered negligible as a previous study in Manitoba demonstrated a low incidence of CRC at 6-months (1.1 cancers per 1,000 person-years) [2]. Nevertheless, there is one issue which remains uncertain – whether advanced adenoma should also be considered as the primary target for CRC colonoscopy screening [3]. It has long been suggested that advanced adenomas represent the most valid neoplastic surrogate for future CRC risk [4], and they could be used as a marker when new screening modalities and preventive interventions are evaluated [4]. This is indeed consistent with recent recommendations from the U.S. Multi-Society Task Force on CRC [5], where removal of high-risk precancerous lesion was listed as an objective of CRC screening. Although practically difficult to compare the incidence of advanced adenoma between the screened and the unscreened group in a large cohort study, future cost-effectiveness analysis should take into account this important precursor for guideline formulation. In addition, given the richness of data in Lee et al’s study [1], the reduction of incidence/mortality stratified by CRC sidedness between the two groups could be further analyzed, as the prevalence of right sided CRC tends to be higher than that in the unscreened population [2].


    1). Lee JK, Jensen CD, Levin TR et al. Long-term Risk of Colorectal Cancer and Related Deaths After a Colonoscopy With Normal Findings. JAMA Intern Med. 2018 Dec 17. doi: 10.1001/jamainternmed.2018.5565
    2). Lee JK, Jensen CD, Levin TR et al. Risk of Developing Colorectal Cancer Following a Negative Colonoscopy Examination Evidence for a 10-Year Interval Between Colonoscopies. JAMA. 2006;295(20):2366-2373
    3). Kim DH, Pickhardt PJ, Taylor AJ et al. CT colonography versus colonoscopy for the detection of advanced neoplasia. N Engl J Med. 2007;357(14):1403-12
    4). Winawer SJ1, Zauber AG. The advanced adenoma as the primary target of screening. Gastrointest Endosc Clin N Am. 2002;12(1):1-9
    5). Rex DK, Boland CR, Dominitz JA et al. Colorectal Cancer Screening: Recommendations for Physicians and Patients from the U.S. Multi-Society Task Force on Colorectal