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Time to Colonoscopy After Abnormal Stool-Based Screening and Risk for Colorectal Cancer Incidence and Mortality

  • Author Footnotes
    ∗ Authors share co-first authorship with Ms. San Miguel listed first.
    Yazmin San Miguel
    Footnotes
    ∗ Authors share co-first authorship with Ms. San Miguel listed first.
    Affiliations
    Division of Gastroenterology, Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, California

    Moores Cancer Center and Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California
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  • Author Footnotes
    ∗ Authors share co-first authorship with Ms. San Miguel listed first.
    Joshua Demb
    Footnotes
    ∗ Authors share co-first authorship with Ms. San Miguel listed first.
    Affiliations
    Division of Gastroenterology, Department of Internal Medicine, University of California San Diego, La Jolla, California
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  • Maria Elena Martinez
    Affiliations
    Moores Cancer Center and Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California
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  • Samir Gupta
    Correspondence
    Samir Gupta, MD, MSCS, AGAF, Department of Internal Medicine, Moores Cancer Center, University of California San Diego, La Jolla, California 92037.
    Affiliations
    Division of Gastroenterology, Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, California

    Division of Gastroenterology, Department of Internal Medicine, University of California San Diego, La Jolla, California
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  • Folasade P. May
    Correspondence
    Correspondence Address correspondence to: Folasade P. May, MD, PhD, Vatche and Tamar Manoukian Division of Digestive Diseases, Center for Health Sciences, 650 Charles Young Drive South, Suite A2–125, Los Angeles, California 90095–6900.
    Affiliations
    Division of Gastroenterology, Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California

    Vatche and Tamar Manoukian Division of Digestive Diseases and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, California
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  • Author Footnotes
    ∗ Authors share co-first authorship with Ms. San Miguel listed first.
Open AccessPublished:February 02, 2021DOI:https://doi.org/10.1053/j.gastro.2021.01.219

      Background and aims

      The optimal time interval for diagnostic colonoscopy completion after an abnormal stool-based colorectal cancer (CRC) screening test is uncertain. We examined the association between time to colonoscopy and CRC outcomes among individuals who underwent diagnostic colonoscopy after abnormal stool-based screening.

      Methods

      We performed a retrospective cohort study of veterans age 50 to 75 years with an abnormal fecal occult blood test (FOBT) or fecal immunochemical test (FIT) between 1999 and 2010. We used multivariable Cox proportional hazards to generate CRC-specific incidence and mortality hazard ratios (HRs) and 95% confidence intervals (CI) for 3-month colonoscopy intervals, with 1 to 3 months as the reference group. Association of time to colonoscopy with late-stage CRC diagnosis was also examined.

      Results

      Our cohort included 204,733 patients. Mean age was 61 years (SD 6.9). Compared with patients who received a colonoscopy at 1 to 3 months, there was an increased CRC risk for patients who received a colonoscopy at 13 to 15 months (HR 1.13; 95% CI 1.00–1.27), 16 to 18 months (HR 1.25; 95% CI 1.10–1.43), 19 to 21 months (HR 1.28; 95% CI: 1.11–1.48), and 22 to 24 months (HR 1.26; 95% CI 1.07–1.47). Compared with patients who received a colonoscopy at 1 to 3 months, mortality risk was higher in groups who received a colonoscopy at 19 to 21 months (HR 1.52; 95% CI 1.51–1.99) and 22 to 24 months (HR 1.39; 95% CI 1.03–1.88). Odds for late-stage CRC increased at 16 months.

      Conclusions

      Increased time to colonoscopy is associated with higher risk of CRC incidence, death, and late-stage CRC after abnormal FIT/FOBT. Interventions to improve CRC outcomes should emphasize diagnostic follow-up within 1 year of an abnormal FIT/FOBT result.

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      BMI (body mass index), CCI (Charlson Comorbidity Index), CRC (colorectal cancer), CI (confidence interval), COVID-19 (coronavirus disease 2019), CDW (Corporate Data Warehouse), FOBT (fecal occult blood test), FIT (fecal immunochemical test), HR (hazard ratio), OR (odds ratio), VA (Veterans Health Administration of the Department of Veterans Affairs)
      See editorial on page 1929.

       Background and Context

      The literature varies on the optimal time interval for diagnostic colonoscopy after an abnormal stool-based colorectal cancer test result (CRC) to maximize prevention of incident and fatal CRC.

       New Findings

      Time to colonoscopy was significantly associated with CRC incidence, CRC mortality, and advanced stage CRC in a retrospective cohort study of 204,733 adults with abnormal stool-based screening test results.

       Limitations

      Study findings may be less generalizable to non-VA settings, and there is the potential for residual and unmeasured confounding in this retrospective cohort study.

       Impact

      Time to colonoscopy after abnormal stool-based screening test results should be monitored as a quality metric. Patients should undergo colonoscopy well within 1 year to avoid poor outcomes.
      Colorectal cancer (CRC) is the second most common cause of cancer-related mortality among men and women in the United States, and there is strong evidence that screening reduces both incidence and CRC-related mortality.
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      The US Preventive Services Task Force recommends several screening modalities for CRC prevention and early detection, including the fecal immunochemical test (FIT) and fecal occult blood test (FOBT).
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      Both tests are common noninvasive studies that, when abnormal (ie, positive), require follow-up with diagnostic colonoscopy to evaluate for precancerous and cancerous colorectal lesions.
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      • et al.
      Adherence to follow-up after a positive fecal occult blood test in an organized colorectal cancer screening program in Korea, 2004–2008.
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      • Libby G.
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      Occult blood in faeces is associated with all-cause and non-colorectal cancer mortality.
      • Robertson D.J.
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      • et al.
      Recommendations on fecal immunochemical testing to screen for colorectal neoplasia: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer.
      Consequences of delays in colonoscopy completion after abnormal stool test results have not been widely studied. Although poor outcomes such as late stage at presentation and increased mortality have been reported with failure to complete colonoscopy, influence of time to colonoscopy on these outcomes has not been well established.
      • Corley D.A.
      • Jensen C.D.
      • Quinn V.P.
      • et al.
      Association between time to colonoscopy after a positive fecal test result and risk of colorectal cancer and cancer stage at diagnosis.
      • Gellad Z.F.
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      Time from positive screening fecal occult blood test to colonoscopy and risk of neoplasia.
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      Consequences of increasing time to colonoscopy examination after positive result from fecal colorectal cancer screening test.
      Existing data examining time to colonoscopy and clinical risk come from international settings or regional US cohorts and support a wide range of follow-up intervals (6 to 24 months).
      • Corley D.A.
      • Jensen C.D.
      • Quinn V.P.
      • et al.
      Association between time to colonoscopy after a positive fecal test result and risk of colorectal cancer and cancer stage at diagnosis.
      ,
      • Gellad Z.F.
      • Almirall D.
      • Provenzale D.
      • et al.
      Time from positive screening fecal occult blood test to colonoscopy and risk of neoplasia.
      ,
      • Beshara A.
      • Ahoroni M.
      • Comanester D.
      • et al.
      Association between time to colonoscopy after a positive guaiac fecal test result and risk of colorectal cancer and advanced stage disease at diagnosis.
      • Ferrat E.
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      Colorectal cancer screening: factors associated with colonoscopy after a positive faecal occult blood test.
      • Lee Y.C.
      • Fann J.C.
      • Chiang T.H.
      • et al.
      Time to colonoscopy and risk of colorectal cancer in patients with positive results from fecal immunochemical tests.
      • Lee Y.C.
      • Li-Sheng Chen S.
      • Ming-Fang Yen A.
      • et al.
      Association between colorectal cancer mortality and gradient fecal hemoglobin concentration in colonoscopy noncompliers.
      • Flugelman A.A.
      • Stein N.
      • Segol O.
      • et al.
      Delayed colonoscopy following a positive fecal test result and cancer mortality.
      • Kaalby L.
      • Rasmussen M.
      • Zimmermann-Nielsen E.
      • et al.
      Time to colonoscopy, cancer probability, and precursor lesions in the Danish colorectal cancer screening program.
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      • Kim S.
      • et al.
      Association of time to colonoscopy after a positive fecal test result and fecal hemoglobin concentration with risk of advanced colorectal neoplasia.
      • Zorzi M.
      • Hassan C.
      • Capodaglio G.
      • et al.
      Colonoscopy later than 270 days in a fecal immunochemical test-based population screening program is associated with higher prevalence of colorectal cancer.
      As a result, there are no national standards or federal quality mandates to guide patients, providers, or health care systems on the clinically acceptable period of time in which a diagnostic colonoscopy should be performed after an abnormal FIT/FOBT.
      • Robertson D.J.
      • Lee J.K.
      • Boland C.R.
      • et al.
      Recommendations on fecal immunochemical testing to screen for colorectal neoplasia: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer.
      As FIT use increases, and especially in the setting of the ongoing global coronavirus disease 2019 (COVID-19) pandemic that has necessitated greater reliance on noninvasive CRC screening modalities,
      • Shaukat A.
      • Church T.
      Colorectal cancer screening in the USA in the wake of COVID-19.
      ,
      EPIC helath research network
      Preventive Cancer Screenings during COVID-19 Pandemic.
      it is critical to further define best practice for optimal time to colonoscopic follow-up after abnormal results. Traditional barriers to follow-up, including patient factors (eg, hesitancy about colonoscopy), provider roles (eg, knowledge of results, referral for colonoscopy), and system-level factors (eg, FIT tracking, provider reminders), are now compounded by competing priorities during the prolonged pandemic.
      • May F.
      • Yano E.M.
      • Provenzale D.
      • et al.
      Barriers to follow-up colonoscopies for patients with positive results from fecal immunochemical tests during colorectal cancer screening.
      ,

      Selby K, Senore C, Wong M, et al. Interventions to ensure follow-up of positive fecal immunochemical tests: an international survey of screening programs [published online ahead of print February 13, 2020]. J Med Screen doi: 0969141320904977.

      Thus, we conducted a national retrospective cohort study of US patients with abnormal FIT/FOBT results to examine the association between time to colonoscopy, CRC incidence, CRC stage at presentation, and CRC mortality. Findings will inform national standards for appropriate timing of colonoscopy after abnormal FIT/FOBT screening and interventions to improve CRC outcomes.

      Methods

       Study Population and Data Collection

      The Veterans Health Administration of the Department of Veterans Affairs (VA) is one of the largest integrated health care systems in the United States and provides care for more than 9 million veterans annually through >1200 health care facilities.
      Providing care for Veterans.
      The VA Corporate Data Warehouse (CDW) was created in 1999 and is the central data warehouse for VA electronic health records. The CDW houses patient demographic data, claims-based diagnoses, procedure codes, prescriptions, anthropometric measures, encounter and procedure notes, laboratory results, and pathology reports. We accessed CDW data to include patients who (1) had an abnormal FIT or FOBT (FIT/FOBT) result between October 1, 1999, and December 31, 2010, (2) had no prior history of CRC or inflammatory bowel disease (Crohn’s or ulcerative colitis), and (3) were ages 50 to 75 at the time of abnormal FIT/FOBT. We excluded patients with (1) a history of colonoscopy before the abnormal FIT/FOBT, (2) a history of colectomy before abnormal FIT/FOBT, (3) fewer than 2 VA primary care visits in the two years prior, (4) no colonoscopy after abnormal FIT/FOBT, and/or (5) colonoscopy within 30 days of abnormal FIT/FOBT. We removed patients with an abnormal FIT/FOBT result who had a colonoscopy within 30 days of the abnormal FIT result to exclude the likely more severely symptomatic patients for whom FIT may have been ordered for diagnostic purposes, estimating that it takes approximately 30 days for patients to receive a diagnostic colonoscopy in the VA. Thus, the final analytic cohort consisted of individuals age 50 to 75 with an abnormal FIT/FOBT between 1999 and 2010 who completed a subsequent diagnostic colonoscopy more than 30 days after the abnormal FIT/FOBT, and no prior history of CRC, inflammatory bowel disease, or colonoscopy before an abnormal stool blood test result. The study was approved by the VA Institutional Review Board and Research and Development Committee at the San Diego Veterans Affairs Healthcare System.

       Outcomes

      We examined 3 primary outcomes: incident CRC, fatal CRC, and stage of CRC at presentation between October 1, 1999, and December 31, 2015. We identified incident CRC using the Oncology Domain database in the CDW, which contains cancer diagnoses from local VA cancer data abstractions
      • Earles A.
      • Liu L.
      • Bustamante R.
      • et al.
      Structured approach for evaluating strategies for cancer ascertainment using large-scale electronic health record data.
      and from patients who died of CRC. We ascertained fatal CRC from National Death Index cause-specific mortality data. Late-stage CRC was defined as patients with CRC stages III and IV according to the American Joint Committee on Cancer staging system.

       Exposure

      Our primary exposure (predictor) variable was time to colonoscopy after abnormal FIT/FOBT. We identified colonoscopy uptake from Current Procedural Terminology codes (Supplementary Table 1). Our continuous exposure variable was defined as days to colonoscopy after abnormal FIT/FOBT. Subsequently, we categorized the variable into 3-month intervals following prior convention: 1 to 3 months, 4 to 6 months, 7 to 9 months, 10 to 12 months, 13 to 15 months, 16 to 18 months, 19 to 21 months, 22 to 24 months, and more than 24 months, where 1 month equates to 30 days.
      • Corley D.A.
      • Jensen C.D.
      • Quinn V.P.
      • et al.
      Association between time to colonoscopy after a positive fecal test result and risk of colorectal cancer and cancer stage at diagnosis.

       Covariates

      We ascertained demographic and clinical factors from the CDW. Demographic data included age at the time of the abnormal FIT/FOBT, sex, race, and ethnicity. We defined race and ethnicity as one variable with 6 mutually exclusive categories: non-Hispanic White, non-Hispanic Black, Hispanic, Asian, American Indian or Alaska Native, and other (Native Hawaiian or other Pacific Islander, multiracial, and those who designated “other” race). Clinical variables were tobacco use, body mass index (BMI, kg/m2) and Charlson Comorbidity Index (CCI) at the time of abnormal FIT/FOBT (or within 1 year before the abnormal FIT for CCI). Tobacco use status was classified into never, former, current, and unknown categories as previously described.
      • McGinnis K.A.
      • Brandt C.A.
      • Skanderson M.
      • et al.
      Validating smoking data from the Veteran's Affairs Health Factors dataset, an electronic data source.
      We used previously developed criteria to remove biologically implausible values for height and weight and to calculate BMI.
      • Noel P.H.
      • Copeland L.A.
      • Perrin R.A.
      • et al.
      VHA Corporate Data Warehouse height and weight data: opportunities and challenges for health services research.
      We used the Deyo modification of the CCI for each patient, in which higher scores reflect greater disease burden and likelihood of death.
      • Deyo R.A.
      • Cherkin D.C.
      • Ciol M.A.
      Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases.
      CCI was classified into 4 categories: 0, 1, 2, and ≥3.
      • Deyo R.A.
      • Cherkin D.C.
      • Ciol M.A.
      Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases.

       Statistical Analyses

      We used descriptive statistics to describe patient demographic and clinical factors for the study cohort and characterize CRC outcome rates by time to colonoscopy. For the analysis examining the relationship between time to colonoscopy and incident and fatal CRC, we used multivariable Cox proportional hazards models to generate CRC-specific hazard ratios (HR) and 95% confidence intervals (CI) to measure the association. Our incident CRC analysis followed patients through CRC diagnosis, CRC death, other death, or the end of the study window (December 31, 2015). For mortality analyses, we followed patients to CRC death, other death, or the end of the study window. For stage at presentation, we performed a multivariable logistic regression to generate CRC-specific odds ratios (OR) and CI to measure the association between time to colonoscopy and late-stage CRC diagnosis, compared with those without late-stage CRC diagnosis. All multivariable models were adjusted for age at time of FIT/FOBT, sex, race/ethnicity, tobacco use, BMI (continuous), and CCI. We used colonoscopy completion within 1 to 3 months as our reference group, consistent with prior studies.
      • Partin M.R.
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      • et al.
      Contribution of patient, physician, and environmental factors to demographic and health variation in colonoscopy follow-up for abnormal colorectal cancer screening test results.
      ,

      Forbes N, Hilsden RJ, Martel M, et al. Association between time to colonoscopy after positive fecal testing and colorectal cancer outcomes: a systematic review [published online ahead of print October 1, 2020]. Clin Gastroenterol Hepatol doi: https://doi.org/10.1016/j.cgh.2020.09.048.

      Statistical tests were 2-sided, and a P value less than .05 was considered statistically significant. We used Schoenfeld residuals to test the proportional hazard assumption.
      • Schoenfeld D.
      Partial residuals for the proportional hazards regression model.
      For these and all subsequently described analyses, HR with CI not crossing unity were considered statistically significant. All analyses were performed with SAS software 9.4 (SAS Institute, Cary, NC).

      Results

       Descriptive Characteristics of Analytic Cohort

      Our final analytic cohort included 204,733 veterans with an abnormal FIT or FOBT result (Figure 1). In all, 6906 were diagnosed with CRC and 1709 died of CRC. The median study follow-up time was 9.2 years with an interquartile range of 5.3 years. Mean age was 61.3 years (SD ± 6.9), 97% were men, 66% were non-Hispanic White, and 19% were non-Hispanic Black. Tobacco use prevalence was 27%, and 44% of patients had a CCI score of 0. Mean BMI of the study cohort was 30.1 kg/m2 (SD ± 5.6) (Table 1). Rates of incident, late-stage, and fatal CRC increased with time to colonoscopy after abnormal FIT/FOBT (Supplementary Figure 1).
      Figure thumbnail gr1
      Figure 1Flowchart of inclusion and exclusion criteria for study cohort, 1999–2015.
      Table 1Demographic and Clinical Characteristics of Study Population
      Patient characteristicTotal n = 204,733
      Age, y (mean ± SD)61.3 ± 6.9
      Sex, n (%)
       Female5453 (2.7)
       Male199280 (97.3)
      Race/ethnicity, n (%)
       Non-Hispanic White135163 (66.0)
       Non-Hispanic Black39111 (19.1)
       Hispanic8112 (4.0)
       Asian2055 (1.0)
       American Indian1084 (0.5)
       Multiracial/Other3256 (1.6)
       Unknown15952 (7.8)
      Smoking, n (%)
       Never47326 (23.1)
       Former41293 (20.2)
       Current55382 (27.1)
       Unknown60732 (29.7)
      BMI, kg/m2 (mean ± SD)30.1 ± 5.6
      BMI categorical, n (%)
       Underweight1360 (0.7)
       Normal31131 (15.2)
       Overweight68381 (33.4)
       Obese85093 (41.6)
       Unknown18768 (9.2)
      Charlson Comorbidity Index, n (%)
       089237 (43.6)
       159421 (29.0)
       225482 (12.5)
       3+30358 (14.8)
       Unknown235 (0.1)

       Association Between Time to Colonoscopy and CRC Incidence

      Table 2 provides results of the multivariable-adjusted model for the association between time to colonoscopy and CRC incidence. Overall, the risk for incident CRC increased with time to colonoscopy. Compared with patients who received a colonoscopy at 1 to 3 months, risk increased at 13 to 15 months (HR 1.13; 95% CI 1.00–1.27), 16 to 18 months (HR 1.25; 95% CI 1.10–1.43), 19 to 21 months (HR 1.28; 95% CI 1.11–1.48), and 22 to 24 months (HR 1.26; 95% CI 1.07–1.47). Risk of incident CRC was decreased for colonoscopy completion at 4 to 6 months (HR 0.91; 95% CI 0.85–0.97), 7 to 9 months (HR 0.89; 95% CI 0.81–0.98), and > 24 months (HR 0.86; 95% CI 0.80–0.92). There was no difference in risk for patients with a colonoscopy at 10 to 12 months. (Figure 2).
      Table 2Association Between Time to Colonoscopy and Risk of Incident and Fatal CRC Among Veterans With an Abnormal FIT/FOBT, Represented as HRs and 95% CIs; 1999–2015 (n = 204,733)
      VariableNo. of patientsNo. CRC casesNo. fatal CRC casesIncident CRC unadjusted HR (95% CI)Incident CRC adjusted HR (95% CI)Fatal CRC unadjusted HR (95% CI)Fatal CRC adjusted HR (95% CI)
      Time to colonoscopy after abnormal FIT/FOBT, mo
       1–361,6132050454REFREFREFREF
       4–639,94813123350.93 (0.87–1.00)0.91 (0.85–0.97)1.00 (0.87–1.15)0.95 (0.83–1.10)
       7–918,2176051680.92 (0.84–1.01)0.89 (0.81–0.98)1.05 (0.88–1.26)1.00 (0.84–1.19)
       10–1210,187354890.96 (0.86–1.08)0.93 (0.83–1.05)0.99 (0.79–1.24)0.94 (0.74–1.17)
       13–157,388308631.17 (1.03–1.31)1.13 (1.00–1.27)0.98 (0.75–1.27)0.93 (0.72–1.21)
       16–185,478253651.29 (1.13–1.47)1.25 (1.10–1.43)1.36 (1.05–1.77)1.27 (0.98–1.65)
       19–214,283200581.31 (1.13–1.51)1.28 (1.11–1.48)1.57 (1.19–2.06)1.52 (1.15–1.99)
       22–243,595166461.28 (1.09–1.50)1.26 (1.07–1.47)1.44 (1.06–1.95)1.39 (1.03–1.88)
       > 2454,02416584310.81 (0.76–0.86)0.86 (0.80–0.92)0.82 (0.72–0.93)0.89 (0.78–1.02)
      NOTE. Adjusted for age, sex, race/ethnicity, smoking, Charlson Comorbidity Index, and BMI. Bold values indicate P<.05.
      Figure thumbnail gr2
      Figure 2Risk for incident CRC based on time to colonoscopy among US veterans with abnormal FIT/FOBT, 1999–2015 (n = 204,733).

       Association Between Time to Colonoscopy and CRC Mortality

      The results of the multivariable Cox proportional hazards model examining the relationship between time to colonoscopy and fatal CRC are shown in Table 2. Compared with patients who received a colonoscopy at 1 to 3 months, the risk of death increased with time to colonoscopy: 19 to 21 months (HR 1.52; 95% CI 1.15-1.99) and 22 to 24 months (HR 1.39; 95% CI 1.03–1.88). There were no differences in the risk of CRC-related mortality for patients with a colonoscopy at the other time intervals (Figure 3).
      Figure thumbnail gr3
      Figure 3Risk for fatal CRC based on time to colonoscopy among US veterans with abnormal FIT/FOBT, 1999–2015 (n = 204,733).

       Association Between Time to Colonoscopy and Late-Stage Colorectal Diagnosis

      The results of the multivariable logistic regression model examining the relationship between time to colonoscopy and CRC stage at presentation are provided in Table 3. Compared with patients without late-stage CRC at the time of diagnosis, the odds of advanced-stage diagnosis increased with time to colonoscopy when colonoscopy was delayed beyond 16 to 18 months: 16 to 18 months (OR 1.33; 95% CI 1.04–1.70), 19 to 21 months (OR 1.51; 95% CI 1.16–1.96), and 22 to 24 months (OR 1.66; 95% CI 1.26–2.18) (Figure 4).
      Table 3Association Between Time to Colonoscopy and Risk for Late-Stage Colorectal Diagnosis Among Veterans With an Abnormal FIT/FOBT, 1999–2015 (n = 204,271)
      VariableNo. of PatientsNo. of Patients with Advanced CRCUnadjusted OR (95% CI)Adjusted OR (95% CI)
      Time to Colonoscopy after abnormal FIT/FOBT, mo
       1–361,483596REFREF
       4–639,8513760.97 (0.86–1.11)0.95 (0.83–1.08)
       7–918,1691680.95 (0.80–1.13)0.92 (0.78–1.09)
       10–1210,1651031.05 (0.85–1.29)1.01 (0.82–1.25)
       13–157,365821.15 (0.91–1.45)1.12 (0.88–1.41)
       16–185,464721.36 (1.07–1.75)1.33 (1.04–1.70)
       19–214,276631.53 (1.18–1.98)1.51 (1.16–1.96)
       22–243,589581.68 (1.28–2.20)1.66 (1.26–2.18)
       > 2453,9095391.03 (0.92–1.16)1.08 (0.96–1.22)
      NOTE. Late-stage colorectal cancer was defined as patients with CRC stages III and IV according to the American Joint Committee on Cancer staging system. Adjusted for age, sex, race/ethnicity, smoking, Charlson Comorbidity Index, and BMI. Bold values indicate P<.05.
      Figure thumbnail gr4
      Figure 4Association between time to colonoscopy and risk for late-stage colorectal diagnosis among veterans with an abnormal FIT/FOBT, 1999–2015 (n = 204,271).

      Discussion

      In a large cohort of more than 204,000 US veterans, increasing time to colonoscopy after abnormal FIT/FOBT was significantly associated with higher CRC incidence, CRC-related mortality, and late stage at CRC presentation. Patients who received diagnostic colonoscopy follow-up 13 to 24 months after abnormal FIT/FOBT were 1.1 to 1.3 times more likely to have a CRC diagnosis than individuals who received a colonoscopy 1 to 3 months after abnormal FIT/FOBT. The risk for CRC-related mortality increased 1.4 to 1.5 times when colonoscopy was delayed by 19 to 24 months. Odds of advanced stage at diagnosis was 1.3 to 1.7 times higher when colonoscopy was delayed beyond 16 months. For all outcomes, risk was increased when colonoscopy was delayed 13 to 24 months after abnormal FIT/FOBT.
      Most existing data examining the relationship between exposure to colonoscopy after abnormal stool-based screening and CRC outcomes come from international settings, do not investigate the role of time to colonoscopy, or support a range of follow-up intervals.
      • Libby G.
      • Fraser C.G.
      • Carey F.A.
      • et al.
      Occult blood in faeces is associated with all-cause and non-colorectal cancer mortality.
      ,
      • Corley D.A.
      • Jensen C.D.
      • Quinn V.P.
      • et al.
      Association between time to colonoscopy after a positive fecal test result and risk of colorectal cancer and cancer stage at diagnosis.
      ,
      • Gellad Z.F.
      • Almirall D.
      • Provenzale D.
      • et al.
      Time from positive screening fecal occult blood test to colonoscopy and risk of neoplasia.
      ,
      • Beshara A.
      • Ahoroni M.
      • Comanester D.
      • et al.
      Association between time to colonoscopy after a positive guaiac fecal test result and risk of colorectal cancer and advanced stage disease at diagnosis.
      ,
      • Lee Y.C.
      • Fann J.C.
      • Chiang T.H.
      • et al.
      Time to colonoscopy and risk of colorectal cancer in patients with positive results from fecal immunochemical tests.
      • Lee Y.C.
      • Li-Sheng Chen S.
      • Ming-Fang Yen A.
      • et al.
      Association between colorectal cancer mortality and gradient fecal hemoglobin concentration in colonoscopy noncompliers.
      • Flugelman A.A.
      • Stein N.
      • Segol O.
      • et al.
      Delayed colonoscopy following a positive fecal test result and cancer mortality.
      • Kaalby L.
      • Rasmussen M.
      • Zimmermann-Nielsen E.
      • et al.
      Time to colonoscopy, cancer probability, and precursor lesions in the Danish colorectal cancer screening program.
      • Kim N.H.
      • Lim J.W.
      • Kim S.
      • et al.
      Association of time to colonoscopy after a positive fecal test result and fecal hemoglobin concentration with risk of advanced colorectal neoplasia.
      • Zorzi M.
      • Hassan C.
      • Capodaglio G.
      • et al.
      Colonoscopy later than 270 days in a fecal immunochemical test-based population screening program is associated with higher prevalence of colorectal cancer.
      Data from a 2017 Korean cohort demonstrated a 1.6-fold increased risk for CRC-specific death among patients who underwent colonoscopy (at any time) compared with those who did not.
      • Lee Y.C.
      • Li-Sheng Chen S.
      • Ming-Fang Yen A.
      • et al.
      Association between colorectal cancer mortality and gradient fecal hemoglobin concentration in colonoscopy noncompliers.
      In the same patient population, CRC risk and advanced-stage disease increased when colonoscopy was delayed by more than 6 months; however, the association between time to colonoscopy and death risk was not reported.
      • Lee Y.C.
      • Fann J.C.
      • Chiang T.H.
      • et al.
      Time to colonoscopy and risk of colorectal cancer in patients with positive results from fecal immunochemical tests.
      A retrospective analysis in Israel suggested that the optimal time interval between an abnormal stool-based screening result and colonoscopy was 12 months to reduce the risk of CRC incidence and late-stage diagnosis.
      • Beshara A.
      • Ahoroni M.
      • Comanester D.
      • et al.
      Association between time to colonoscopy after a positive guaiac fecal test result and risk of colorectal cancer and advanced stage disease at diagnosis.
      In the same population-based screening program, the hazard of CRC-related mortality increased by 50% when colonoscopy was delayed more than 12 months compared with 0 to 3 months.
      • Flugelman A.A.
      • Stein N.
      • Segol O.
      • et al.
      Delayed colonoscopy following a positive fecal test result and cancer mortality.
      The few published reports from US studies have small cohort size or used either regional or state populations. One study that included 231 veterans from a single VA facility reported an association between longer time to colonoscopy after abnormal FOBT and adenoma risk but was not powered to evaluate a malignancy endpoint.
      • Gellad Z.F.
      • Almirall D.
      • Provenzale D.
      • et al.
      Time from positive screening fecal occult blood test to colonoscopy and risk of neoplasia.
      In a retrospective analysis of FIT-positive Kaiser Permanente patients, individuals who waited 10 to 12 months were more likely to have CRC and advanced-stage disease at the time of diagnostic colonoscopy when compared with FIT-positive individuals who underwent colonoscopy within 1 month.
      • Corley D.A.
      • Jensen C.D.
      • Quinn V.P.
      • et al.
      Association between time to colonoscopy after a positive fecal test result and risk of colorectal cancer and cancer stage at diagnosis.
      A microsimulation model to estimate the consequences of different times to colonoscopy after an abnormal FIT supported this time interval.
      • Meester R.G.
      • Zauber A.G.
      • Doubeni C.A.
      • et al.
      Consequences of increasing time to colonoscopy examination after positive result from fecal colorectal cancer screening test.
      Our study confirms an increased risk of CRC and advanced stage with time from colonoscopy but extends these findings by evaluating how time to colonoscopy impacts CRC-related mortality.
      • Corley D.A.
      • Jensen C.D.
      • Quinn V.P.
      • et al.
      Association between time to colonoscopy after a positive fecal test result and risk of colorectal cancer and cancer stage at diagnosis.
      ,
      • Meester R.G.
      • Zauber A.G.
      • Doubeni C.A.
      • et al.
      Consequences of increasing time to colonoscopy examination after positive result from fecal colorectal cancer screening test.
      • Beshara A.
      • Ahoroni M.
      • Comanester D.
      • et al.
      Association between time to colonoscopy after a positive guaiac fecal test result and risk of colorectal cancer and advanced stage disease at diagnosis.
      • Ferrat E.
      • Le Breton J.
      • Veerabudun K.
      • et al.
      Colorectal cancer screening: factors associated with colonoscopy after a positive faecal occult blood test.
      • Lee Y.C.
      • Fann J.C.
      • Chiang T.H.
      • et al.
      Time to colonoscopy and risk of colorectal cancer in patients with positive results from fecal immunochemical tests.
      • Lee Y.C.
      • Li-Sheng Chen S.
      • Ming-Fang Yen A.
      • et al.
      Association between colorectal cancer mortality and gradient fecal hemoglobin concentration in colonoscopy noncompliers.
      • Flugelman A.A.
      • Stein N.
      • Segol O.
      • et al.
      Delayed colonoscopy following a positive fecal test result and cancer mortality.
      ,
      • Wattacheril J.
      • Kramer J.R.
      • Richardson P.
      • et al.
      Lagtimes in diagnosis and treatment of colorectal cancer: determinants and association with cancer stage and survival.
      • Doubeni C.A.
      • Gabler N.B.
      • Wheeler C.M.
      • et al.
      Timely follow-up of positive cancer screening results: A systematic review and recommendations from the PROSPR Consortium.
      • Rutter C.M.
      • Kim J.J.
      • Meester R.G.S.
      • et al.
      Effect of time to diagnostic testing for breast, cervical, and colorectal cancer screening abnormalities on screening efficacy: a modeling study.
      The association between time to colonoscopy and CRC incidence reflects the 2 mechanisms by which FIT/FOBT can interfere with CRC tumorigenesis. CRC is the result of a series of sequential mutations that impact cell proliferation and apoptosis in the transition from normal colonic mucosa to polyp to CRC.
      • Chung D.C.
      The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis.
      Stool-based CRC screening modalities contribute to CRC prevention through the detection of colon and rectal polyps (usually adenomas) and the diagnosis of malignant lesions. Thus, the low rate of incident CRC among patients who underwent colonoscopy at 4 to 6 months and 7 to 9 months compared with 1 to 3 months most likely reflects a higher relative likelihood of prevalent CRC at the time of the FIT/FOBT in the 1- to 3-month group. Some of these individuals may have had additional symptoms concurrent with or after the abnormal FIT, prompting rapid colonoscopic follow-up.
      • Brenner H.
      • Hoffmeister M.
      • Stegmaier C.
      • et al.
      Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 840,149 screening colonoscopies.
      Although these differences appear small in absolute terms, the findings are clinically important due to the large number of individuals in the United States who undergo stool-based CRC screening. Conversely, the increased incidence at 13 to 15 months and later most likely represents FIT/FOBT detection of advanced adenomas that transitioned to CRC in the interval between the abnormal FIT/FOBT result and colonoscopy, or cancers that were early and asymptomatic, and thus less likely to prompt more rapid follow-up. That the risk of CRC incidence was not significantly increased at 10 to 12 months further supports this hypothesis and the tumorigenesis model. Patients with a nonadvanced adenomatous polyp at the time of abnormal FIT/FOBT may have required a longer dwell time than 10 to 12 months to transition to CRC.
      • Brenner H.
      • Hoffmeister M.
      • Stegmaier C.
      • et al.
      Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 840,149 screening colonoscopies.
      Given the relatively low estimated rate of adenoma to cancer progression, this group may also represent polyps that do not transition to CRC, as well as false positive FIT results and abnormal results that result from non-neoplastic lesions (ie, hemorrhoids) in the lower gastrointestinal tract.
      • Robertson D.J.
      • Lee J.K.
      • Boland C.R.
      • et al.
      Recommendations on fecal immunochemical testing to screen for colorectal neoplasia: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer.
      ,
      • Brenner H.
      • Hoffmeister M.
      • Stegmaier C.
      • et al.
      Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 840,149 screening colonoscopies.
      Our mortality findings coincide with the incidence results. Risk of mortality was elevated at 19 months after abnormal FIT/FOBT, which suggests less advanced neoplasia at the time of FIT/FOBT and stage migration in the interval between the abnormal FIT and colonoscopy. These findings are supported by our secondary analyses by stage and by prior studies that assessed stage at diagnosis but that were not able to evaluate a mortality outcome.
      • Corley D.A.
      • Jensen C.D.
      • Quinn V.P.
      • et al.
      Association between time to colonoscopy after a positive fecal test result and risk of colorectal cancer and cancer stage at diagnosis.
      ,
      • Beshara A.
      • Ahoroni M.
      • Comanester D.
      • et al.
      Association between time to colonoscopy after a positive guaiac fecal test result and risk of colorectal cancer and advanced stage disease at diagnosis.
      Beyond 16 months, there was increased odds for advanced stage, and this relationship was stronger as time to colonoscopy increased. As with incidence, patients with an abnormal FIT/FOBT caused by a slowly progressing polyp, nonprogressing polyp, or non-neoplastic lesion likely represent the group that do not develop a CRC or death endpoint at 4 to 18 months or beyond 24 months. A lag between CRC incidence and CRC-related mortality is consistent with the CRC tumorigenesis model. The absence of significant findings for patients who underwent colonoscopy >24 months after abnormal FIT/FOBT likely reflects a large and heterogeneous group of patients who did not have an abnormal FIT/FOBT due to a polyp or malignancy, who had an abnormal FIT/FOBT due to a nonprogressive adenoma, or who underwent colonoscopy for a reason other than the abnormal FIT/FOBT result years later. This interpretation is subject to potential survivor bias given that we were only able to study outcomes for individuals who survived to at least 24 months after abnormal FIT/FOBT. However, prevalent CRC or premalignant advanced adenomas at the time of an abnormal FIT/FOBT would have likely become apparent before 24 months. In addition, a lower percentage of advanced CRC (Table 3) is supportive of these explanations.
      Currently, there is no national policy or standard for the clinically acceptable time interval between an abnormal FIT/FOBT result and diagnostic colonoscopy. Time to colonoscopic follow-up varies widely in practice and across health care settings.
      • Gellad Z.F.
      • Almirall D.
      • Provenzale D.
      • et al.
      Time from positive screening fecal occult blood test to colonoscopy and risk of neoplasia.
      ,
      • May F.
      • Yano E.M.
      • Provenzale D.
      • et al.
      Barriers to follow-up colonoscopies for patients with positive results from fecal immunochemical tests during colorectal cancer screening.
      ,
      • Doubeni C.A.
      • Gabler N.B.
      • Wheeler C.M.
      • et al.
      Timely follow-up of positive cancer screening results: A systematic review and recommendations from the PROSPR Consortium.
      ,
      • Robertson D.J.
      • Lee J.K.
      • Boland C.R.
      • et al.
      Recommendations on fecal immunochemical testing to screen for colorectal neoplasia: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer.
      • Miglioretti D.L.
      • Rutter C.M.
      • Bradford S.C.
      • et al.
      Improvement in the diagnostic evaluation of a positive fecal occult blood test in an integrated health care organization.
      • Issaka R.B.
      • Singh M.H.
      • Oshima S.M.
      • et al.
      Inadequate utilization of diagnostic colonoscopy following abnormal FIT results in an integrated safety-net system.
      • Correia A.
      • Rabeneck L.
      • Baxter N.N.
      • et al.
      Lack of follow-up colonoscopy after positive FOBT in an organized colorectal cancer screening program is associated with modifiable health care practices.
      • Chubak J.
      • Garcia M.P.
      • Burnett-Hartman A.N.
      • et al.
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      • Partin M.R.
      • Burgess D.J.
      • Burgess Jr., J.F.
      • et al.
      Organizational predictors of colonoscopy follow-up for positive fecal occult blood test results: an observational study.
      • Fisher D.A.
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      • et al.
      Barriers to full colon evaluation for a positive fecal occult blood test.
      Although data from our study and others suggest that the largest burden of CRC cases and deaths occur when colonoscopy is delayed several months after abnormal FIT/FOBT, we do not interpret these results to suggest that it is clinically appropriate to wait over a year for colonoscopic follow-up after abnormal FIT/FOBT. A recommended interval that is too long can contribute to polyp progression and stage migration of CRC, risking the need for more aggressive and morbid treatment, as well as less favorable outcomes. However, too short of a time interval could place undue burden on the patient and health care system. Thus, we feel that the strategy should be to intervene with colonoscopy well before 13 months and closer to 6 months after abnormal FIT. One systematic review and consortium has recommended setting a goal of 3 months and avoiding a delay of more than 6 months.
      • Doubeni C.A.
      • Gabler N.B.
      • Wheeler C.M.
      • et al.
      Timely follow-up of positive cancer screening results: A systematic review and recommendations from the PROSPR Consortium.
      Notably setting a goal of follow-up within 30 days likely contributed to the very high follow-up rates achieved by a large integrated health care system.
      • Selby K.
      • Jensen C.D.
      • Zhao W.K.
      • et al.
      Strategies to improve follow-up after positive fecal immunochemical tests in a community-based setting: a mixed-methods study.
      Establishing national recommendations on follow-up intervals and requiring health systems to measure, monitor, and report FIT/FOBT follow-up rates will help address national variation in FIT/FOBT follow-up rates. Although CRC screening is a Healthcare Effectiveness Data and Information Set measure, there is currently no requirement to report follow-up of abnormal screening. As FIT/FOBT is a 2-step process that is not truly complete for individuals with abnormal results until screening is completed with a follow-up colonoscopy, there should also be Healthcare Effectiveness Data and Information Set or similar quality metrics to make health systems accountable for follow-up.
      There were many strengths to this study. The analyses included a racially and ethnically diverse sample of 204,733 patients with abnormal FIT/FOBT results resulting in 6906 CRC cases and 1709 CRC-related deaths over 16 years. The study size far exceeds prior studies that have examined the association between time to colonoscopy and CRC outcomes among patients with abnormal stool-based CRC screening results. In addition, we used validated approaches to capture both colonoscopy and CRC outcome data. Our study is also the first that we are aware of in the United States to examine the relationship between time to colonoscopy and CRC-related mortality in individuals with abnormal CRC stool blood test results. The work will inform guidelines and standard of care for patients who undergo stool-based CRC screening. This guidance is especially relevant now in the setting of the COVID-19 pandemic and recommendations to increase use of noncolonoscopic screening modalities.
      • Brooks D.
      • Issaka R.
      • Itzkowitz S.
      • et al.
      Reigniting colorectal cancer screening as communities face and respond to the COVID-19 pandemic: a playbook.
      Our findings emphasize the importance of colonoscopic follow-up and a need for attention to time to follow-up to avoid excess deaths from CRC during this time of limited access.
      This study is not without limitations. First, our findings may be less generalizable to non-VA settings and to women given the largely male VA study population. However, the VA is one of few health systems in the United States that provides access to a patient population of adequate size and data to perform these analyses. It is also reassuring that the absolute number of women included in the study was substantial (n = 5453), especially compared with previous studies and the general lack of data on women. Second, despite including data on probable confounders, there is the potential for residual and unmeasured confounding in this retrospective cohort study. Third, we restricted our analyses to veterans who had a follow-up colonoscopy in the VA.
      In conclusion, among US veterans age 50 to 75 with an abnormal FIT/FOBT result, increased time to colonoscopy was significantly associated with CRC incidence, late-stage CRC, and CRC-related mortality. These findings extend current knowledge about the clinical implications of time to diagnostic follow-up after abnormal FIT/FOBT. Further work should include interventions that address barriers to uptake of diagnostic colonoscopy after abnormal noncolonoscopic screening results and policies to encourage the routine measuring and monitoring of follow-up rates.

      Acknowledgments

      The authors acknowledge Hanin Yassin, BS, for assistance with preparation of this submission.

      CRediT Authorship Contributions

      Yazmin San Miguel, MPH (Data curation: Lead; Formal analysis: Lead; Methodology: Equal; Validation: Equal; Visualization: Equal; Writing – original draft: Lead; Writing – review & editing: Equal).
      Joshua Demb, PhD, MPH (Formal analysis: Lead; Methodology: Lead; Supervision: Supporting; Visualization: Equal; Writing – original draft: Equal; Writing – review & editing: Equal).
      Maria Elena Martinez, PhD (Formal analysis: Equal; Funding acquisition: Lead; Methodology: Equal; Resources: Lead; Writing – original draft: Equal; Writing – review & editing: Equal).
      Samir Gupta, MD, MSCS (Conceptualization: Lead; Formal analysis: Lead; Funding acquisition: Lead; Methodology: Lead; Resources: Lead; Supervision: Lead; Visualization: Equal; Writing – original draft: Equal; Writing – review & editing: Lead).
      Folasade Popoola May, MD, PhD, MPhil (Conceptualization: Lead; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Project administration: Lead; Resources: Supporting; Supervision: Equal; Validation: Lead; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Lead).

      Supplementary Material

      Supplementary Table 1Current Procedural Terminology Codes Used to Identify Colonoscopy
      CodeDefinition
      44388Colonoscopy through stoma; diagnostic, including collection of specimen(s) by brushing or washing, when performed (separate procedure)
      44389Colonoscopy through stoma; with biopsy, single or multiple
      44390Colonoscopy through stoma; with removal of foreign body
      44391Colonoscopy through stoma; with control of bleeding (eg, injection, bipolar cautery, unipolar cautery, laser, heater probe, stapler, plasma coagulator)
      44392Colonoscopy through stoma; with removal of tumor(s), polyp(s), or other lesion(s) by hot biopsy forceps or bipolar cautery
      44393Colonoscopy through stoma; with ablation of tumor(s), polyp(s), or other lesion(s) not amenable to removal by forceps, cautery or snare
      44394Colonoscopy through stoma; with removal of tumor(s), polyp(s), or other lesion(s) by snare technique
      44397Colonoscopy through stoma; with transendoscopic stent placement (includes predilation)
      44401Colonoscopy through stoma; with ablation of tumor(s), polyp(s), or other lesion(s) (includes pre-and post-dilation and guide wire passage)
      44402Colonoscopy through stoma; with endoscopic stent placement (including pre- and post-dilation and guide wire passage, when performed)
      44403Colonoscopy through stoma; with endoscopic mucosal resection
      44404Colonoscopy through stoma; with directed submucosal injection(s), any substance
      44405Colonoscopy through stoma; with transendoscopic balloon dilation
      44406Colonoscopy through stoma; with endoscopic ultrasound examination, limited to the sigmoid, descending, transverse, or ascending colon and cecum
      44407Colonoscopy through stoma; with transendoscopic ultrasound guided intramural/transmural fine needle aspiration/biopsy(s)
      45355Colonoscopy, rigid or flexible, transabdominal via colotomy, single or multiple
      45378Colonoscopy, flexible, proximal to splenic flexure; diagnostic, with or without collection of specimen(s) by brushing or washing
      45379Colonoscopy, flexible, proximal to splenic flexure; with removal of foreign body
      45380Colonoscopy, flexible, proximal to splenic flexure; with biopsy, single or multiple
      45381Colonoscopy, flexible; with directed submucosal injection(s), any substance submucosal injection(s), any substance
      45382Colonoscopy, flexible; with control of bleeding, any method bleeding (eg, injection, cautery, laser, heater probe, stapler, plasma coagulator)
      45383Colonoscopy, flexible, proximal to splenic flexure; with ablation of tumors, polyps, or other lesions not removable by forceps, cautery or snare
      45384Colonoscopy, flexible; with removal of tumor(s), polyp(s), or other lesion(s) by hot biopsy forceps cautery
      45385Colonoscopy, flexible; with removal of tumor(s), polyp(s), or other lesion(s) by snare technique
      45386Colonoscopy, flexible; with transendoscopic balloon dilation balloon, 1 or more strictures
      45387Colonoscopy, flexible, proximal to splenic flexure; with transendoscopic stent placement (includes predilation)
      45388Colonoscopy, flexible; with ablation of tumor(s), polyp(s), or other lesion(s) (includes pre- and post-dilation and guide wire passage, when performed)
      45389Colonoscopy, flexible; with endoscopic stent placement (includes pre- and post-dilation and guide wire passage, when performed)
      45390Colonoscopy, flexible; with endoscopic mucosal resection
      45391Colonoscopy, flexible, proximal to splenic flexure; with endoscopic ultrasound examination
      45392Colonoscopy, flexible, proximal to splenic flexure; with transendoscopic ultrasound guided intramural or transmural fine needle aspiration/biopsy(s)
      45393Colonoscopy, flexible; with decompression (for pathologic distention) (eg, volvulus, megacolon), including placement of decompression tube
      45398Colonoscopy, flexible; with band ligation(s) (eg, hemorrhoids)
      G0105Colorectal cancer screening; colonoscopy on individual at high risk
      G0121Colorectal cancer screening; colonoscopy on individual not meeting criteria for high risk
      G6019Colonoscopy through stoma; with ablation of tumor(s), polyp(s), or other lesion(s) not amenable to removal by forceps, cautery or snare
      G6020Colonoscopy through stoma; with transendoscopic stent placement (includes predilation)
      G6024Colonoscopy, flexible; proximal to splenic flexure; with ablation of tumors, polyps, or other lesions not removable by forceps, cautery or snare
      G6025Colonoscopy, flexible, proximal to splenic flexure; with transendoscopic stent placement (includes predilation)
      Figure thumbnail fx2
      Supplementary Figure 1Rates of incident CRC, late-stage CRC, and fatal CRC stratified by time to colonoscopy after abnormal FIT/FOBT, 1999-2015.

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