Long-term Follow-up Study Designed to Evaluate the Relative Risk of Two Colonoscopy Schedules for Patients With Small Polyps
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Study type: Interventional
Phase: Phase 3

Summary: 
      Colorectal cancer is a leading cause of cancer death in the United States. Mortality remains
      high because most colorectal cancers are detected after there has been regional or distant
      spread, precluding curative surgical resection. With this in mind, screening strategies have
      been recommended for asymptomatic individuals which hope to reduce mortality from colon
      cancer by detecting and removing premalignant adenomatous polyps or early malignant lesions.
      Screening of asymptomatic individuals over age 50 with sigmoidoscopy and fecal occult blood
      tests has been advocated by the American Cancer Society. However, current screening will
      identify only 50% of patients who have adenomatous polyps. More sensitive tests for polyp
      detection, like colonoscopy, are costly, require extensive resources and are unlikely to be
      used for screening large populations. Ideal screening would identify patients with the
      highest risk of cancer and target more sensitive screening tests at this population. The
      identification of low cost, easily collectible risk factors which can be used to target
      patients for the more sensitive screening tests is the primary purpose of this study. Since a
      major segment of the veteran population is over the age of 50, there will be a substantial
      impact in reduction of both mortality and morbidity due to colon cancer and attendant cost
      savings to the VA for treatment if such risk factors can be identified.

      Phase I is a cross-sectional study designed to identify risk factors for large (>1 cm)
      adenomatous polyps. Approximately 3200 asymptomatic subjects (age 50-75) have completed risk
      factor assessment, medical and dietary histories, and have undergone complete colonoscopy
      examination. This will identify for comparison purposes a polyp-free control group and is the
      first large prospective study to include such a group. Data at colonoscopy will characterize
      the prevalence, size and distribution of adenomatous polyps. This will permit an assessment
      of sensitivity of sigmoidoscopy in this population. In addition, tissue from normal rectal
      mucosa will be analyzed for evidence of cell proliferation activity. The primary focus of
      Phase I is a risk factor analysis. A multivariate analysis will be performed to determine the
      relationship of historical and environmental factors as well as cell proliferation activity
      with the presence of adenomatous polyps. A cohort consisting of a subgroup of polyp patients
      (large and small) and matched polyp-free controls will be tracked longitudinally to determine
      polyp occurrence/recurrence rates.

      Phase II of the study is a long-term follow-up study designed to evaluate the relative risk
      of two repeat colonoscopies.

      Phase III is an extension in follow-up of an additional five years, a total of ten years in
      all, to include all study patients. The primary focus will be on documenting long-term
      mortality and medical outcomes as well as occurrence/reoccurrence of neoplasia with special
      emphasis on ten-year cancer rates.
    

Detailed description: 
      Primary Hypothesis: Risk factors can be determined for large (>1 cm) adenomas, precursor
      lesions for colorectal cancer.

      Secondary Hypothesis: Determine long-term rates for development or recurrence of polyps;
      determine sensitivity/specificity of current colon cancer screening strategies; determine
      relationship of dietary factors and biomarkers of cell proliferation; determine the efficacy
      and safety of long-term (5 years) repeat colonoscopy in patients with small polyps.

      Intervention: Phase I: All patients undergo full colonoscopy. Phase II: Randomization to
      repeat colonoscopy at 2-3 years and 5 years after baseline, or, repeat colonoscopy at 5 years
      only. Phase III: Ten-year follow-up on all Phase I patients for medical outcomes. Repeat
      colonoscopy at 10 years on polyp-free patients (Phase I) aged 50-64.

      Primary Outcomes: Presence of risk factors and adenomatous polyps including prevalence,
      descriptive characteristics, and long-term occurrence/recurrence rates.

      Study Abstract: Phase I is a cross-sectional study designed to identify risk factors for
      large (>1 cm) adenomatous polyps. Approximately 3200 asymptomatic subjects (age 50-75) have
      completed risk factor assessment, medical and dietary histories, and have undergone complete
      colonoscopy examination. This will identify for comparison purposes a polyp-free control
      group and is the first large prospective study to include such a group. Data at colonoscopy
      will characterize the prevalence, size and distribution of adenomatous polyps. This will
      permit an assessment of sensitivity of sigmoidoscopy in this population. In addition, tissue
      from normal rectal mucosa will be analyzed for evidence of cell proliferation activity. The
      primary focus of Phase I is a risk factor analysis. A multivariate analysis will be performed
      to determine the relationship of historical and environmental factors as well as cell
      proliferation activity with the presence of adenomatous polyps. A cohort consisting of a
      subgroup of polyp patients (large and small) and matched polyp-free controls will be tracked
      longitudinally to determine polyp occurrence/recurrence rates.

      Phase II of the study is a long-term follow-up study designed to evaluate the relative risk
      of two repeat colonoscopy schedules for patients with small polyps identified in Phase I of
      the study. Recruitment is complete with 615 patients eligible (of the target 808) assigned at
      random to either repeat colonoscopy at 2-3 years and 5 years, or to repeat colonoscopy at 5
      years only. This phase will also provide preliminary longitudinal risk factor information
      related to occurrence/recurrence of polyps.

      Phase III was a 5-year extension of follow-up period. All Phase I patients were to be
      reconsented to provide medical outcome data for a period of 10 years from baseline exam.
      Phase I patients polyp-free, aged 50-64 will be offered repeat colonoscopy at 10 years to
      evaluate long-term risk.

      Results (Phase I): 3121 patients had complete colonoscopy which revealed high rates of
      neoplasia: 37.5% had one or more neoplastic lesions; 10.5% had advanced neoplasia including
      30 cases of invasive cancer (1%). There were 3.7% of patients with no lesions in the rectum
      or sigmoid colon who had advanced neoplasia elsewhere in the colon: 32% of all patients with
      advanced neoplasia would not be detected with an exam of the rectum or sigmoid colon
      (distal); 62% of patients with proximal advanced neoplasia would not be detected with an exam
      of the rectum and sigmoid colon. There were few serious complications (0.3%).

      The one-time fecal occult blood test (FOBT) was evaluated as a diagnostic test for advanced
      neoplasia. A positive FOBT indicated an increased likelihood (3-4x) of advanced neoplasia.
      However, one-time FOBT failed to detect 75% of patients with advanced neoplasia.

      The primary analysis of risk factors (Phase I) found positive associations (for advanced
      neoplasia) for history of a first degree relative with colorectal cancer (OR, 1.66; 95% CI,
      1.16-2.35), current smoking (OR, 1.85; 95% CI, 1.33-2.58), and current moderate to heavy
      alcohol use (OR, 1.02, 95% CI, 1.01-1.03). Inverse associations were found for cereal fiber
      intake (OR, 0.95, 95% CI, 0.91-0.99), vitamin D intake (OR, 0.94, 95% CI, 0.90-0.99), and use
      of NSAIDs (OR, 0.66, 95% CI, 0.48-0.91). Results appeared in JAMA (2003;290:2959-2967).

      Phase III is completed with patients completing their scheduled follow-ups. A major
      manuscript on the sensitivity/specificity of digital rectal exam appeared in Annals of
      Internal Medicine January, 2005. The Phase II results manuscript appeared in Gastroenterology
      in October 2007.
    

Intervention name(s): Colonoscopy
Intervention type(s): Procedure
Intervention description(s): Phase I - Cross-sectional; Phase II - 5 year follow-up; Phase III - 10 year follow-up
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: large (>1 cm) adenomas