Clinical trial NCT00032344: Long-term Follow-up Study Designed to Evaluate the Relative Risk of Two Colonoscopy Schedules for Patients With Small Polyps
Official title: CSP #380 - Prospective Evaluation of Risk Factors for Large (> 1 CM) Colonic Adenomas in Asymptomatic Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: large (>1 cm) adenomas
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2002-03-19
Enrollment: 3200
Sex: ALL
Minimum age (years): 50
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief 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.

Eligibility criteria: Inclusion Criteria:

Study Complete

Exclusion Criteria:

Primary outcomes:
measure: Phase I: Risk factors include: family history; dietary; fat, fiber, calcium; alcohol history; tobacco use; physical activity; obesity; NSAID use; and, biomarkers: BRDU, PCNA
timeFrame: Cross-sectional
Secondary outcomes:
measure: Phase II: Colonoscopy outcomes to determine recurrence rates and compare surveillance strategies
timeFrame: 5 years
measure: Phase III: Medical outcomes including mortality. Colonoscopy outcomes in subgroup of polyp free patient at baseline to determine long term risk.
timeFrame: 10 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Carl T. Hayden VA Medical Center
state: Arizona
city: Tucson
country: United States
facility: Southern Arizona VA Health Care System, Tucson
state: Arizona
city: Long Beach
country: United States
facility: VA Medical Center, Long Beach
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System
state: California
city: San Francisco
country: United States
facility: VA Medical Center, San Francisco
state: California
city: Denver
country: United States
facility: VA Eastern Colorado Health Care System, Denver
state: Colorado
city: Hines
country: United States
facility: Edward Hines, Jr. VA Hospital
state: Illinois
city: Minneapolis
country: United States
facility: VA Medical Center, Minneapolis
state: Minnesota
city: Kansas City
country: United States
facility: VA Medical Center, Kansas City MO
state: Missouri
city: Durham
country: United States
facility: VA Medical Center, Durham
state: North Carolina
city: Portland
country: United States
facility: VA Medical Center, Portland
state: Oregon
city: Dallas
country: United States
facility: VA North Texas Health Care System, Dallas
state: Texas
city: White River Junction
country: United States
facility: VA Medical & Regional Office Center, White River
state: Vermont
Study officials:
affiliation: VA Medical Center, Portland
name: David Lieberman, MD
role: STUDY_CHAIR
References:
citation: Schreiner MA, Weiss DG, Lieberman DA. Proximal and large hyperplastic and nondysplastic serrated polyps detected by colonoscopy are associated with neoplasia. Gastroenterology. 2010 Nov;139(5):1497-502. doi: 10.1053/j.gastro.2010.06.074. Epub 2010 Jul 13.