Screening Tests in Detecting Colorectal Cancer

Primary objectives:

1. To compare the performance characteristics (sensitivity, specificity, predictive
values) of the fecal MTAP and most widely-used fecal occult blood test (Hemoccult) for
identification of screen-relevant colorectal neoplasia (curablestage cancer and
advanced adenomas with high-grade dysplasia/carcinoma in situ or size ≥ 1.0 cm.)

2. To evaluate the necessity of formal pretest preparation for MTAP by comparing the
specificity of both the MTAP and Hemoccult tests in subject groups randomized to
pre-test preparation versus no pre-test preparation.

Secondary objectives:

1. To compare detection rates of colorectal neoplasia by the fecal MTAP alone with those
by flexible sigmoidoscopy (distal 60 cm of colonoscopic examination to serve as
surrogate) and by the combination of sigmoidoscopy plus Hemoccult.

2. To characterize and compare the pathological and molecular features of screen-relevant
colorectal neoplasms detected and not detected by the fecal MTAP.

3. To explore the sensitivity and specificity of the MTAP applied to plasma for the
detection of screen-relevant colorectal neoplasia.

4. To maintain a specimen bank comprising stools and blood (plasma) from all subjects and
tissue from screen-relevant neoplasms.

OUTLINE: This is a randomized, multicenter study. Participants are stratified according to
age (50-64 [closed to accrual as of 6/5/03] vs 65-80), gender (male vs female), and
participating center. Participants are randomized to one of two screening arms.

- Arm I: Participants eat no red meat and take no nonsteroidal anti-inflammatory drugs
(NSAIDs) and no vitamin C or multivitamins for 3 days prior to and during stool sample
collection. Participants collect stool samples 3 different times and perform fecal
occult blood (FOB) test smears from each stool. After each collection, participants
ship the whole stool and FOB test smear to their participating center for blinded
multitarget DNA-based assay panel (MTAP) testing.

- Arm II: Participants take no vitamin C or multivitamins for 3 days before and during
stool sample collection. Participants collect stool samples and FOB test smears and
samples are tested as in arm I.

Within 2 months after stool sample collection, participants have their blood drawn for
additional MTAP testing and undergo colonoscopy.

PROJECTED ACCRUAL: A total of 4,000 participants (2,000 per arm) will be accrued for this
study.

Required Characteristics:

1. ≥ 65 and ≤ 80 years of age.

2. Females must be postmenopausal (absence of menstrual periods for at least one year;
patients on regular hormone replacement therapy; surgical intervention).

Contraindications:

1. FOBT screening ≤1 year prior to randomization.

2. Structural colorectal evaluation (i.e. colonoscopy, colon x-ray, or sigmoidoscopy)
≤10 years prior to randomization.

3. Overt rectal bleeding (hematochezia or melena) ≤1 month prior to randomization.

4. Prior colorectal resection for any reason.

5. Inability to stop therapeutic doses of NSAIDs (prophylactic doses of aspirin (≤325
mg) allowed [121] and Cox2 inhibitors (i.e. Celebrex, Vioxx) allowed.)

6. Coagulopathy or inablitity to discontinue anticoagulants (discontinuation must be
superviesed by a physician).

7. Aerodigestive cancer ≤5 years prior to randomization.

8. Contraindications to colonoscopy (e.g., serious cardiopulmonary disease).

9. High-risk conditions for colorectal cancer (familial adenomatous polyposis,
hereditary nonpolyposis colorectal cancer syndrome, other hereditary cancer
syndromes, prior colorectal cancer or adenoma, inflammatory bowel disease, and

- 2 first-degree relatives with colorectal cancer).

10. Chemotherapy ≤ 3 months prior to registration.