Colon Cancer, Precancerous Condition, Rectal Cancer
Conditions
Brief summary
This randomized phase II trial is studying atorvastatin calcium to see how well it works compared to oligofructose-enriched inulin, sulindac, or a placebo in preventing cancer in patients at increased risk of developing colorectal neoplasia. Chemoprevention is the use of certain drugs or substances to keep cancer from forming, growing, or coming back. The use of atorvastatin calcium, oligofructose-enriched inulin, or sulindac may stop cancer from forming in patients at increased risk of colorectal neoplasia. It is not yet known whether atorvastatin calcium, oligofructose-enriched inulin, or sulindac are more effective than a placebo in preventing cancer in patients at increased risk of developing colorectal neoplasia.
Detailed description
PRIMARY OBJECTIVE: I. Percent change in number of rectal aberrant cryptic foci (ACF) as measured by magnification chromoendoscopy SECONDARY OBJECTIVES: I. Screening for possible phase III testing II. Effects on proliferation (Ki67 expression) and apoptosis (caspase-3 expression) as measured by biopsy samples obtained from normal-appearing rectal mucosa at baseline and after completion of study treatment III. Correlation of endoscopic features with histologic characteristics of rectal ACF IV. Observation of the natural history of rectal ACF in patients receiving placebo V. Adverse events VI. Utilization of a biospecimen repository archive OUTLINE: This is a multicenter, prospective, randomized, partially blinded, placebo-controlled study. Patients are stratified according to history of prior surgical resection of the colon (yes vs no) and number of rectal aberrant cryptic foci (ACF) (5-9 vs \>= 10). Patients are randomized to 1 of 4 treatment arms. ARM I: Patients receive oral atorvastatin calcium once daily. ARM II: Patients receive oral sulindac twice daily. ARM III (blinded arm): Patients receive oral oligofructose-enriched inulin (Raftilose Synergy 1) twice daily. ARM IV (blinded arm): Patients receive an oral placebo twice daily. In all arms, treatment continues for 6 months in the absence of unacceptable toxicity. Tissue samples are collected at baseline and at the completion of study treatment. Tissue is examined by immunohistochemistry for proliferation (Ki67) and apoptosis (cleaved caspase-3). After completion of study treatment, patients are followed at approximately 30 days.
Interventions
DRUGoligofructose-enriched inulin
Given orally
DRUGsulindac
Given orally
DRUGplacebo
Given orally
DRUGatorvastatin calcium
Given orally
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Criteria: * ECOG performance status 0-2 * Platelet count \>= 100,000/mm\^3 * Fertile patients must agree to use effective contraception * No history of inflammatory bowel disease (i.e., Crohn's disease or ulcerative colitis) * No invasive malignancy within the past 5 years except nonmelanoma skin cancer or colorectal cancer * No history of endoscopically-confirmed peptic ulcer disease * No history of allergic reactions attributed to compounds of similar chemical or biological composition to the study agents * No history of chronic liver disease or unexplained persistent elevations of serum transaminases * No history of allergic-type reactions, including asthma or urticaria, to aspirin or NSAIDs * No uncontrolled intercurrent illness including, but not limited to, any of the following: * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness or social situations that would preclude study compliance * At least 6 weeks since prior oral corticosteroids * Creatinine =\< 1.5 times ULN * Creatine phosphokinase =\< 1.5 times ULN * Not pregnant or nursing * At least 6 weeks since prior statins * At increased risk for developing sporadic colorectal neoplasia, as defined by 1 of the following: * History of colon cancer (excluding stage IV or Dukes' D tumors) * Must have completed prior adjuvant therapy for colon cancer \>= 12 months ago * History of colorectal adenomas, meeting any of the following criteria: * \>= 1 cm in diameter * \>= 3 in total number * Any component of villous morphology * High-grade dysplasia * At least 5 rectal aberrant cryptic foci (ACF), by magnification chromoendoscopy, meeting both of the following criteria: * At least 5 aggregated crypts in a single grouping (maximum spacing between crypts must be =\< 2 times the average crypt diameter) * Crypt diameter \>= 1.5 times the diameter of surrounding normal crypts * No history of rectal cancer, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer * Negative pregnancy test * At least 6 months since prior and no concurrent regular use\* of nonsteroidal anti-inflammatory drugs\*\* (NSAIDs) or statins * Concurrent aspirin at cardioprotective doses (=\< 162.5 mg/day or 325 mg every other day) allowed * No prior rectal surgery involving mucosal resection * No prior pelvic radiation therapy * No concurrent regular use\* of cyclooxygenase-2 inhibitors * No concurrent anticoagulant drugs (i.e., warfarin, heparin, clopidogrel bisulfate, or extended-release dipyridamole) * No concurrent use of any of the following: * Fibrates (e.g., gemfibrozil or fenofibrate) * Cyclosporine * Erythromycin or macrolide antibiotics * Protease inhibitors * Azole antifungals * Diltiazem * Verapamil * Compounds containing niacin or nicotinic acid * Defined as 7 consecutive days for \> 3 weeks OR \> 21 days total during study participation * Patients may be eligible for study treatment after discontinuing NSAIDs for 12 weeks, at the discretion of their health care provider * No other concurrent investigational agents * No planned (or likely to require) clinically indicated colonoscopy or flexible sigmoidoscopy during study treatment * Bilirubin =\< 1.5 times ULN * Hemoglobin \>= lower limit of normal * AST =\< 1.5 times upper limit of normal (ULN) * Alkaline phosphatase =\< 1.5 times ULN
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Number of Rectal Aberrant Cryptic Foci (ACF) as Measured by Magnification Chromoendoscopy | 6 months | At the Pre-Intervention Evaluation, rectal ACF will be classified with respect to ACF number, crypt number, crypt size, tissue plane, staining intensity, and (optional) lumen shape for each subject. At the Post- Intervention Evaluation, these same parameters will be recorded and incident vs prevalent rectal ACF status will also be recorded. Compare each non-placebo arms versus the placebo arm to screen the three active study agents for possible phase III testing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effects on Proliferation (Ki67 Expression). | Up to 6 months | Tissue is examined by immunohistochemistry for Ki67. Measured by biopsy samples obtained from normal-appearing rectal mucosa at baseline and after completion of study treatment. Wilcoxon will be used to assess significant differences between the intervention arms. |
| Effects on Apoptosis (Caspase-3 Expression). | Up to 6 months | Tissue is examined by immunohistochemistry for cleaved caspase-3. Measured by biopsy samples obtained from normal-appearing rectal mucosa at baseline and after completion of study treatment. Wilcoxon will be used to assess significant differences between the intervention arms. |
| Adverse Events. | Up to 30 days after completion of study treatment | Defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with participation in a study, whether or not related to that participation. Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 3.0. Number of adverse events per grade level. |
Countries
United States
Participant flow
Recruitment details
142 subjects were pre-registered through 10 Cancer Prevention Network (CPN) member organizations from April 2006 to August 2008.
Pre-assignment details
57 subjects were excluded from the trial before assignment to groups: 13 did not have baseline Magnification chromoendoscopy (MCE), 33 had \< 5 rectal ACF, 8 did not meet eligibility criteria, and 3 were withdrawn.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Atorvastatin Calcium) Patients receive 20 mg tablet oral atorvastatin once daily. | 22 |
| Arm II (Sulindac) Patients receive 150 mg tablet oral sulindac twice daily. | 21 |
| Arm III (Oligofructose-enriched Inulin) Patients receive 6gm powder oral oligofructose-enriched inulin (Raftilose Synergy 1) twice daily. | 20 |
| Arm IV (Placebo) Patients receive an oral placebo (maltodextrin powder) twice daily. | 22 |
| Total | 85 |
Baseline characteristics
| Characteristic | Arm I (Atorvastatin Calcium) | Arm II (Sulindac) | Arm III (Oligofructose-enriched Inulin) | Arm IV (Placebo) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 61 Years | 55 Years | 64 Years | 57 Years | 58 Years |
| Gender Female | 5 Participants | 9 Participants | 8 Participants | 7 Participants | 29 Participants |
| Gender Male | 17 Participants | 12 Participants | 12 Participants | 15 Participants | 56 Participants |
| History of Surgical Resection No | 15 participants | 15 participants | 14 participants | 16 participants | 60 participants |
| History of Surgical Resection Yes | 7 participants | 6 participants | 6 participants | 6 participants | 25 participants |
| Region of Enrollment United States | 22 participants | 21 participants | 20 participants | 22 participants | 85 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 22 | 14 / 21 | 12 / 20 | 19 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 21 | 0 / 20 | 0 / 22 |
Outcome results
Primary
Percent Change in Number of Rectal Aberrant Cryptic Foci (ACF) as Measured by Magnification Chromoendoscopy
At the Pre-Intervention Evaluation, rectal ACF will be classified with respect to ACF number, crypt number, crypt size, tissue plane, staining intensity, and (optional) lumen shape for each subject. At the Post- Intervention Evaluation, these same parameters will be recorded and incident vs prevalent rectal ACF status will also be recorded. Compare each non-placebo arms versus the placebo arm to screen the three active study agents for possible phase III testing.
Time frame: 6 months
Population: The population used for the analysis is patients having at least 5 rectal ACF and completing both the pre- and post-intervention MCE assessments and using intention to treat principles.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Atorvastatin Calcium) | Percent Change in Number of Rectal Aberrant Cryptic Foci (ACF) as Measured by Magnification Chromoendoscopy | 8.4 percent change in number of ACF | Standard Deviation 49.1 |
| Arm II (Sulindac) | Percent Change in Number of Rectal Aberrant Cryptic Foci (ACF) as Measured by Magnification Chromoendoscopy | -13.3 percent change in number of ACF | Standard Deviation 55.4 |
| Arm III (Oligofructose-enriched Inulin) | Percent Change in Number of Rectal Aberrant Cryptic Foci (ACF) as Measured by Magnification Chromoendoscopy | -8.8 percent change in number of ACF | Standard Deviation 49.2 |
| Arm IV (Placebo) | Percent Change in Number of Rectal Aberrant Cryptic Foci (ACF) as Measured by Magnification Chromoendoscopy | -8.6 percent change in number of ACF | Standard Deviation 48.8 |
Comparison: The study was designed to test the hypotheses of observing a 25% difference in % change ACF over baseline, between patients treated with atorvastatin compared to placebo. N=25 subjects per group yielded 93% power to detect this difference using a 2 sided t-test at significance level of 0.05. Non-parametric tests (eg, Wilcoxon Rank Sum) could be used if the statistical assumptions of the t-test were violated.p-value: 0.3Wilcoxon (Mann-Whitney)
Comparison: The study was designed to test the hypotheses of observing a 25% difference in % change ACF over baseline, between patients treated with sulindac compared to placebo. N=25 subjects per group yielded 93% power to detect this difference using a 2 sided t-test at significance level of 0.05. Non-parametric tests (eg, Wilcoxon Rank Sum) could be used if the statistical assumptions of the t-test were violated.p-value: 0.6Wilcoxon (Mann-Whitney)
Comparison: The study was designed to test the hypotheses of observing a 25% difference in % change ACF over baseline, between patients treated with oligofructose-enriched inulin compared to placebo. N=25 subjects per group yielded 93% power to detect this difference using a 2 sided t-test at significance level of 0.05. Non-parametric tests (eg, Wilcoxon Rank Sum) could be used if the statistical assumptions of the t-test were violated.p-value: 0.92Wilcoxon (Mann-Whitney)
Comparison: Signed Rank p-value for comparison of % change in ACF within each randomization arm.p-value: 0.59Sign test
Comparison: Signed Rank p-value for comparison of % change in ACF within each randomization arm.p-value: 0.12Sign test
Comparison: Signed Rank p-value for comparison of % change in ACF within each randomization arm.p-value: 0.54Sign test
Comparison: Signed Rank p-value for comparison of % change in ACF within each randomization arm.p-value: 0.41Sign test
Secondary
Adverse Events.
Defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with participation in a study, whether or not related to that participation. Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 3.0. Number of adverse events per grade level.
Time frame: Up to 30 days after completion of study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Atorvastatin Calcium) | Adverse Events. | Grade 3 | 2 adverse events |
| Arm I (Atorvastatin Calcium) | Adverse Events. | Grade 2 | 5 adverse events |
| Arm I (Atorvastatin Calcium) | Adverse Events. | Grade 1 | 11 adverse events |
| Arm II (Sulindac) | Adverse Events. | Grade 3 | 2 adverse events |
| Arm II (Sulindac) | Adverse Events. | Grade 1 | 12 adverse events |
| Arm II (Sulindac) | Adverse Events. | Grade 2 | 4 adverse events |
| Arm III (Oligofructose-enriched Inulin) | Adverse Events. | Grade 1 | 10 adverse events |
| Arm III (Oligofructose-enriched Inulin) | Adverse Events. | Grade 3 | 0 adverse events |
| Arm III (Oligofructose-enriched Inulin) | Adverse Events. | Grade 2 | 4 adverse events |
| Arm IV (Placebo) | Adverse Events. | Grade 2 | 13 adverse events |
| Arm IV (Placebo) | Adverse Events. | Grade 3 | 1 adverse events |
| Arm IV (Placebo) | Adverse Events. | Grade 1 | 15 adverse events |
Secondary
Effects on Apoptosis (Caspase-3 Expression).
Tissue is examined by immunohistochemistry for cleaved caspase-3. Measured by biopsy samples obtained from normal-appearing rectal mucosa at baseline and after completion of study treatment. Wilcoxon will be used to assess significant differences between the intervention arms.
Time frame: Up to 6 months
Population: Patients with assay data from baseline and post-intervention biopsy samples of normal-appearing rectal mucosa.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Atorvastatin Calcium) | Effects on Apoptosis (Caspase-3 Expression). | 106.0 Percent change of caspase-3 | Standard Deviation 140.3 |
| Arm II (Sulindac) | Effects on Apoptosis (Caspase-3 Expression). | 131.9 Percent change of caspase-3 | Standard Deviation 154.1 |
| Arm III (Oligofructose-enriched Inulin) | Effects on Apoptosis (Caspase-3 Expression). | 120.5 Percent change of caspase-3 | Standard Deviation 195.6 |
| Arm IV (Placebo) | Effects on Apoptosis (Caspase-3 Expression). | 130.6 Percent change of caspase-3 | Standard Deviation 81.8 |
Comparison: Wilcoxon Rank Sum p-value for comparison of % change in apoptosis between atorvastatin calcium and placebo.p-value: 0.26Wilcoxon (Mann-Whitney)
Comparison: Wilcoxon Rank Sum p-value for comparison of % change in apoptosis between sulindac and placebo.p-value: 0.88Wilcoxon (Mann-Whitney)
Comparison: Wilcoxon Rank Sum p-value for comparison of % change in apoptosis between oligofructose-enriched inulin and placebo.p-value: 0.38Wilcoxon (Mann-Whitney)
Secondary
Effects on Proliferation (Ki67 Expression).
Tissue is examined by immunohistochemistry for Ki67. Measured by biopsy samples obtained from normal-appearing rectal mucosa at baseline and after completion of study treatment. Wilcoxon will be used to assess significant differences between the intervention arms.
Time frame: Up to 6 months
Population: Patients with assay data from baseline and post-intervention biopsy samples of normal-appearing rectal mucosa.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Atorvastatin Calcium) | Effects on Proliferation (Ki67 Expression). | 6.5 Percent change | Standard Deviation 62.3 |
| Arm II (Sulindac) | Effects on Proliferation (Ki67 Expression). | 12.2 Percent change | Standard Deviation 52.8 |
| Arm III (Oligofructose-enriched Inulin) | Effects on Proliferation (Ki67 Expression). | 34.7 Percent change | Standard Deviation 70.6 |
| Arm IV (Placebo) | Effects on Proliferation (Ki67 Expression). | 13.6 Percent change | Standard Deviation 44.1 |
Comparison: Wilcoxon Rank Sum p-value for comparison of % change in Ki67 between atorvastatin and placebo.p-value: 0.37Wilcoxon (Mann-Whitney)
Comparison: Wilcoxon Rank Sum p-value for comparison of % change in Ki67 between sulindac and placebo.p-value: 1Wilcoxon (Mann-Whitney)
Comparison: Wilcoxon Rank Sum p-value for comparison of % change in Ki67 between oligofructose-enriched inulin and placebo.p-value: 0.58Wilcoxon (Mann-Whitney)