Colon Cancer, Precancerous Condition, Rectal Cancer
Conditions
Brief summary
This randomized phase II trial is studying how well aspirin works in preventing colorectal cancer in patients at increased risk of colorectal cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of aspirin may prevent colorectal cancer.
Detailed description
PRIMARY OBJECTIVE: I. Determine whether acetylsalicylic acid (aspirin) will alter spectral markers (i.e., spectral slope and fractal dimension) in distal colonic mucosa of patients who are at increased risk for the development or recurrence of colorectal cancer. SECONDARY OBJECTIVES: I. Assess the effect of this drug on colonic epithelial apoptosis and cell proliferation in these patients. II. Assess the effect of this drug on rectal prostaglandin levels in these patients. III. Assess the effect of this drug on platelet cyclooxygenase activity in these patients. IV. Correlate changes in spectral markers with UGT1A6 genotype in patients treated with this drug. OUTLINE: This is a multicenter, randomized, double-blind, placebo-controlled study. Patients are stratified by clinical site and adenoma/carcinoma maximal size. Patients with abnormal spectral biomarkers are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral acetylsalicylic acid (aspirin) once daily. ARM II: Patients receive oral placebo once daily. In both arms, treatment continues for 3 months in the absence of unacceptable toxicity. Patients undergo flexible sigmoidoscopy and biopsies as well as blood collection at baseline (during prestudy colonoscopy) and at completion of study treatment for comparison of spectral signatures with biomarkers of both aspirin activity (including plasma cyclooxygenase activity and rectal prostaglandin levels) as well as with biomarkers associated with antineoplastic alteration (including apoptosis and cell proliferation). UGT1A6 genotyping analysis is also performed. After completion of study treatment, patients are followed at 3 months.
Interventions
DRUGacetylsalicylic acid
Given orally
DRUGplacebo
Given orally
OTHERlaboratory biomarker analysis
Correlative study
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 75 Years
Healthy volunteers
No
Inclusion criteria
Criteria: * No active or metastatic cancer within the past 6 months * Scheduled to undergo colonoscopy for colonic neoplasia surveillance * Hemoglobin \>= 12.0 g/dL * Platelet count \>= 120,000/mm\^3 * AST or ALT =\< 1.5 times upper limit of normal (ULN) * Alkaline phosphatase =\< 1.5 times ULN * Bilirubin =\< 1.5 times ULN * BUN =\< 40 mg/dL * Glomerular filtration rate \>= 45 mL/min * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No coagulopathy * No anemia * No history of peptic ulcer disease or gastrointestinal hemorrhage * No history of cerebrovascular accident * No uncontrolled hypertension * No history of intolerance or allergy to aspirin or to NSAIDs * No liver disease as manifested by signs or symptoms of cirrhosis * No endoscopic or radiographic evidence of portal hypertension * No active colitis by endoscopy * No history of inflammatory bowel disease * No requirement for aspirin as medical therapy (i.e., post-myocardial infarction or transient ischemic attack) * No untreated helicobacter pylori infection * History of significant colonic neoplasia, defined as 1 of the following: * Adenoma within the past 6 years * Colorectal cancer within the past 6 years * Known adenoma on present exam * Histologically confirmed polyps seen on imaging * INR =\< 1.5 * At least 6 months since prior cancer treatment * No other concurrent acetylsalicylic acid (aspirin)-containing products or non-steroidal anti-inflammatory drugs (NSAIDs) * No concurrent systemic corticosteroids * No other concurrent anticoagulants or antiplatelet agents * No concurrent investigational drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Spectral Slope or SPEC) From Baseline to 3 Months. | 3 months from baseline colonoscopy to end of intervention. | Spectral marker assessment was performed via LEBS analysis (low-coherence enhanced backscattering spectroscopy) on the uninvolved mucosal biopsies of subjects taken at baseline and after 3 months of treatment with either aspirin or placebo. SPEC characterizes the size distribution of macromolecular complexes and other intracellular structures, with a decrease of the spectral slope implying a shift of the size distribution of intracellular structures toward smaller sizes. Spectral markers SPEC and FRAC provide a measure of the fundamental characteristics of the tissue nanoscale architecture. |
| Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Fractal Dimension or FRAC) From Baseline to 3 Months. | 3 months from baseline colonoscopy to end of intervention. | Spectral marker assessment was performed via LEBS analysis (low-coherence enhanced backscattering spectroscopy) on the uninvolved mucosal biopsies of subjects taken at baseline and after 3 months of treatment with either aspirin or placebo. FRAC characterizes the spatial autocorrelation function of mass density distribution in tissue. SPEC and FRAC provide a measure of the fundamental characteristics of the tissue nanoscale architecture |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Colonic Epithelial Apoptosis as Measured by Immunohistochemical Detection of Cleaved Caspase 3 | 3 months from baseline colonoscopy to end of intervention. | Evaluate the effect of aspirin on colonic epithelial apoptosis and cell proliferation as assessed by immunohistochemical detection of cleaved caspase 3 .These were performed on samples that had been previously analyzed for 4D-ELF. |
| Changes in Colonic Cell Proliferation as Measured by Immunohistochemical Detection of Ki67 | 3 months from baseline colonoscopy to end of intervention. | Evaluate the effect of aspirin on colonic epithelial apoptosis and cell proliferation as assessed by immunohistochemical detection of Ki-67. These were performed on samples that had been previously analyzed for 4D-ELF. |
| Rectal Prostaglandin Levels as Measured by ELISA | 3 months from baseline colonoscopy to end of intervention. | Evaluate the effect of aspirin on rectal prostaglandin levels. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Platelet Cyclooxygenase (COX) Activity as Measured by a Peroxidase-based COX Enzyme Activity Assay | 3 months from baseline colonoscopy to end of intervention. | Evaluate the effect of aspirin on platelet COX activity as measured by a peroxidase-based Cox enzyme activity assay. |
Countries
United States
Participant flow
Recruitment details
The study opened to accrual 02/22/2007 and closed to accrual 08/10/2009. Subjects were recruited at Northwestern University and University of Chicago.
Pre-assignment details
A total of 110 subjects met the clinical definition of high risk for colorectal cancer, were entered onto the trial, and underwent initial spectral analysis. Of these, 81 had a cancer-associated spectral signature in histologically normal colonic mucosa.79 of these 81 subjects were randomized and began the study intervention
Participants by arm
| Arm | Count |
|---|---|
| Acetylsalicylic Acid Patients receive oral acetylsalicylic acid (aspirin) once daily. | 40 |
| Placebo Patients receive oral placebo once daily. | 39 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Medical Contraindication | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Acetylsalicylic Acid | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 5 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 34 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 39 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 37 Participants | 36 Participants | 73 Participants |
| Sex: Female, Male Female | 15 Participants | 16 Participants | 31 Participants |
| Sex: Female, Male Male | 25 Participants | 23 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 40 | 21 / 39 |
| serious Total, serious adverse events | 0 / 40 | 0 / 39 |
Outcome results
Primary
Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Fractal Dimension or FRAC) From Baseline to 3 Months.
Spectral marker assessment was performed via LEBS analysis (low-coherence enhanced backscattering spectroscopy) on the uninvolved mucosal biopsies of subjects taken at baseline and after 3 months of treatment with either aspirin or placebo. FRAC characterizes the spatial autocorrelation function of mass density distribution in tissue. SPEC and FRAC provide a measure of the fundamental characteristics of the tissue nanoscale architecture
Time frame: 3 months from baseline colonoscopy to end of intervention.
Population: Subjects at high risk for colorectal cancer (CRC) with a cancer-associated spectral marker signature in histologically normal colonic mucosa
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetylsalicylic Acid | Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Fractal Dimension or FRAC) From Baseline to 3 Months. | Baseline | 142.41 unitless | Standard Deviation 2570.86 |
| Acetylsalicylic Acid | Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Fractal Dimension or FRAC) From Baseline to 3 Months. | Post Intervention | -407.78 unitless | Standard Deviation 3470.69 |
| Placebo | Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Fractal Dimension or FRAC) From Baseline to 3 Months. | Baseline | 23.28 unitless | Standard Deviation 2699.82 |
| Placebo | Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Fractal Dimension or FRAC) From Baseline to 3 Months. | Post Intervention | 650.97 unitless | Standard Deviation 3201.77 |
p-value: 0.17Wilcoxon (Mann-Whitney)
Primary
Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Spectral Slope or SPEC) From Baseline to 3 Months.
Spectral marker assessment was performed via LEBS analysis (low-coherence enhanced backscattering spectroscopy) on the uninvolved mucosal biopsies of subjects taken at baseline and after 3 months of treatment with either aspirin or placebo. SPEC characterizes the size distribution of macromolecular complexes and other intracellular structures, with a decrease of the spectral slope implying a shift of the size distribution of intracellular structures toward smaller sizes. Spectral markers SPEC and FRAC provide a measure of the fundamental characteristics of the tissue nanoscale architecture.
Time frame: 3 months from baseline colonoscopy to end of intervention.
Population: Subjects at high risk for colorectal cancer (CRC) with a cancer-associated spectral marker signature in histologically normal colonic mucosa.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetylsalicylic Acid | Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Spectral Slope or SPEC) From Baseline to 3 Months. | Baseline | 40.72 micron^-1 | Standard Deviation 16.91 |
| Acetylsalicylic Acid | Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Spectral Slope or SPEC) From Baseline to 3 Months. | Post Intervention | 43.45 micron^-1 | Standard Deviation 26.84 |
| Placebo | Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Spectral Slope or SPEC) From Baseline to 3 Months. | Baseline | 37.54 micron^-1 | Standard Deviation 21.64 |
| Placebo | Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Spectral Slope or SPEC) From Baseline to 3 Months. | Post Intervention | 37.52 micron^-1 | Standard Deviation 28.15 |
Comparison: The study was powered to detect an attributable change in the aspirin group of 50% relative to baseline values - an approximate 50% increase in spectral slope.p-value: 0.11Wilcoxon (Mann-Whitney)
Secondary
Changes in Colonic Cell Proliferation as Measured by Immunohistochemical Detection of Ki67
Evaluate the effect of aspirin on colonic epithelial apoptosis and cell proliferation as assessed by immunohistochemical detection of Ki-67. These were performed on samples that had been previously analyzed for 4D-ELF.
Time frame: 3 months from baseline colonoscopy to end of intervention.
Population: Subjects at high risk for colorectal cancer (CRC) with a cancer-associated spectral marker signature in histologically normal colonic mucosa.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetylsalicylic Acid | Changes in Colonic Cell Proliferation as Measured by Immunohistochemical Detection of Ki67 | Baseline | 38.07 Percentage of Total Cells | Standard Deviation 16.83 |
| Acetylsalicylic Acid | Changes in Colonic Cell Proliferation as Measured by Immunohistochemical Detection of Ki67 | 3 Months Intervention | 43.60 Percentage of Total Cells | Standard Deviation 14.77 |
| Placebo | Changes in Colonic Cell Proliferation as Measured by Immunohistochemical Detection of Ki67 | Baseline | 40.45 Percentage of Total Cells | Standard Deviation 12.26 |
| Placebo | Changes in Colonic Cell Proliferation as Measured by Immunohistochemical Detection of Ki67 | 3 Months Intervention | 37.74 Percentage of Total Cells | Standard Deviation 13.37 |
Secondary
Colonic Epithelial Apoptosis as Measured by Immunohistochemical Detection of Cleaved Caspase 3
Evaluate the effect of aspirin on colonic epithelial apoptosis and cell proliferation as assessed by immunohistochemical detection of cleaved caspase 3 .These were performed on samples that had been previously analyzed for 4D-ELF.
Time frame: 3 months from baseline colonoscopy to end of intervention.
Population: Subjects at high risk for colorectal cancer (CRC) with a cancer-associated spectral marker signature in histologically normal colonic mucosa.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetylsalicylic Acid | Colonic Epithelial Apoptosis as Measured by Immunohistochemical Detection of Cleaved Caspase 3 | Baseline | 4.56 Percentage of Total Cells | Standard Deviation 4.27 |
| Acetylsalicylic Acid | Colonic Epithelial Apoptosis as Measured by Immunohistochemical Detection of Cleaved Caspase 3 | At 3 Months | 4.26 Percentage of Total Cells | Standard Deviation 4.44 |
| Placebo | Colonic Epithelial Apoptosis as Measured by Immunohistochemical Detection of Cleaved Caspase 3 | Baseline | 5.24 Percentage of Total Cells | Standard Deviation 3.69 |
| Placebo | Colonic Epithelial Apoptosis as Measured by Immunohistochemical Detection of Cleaved Caspase 3 | At 3 Months | 7.26 Percentage of Total Cells | Standard Deviation 6.77 |
Secondary
Rectal Prostaglandin Levels as Measured by ELISA
Evaluate the effect of aspirin on rectal prostaglandin levels.
Time frame: 3 months from baseline colonoscopy to end of intervention.
Population: Subjects at high risk for colorectal cancer (CRC) with a cancer-associated spectral marker signature in histologically normal colonic mucosa.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetylsalicylic Acid | Rectal Prostaglandin Levels as Measured by ELISA | Baseline | 305.93 pg/ml | Standard Deviation 300.01 |
| Acetylsalicylic Acid | Rectal Prostaglandin Levels as Measured by ELISA | Post Intervention | 211.97 pg/ml | Standard Deviation 134.32 |
| Placebo | Rectal Prostaglandin Levels as Measured by ELISA | Baseline | 654.64 pg/ml | Standard Deviation 1536.52 |
| Placebo | Rectal Prostaglandin Levels as Measured by ELISA | Post Intervention | 209.02 pg/ml | Standard Deviation 134.33 |
Other Pre-specified
Platelet Cyclooxygenase (COX) Activity as Measured by a Peroxidase-based COX Enzyme Activity Assay
Evaluate the effect of aspirin on platelet COX activity as measured by a peroxidase-based Cox enzyme activity assay.
Time frame: 3 months from baseline colonoscopy to end of intervention.
Population: Subjects at high risk for colorectal cancer (CRC) with a cancer-associated spectral marker signature in histologically normal colonic mucosa.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acetylsalicylic Acid | Platelet Cyclooxygenase (COX) Activity as Measured by a Peroxidase-based COX Enzyme Activity Assay | Baseline | 712976.73 pg/ml | Standard Deviation 2082413.36 |
| Acetylsalicylic Acid | Platelet Cyclooxygenase (COX) Activity as Measured by a Peroxidase-based COX Enzyme Activity Assay | Post Intervention | 6914.87 pg/ml | Standard Deviation 20891.41 |
| Placebo | Platelet Cyclooxygenase (COX) Activity as Measured by a Peroxidase-based COX Enzyme Activity Assay | Baseline | 430109.56 pg/ml | Standard Deviation 798782.31 |
| Placebo | Platelet Cyclooxygenase (COX) Activity as Measured by a Peroxidase-based COX Enzyme Activity Assay | Post Intervention | 200233.5 pg/ml | Standard Deviation 463029.1 |