Colorectal Cancer, Precancerous Condition
Conditions
Keywords
adenomatous polyp, stage I colon cancer, stage II colon cancer, adenocarcinoma of the colon
Brief summary
RATIONALE: Rosuvastatin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving rosuvastatin after surgery may kill any tumor cells that remain after surgery. It may also keep polyps from forming or colon cancer from coming back. It is not yet known whether rosuvastatin is more effective than a placebo in treating colon cancer that was removed by surgery. PURPOSE: This randomized phase III trial is studying rosuvastatin to see how well it works compared with placebo in treating patients with stage I or stage II colon cancer that was removed by surgery.
Detailed description
OBJECTIVES: Primary * To compare the effect of rosuvastatin vs placebo on the 5-year occurrence of adenomatous polyps of the colon or rectum, metachronous colorectal carcinoma, or colon cancer recurrence (APMC+R) in patients with resected stage I or II colon cancer. Secondary * To determine whether the effect of rosuvastatin vs placebo is of the same magnitude in patients taking aspirin (regardless of dose) compared to patients not taking aspirin. * To determine whether taking aspirin (regardless of dose) vs no aspirin will decrease the occurrence or APMC+R and, if there is an effect, to explore the relationship to dose. * To determine the effect of rosuvastatin in patients with familial colorectal cancer. * To determine the effect of rosuvastatin in patients with microsatellite unstable tumors (i.e., tumors displaying loss of MLH1 or MSH2 expression by IHC). * To determine the relationship between rosuvastatin therapy and features of colorectal adenomas as well as the size and number of colorectal adenomas. * To compare the time to APMC+R in patients treated with rosuvastatin vs placebo. * To compare the disease-free survival of patients treated with rosuvastatin vs placebo. * To compare the overall survival of patients treated with rosuvastatin vs placebo. * To compare the rate of recurrence of colon cancer in patients treated with rosuvastatin vs placebo. * To compare the rate of second non-colorectal primary cancers in patients treated with rosuvastatin vs placebo. * To determine the effect of rosuvastatin on health-related quality of life, global quality of life, and self-reported symptoms. * To compare the incidence and severity of adverse events associated with rosuvastatin vs placebo. * To assess relevant tumor and blood markers that may affect the metabolism, activity, or effect of the study drugs, such as HMG-CoA reductase, UGT1A6, P450-2C9, PTGS2 (COX-2), and other possible markers. OUTLINE: This is a multicenter study. Patients are stratified according to family history of a first-degree relative with colorectal cancer (yes vs no), intended aspirin dose (none vs 81 mg vs 325 mg), and adjuvant therapy for colon cancer (yes vs no). Patients are randomized to 1 of 2 treatment arms. * Group 1: Patients receive oral placebo once daily for 5 years. * Group 2: Patients receive oral rosuvastatin once daily for 5 years. Patients may complete a quality-of-life questionnaire at baseline and at 6, 12, 36, 60, and 84 months. Tumor tissue, serum, and blood samples may be collected periodically for biomarker and other analyses. After completion of study treatment, patients are followed up periodically for up to 2 years.
Interventions
DRUGrosuvastatin
OTHERplacebo
Sponsors
National Cancer Institute (NCI)
NSABP Foundation Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Patients must have the ability to swallow oral medication. * Patients must have resected adenocarcinoma of the colon staged as American Joint Committee on Cancer (AJCC) Stage 0, I, II, or III. * Patients must have had surgical resection of the colon adenocarcinoma with curative intent within 1 year prior to randomization. (Laparoscopically-assisted colectomy is permitted.) * Patients must have completed any adjuvant therapy prior to randomization. * Patients who are taking cardioprotective low-dose aspirin at study entry must not have clinically significant toxicity, as determined by the investigator, that precludes continuation of aspirin, and the patient must be willing to continue aspirin therapy (81 mg or 325 mg) throughout study therapy. * Colonoscopy requirements within 180 days prior to randomization: * The patient must have either undergone a preoperative or postoperative documented colonoscopy to the cecum (or small bowel anastomosis) with adequate bowel preparation. * All observed polyps must have been removed. (Polyps can be removed during colonoscopy or surgery performed prior to randomization.) * Postoperative serum creatinine performed within 90 days prior to randomization must be less than or equal to 1.5 x upper limit of normal (ULN) for the lab. * The following criteria for evidence of adequate hepatic function based on postoperative testing performed within 90 days prior to randomization must be met: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) less than or equal to 3.0 x ULN for the lab, and Total bilirubin less than or equal to 1.5 x ULN for the lab
Exclusion criteria
* Tumor with the distal border located less than 12 cm from the anal verge. * Total colectomy or total proctocolectomy. * Classic Familial Adenomatous Polyposis, Attenuated Familial Adenomatous Polyposis (i.e., 20 or more adenomas, either synchronous or metachronous), or Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome). * Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease significantly affecting gastrointestinal function. * History of documented upper GI bleeding or upper GI ulcerative disease. * Statin use within 30 days prior to randomization. * Hyperlipidemia with clinical indication for statin therapy or other prescribed medication. Determination of acceptable fasting lipid values, within 90 days prior to randomization, should be in accordance with current dyslipidemia management guidelines. * Unwillingness to discontinue chronic use of nonsteroidal antiinflammatory drugs (NSAIDs) (other than cardioprotective low-dose aspirin 81 mg or 325 mg) prior to randomization. * Anticipated need for chronic use of NSAIDs (other than cardioprotective low-dose aspirin 81 mg or 325 mg). * Inadequately treated hypothyroidism, as determined by the investigator. * History of myopathy or rhabdomyolysis. * Hypersensitivity or intolerance to statins. * Chronic drug therapy with cyclosporine, coumarin anticoagulants, gemfibrozil, some other lipid-lowering therapies (fibrates or niacin), lopinavir/ritonavir, or drugs (such as ketoconazole, spironolactone, or cimetidine) that lower levels or activity of steroid hormones. * Pregnancy or lactation at the time of study entry. (Pregnancy testing must be performed within 14 days prior to randomization according to institutional standards for women of childbearing potential.) * Previous malignancies unless the patient has been disease-free for 5 or more years prior to randomization and is deemed by the physician to be at low risk for recurrence. Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: all in situ cancers and basal cell and squamous cell carcinoma of the skin. * Other non-malignant systemic disease that would preclude a patient from receiving rosuvastatin or would prevent prolonged follow-up. * Administration of any investigational agent within 30 days before randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of ≥ 1 Adenomatous Polyp of the Colon or Rectum, Metachronous Colorectal Carcinoma, or Colon Cancer Recurrence (APMC+R) | Up to 4.8 years | Percentage of patients with occurrence of APMC+R event. APMC+R events include at least one adenomatous polyp of the colon or rectum, metachronous colorectal carcinoma, or colon cancer recurrence |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival | Up to 4.8 years | Number of patients with DFS event (colon cancer recurrence, second primary cancer, or death from any cause) |
| Overall Survival (OS) | Up to 4.8 years | Number of patients with the OS event (death from any cause) |
| Recurrence-free Interval (RFI) | Up to 4.8 years | Number of patients with the RFI event (First recurrence of colon cancer) |
| Size of Colorectal Adenomas, Including Advanced Adenomas | Up to 4.8 years | The histologic size (diameter of adenoma into the wall of the colon; as per AJCC staging) of the largest adenoma among patients who have at least one adenoma detected. If histologic size was not available, the endoscopic size was provided. |
| Behavioral and Health Outcomes as Measured by SF-12 Component Scores, Global Quality-of-life Scale, and Symptom Checklist | 12-month time point | Global Quality-of-life Scale score, ranges from 0 (worst imaginable health status) to 10 (best imaginable health status. |
| Toxicity Assessed by Adverse Events | Up to 4.8 years | Percentage of patients with at least one grade 2 or higher adverse event reported. |
| Measurements of Relevant Tumor and Blood Markers | At randomization | This study terminated early. Data on samples was not collected, the relevant analyses were not performed. |
| Second Non-colorectal Primary Cancer-free Interval | Up to 4.8 years | Number of patients with the first occurrence of non-colorectal primary cancer |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo | 204 |
| Rosuvastatin Rosuvastatin | 202 |
| Total | 406 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | No follow up data | 12 | 7 |
Baseline characteristics
| Characteristic | Placebo | Rosuvastatin | Total |
|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 10.3 | 58 years STANDARD_DEVIATION 10.9 | 58 years STANDARD_DEVIATION 10.6 |
| Sex: Female, Male Female | 113 Participants | 108 Participants | 221 Participants |
| Sex: Female, Male Male | 91 Participants | 94 Participants | 185 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / 191 | 34 / 196 |
| serious Total, serious adverse events | 17 / 191 | 14 / 196 |
Outcome results
Primary
Occurrence of ≥ 1 Adenomatous Polyp of the Colon or Rectum, Metachronous Colorectal Carcinoma, or Colon Cancer Recurrence (APMC+R)
Percentage of patients with occurrence of APMC+R event. APMC+R events include at least one adenomatous polyp of the colon or rectum, metachronous colorectal carcinoma, or colon cancer recurrence
Time frame: Up to 4.8 years
Population: NOTE: No conclusions should be drawn due to insufficient number of patients randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo | Occurrence of ≥ 1 Adenomatous Polyp of the Colon or Rectum, Metachronous Colorectal Carcinoma, or Colon Cancer Recurrence (APMC+R) | 25.0 percentage of patients |
| Group 2: Rosuvastatin | Occurrence of ≥ 1 Adenomatous Polyp of the Colon or Rectum, Metachronous Colorectal Carcinoma, or Colon Cancer Recurrence (APMC+R) | 28.2 percentage of patients |
Secondary
Behavioral and Health Outcomes as Measured by SF-12 Component Scores, Global Quality-of-life Scale, and Symptom Checklist
Global Quality-of-life Scale score, ranges from 0 (worst imaginable health status) to 10 (best imaginable health status.
Time frame: 12-month time point
Population: Patients who have submitted a 12 months QOL assessment. NOTE: No conclusions should be drawn due to insufficient number of patients randomized to the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Placebo | Behavioral and Health Outcomes as Measured by SF-12 Component Scores, Global Quality-of-life Scale, and Symptom Checklist | 8.0 score on a scale |
| Group 2: Rosuvastatin | Behavioral and Health Outcomes as Measured by SF-12 Component Scores, Global Quality-of-life Scale, and Symptom Checklist | 8.0 score on a scale |
Secondary
Disease-free Survival
Number of patients with DFS event (colon cancer recurrence, second primary cancer, or death from any cause)
Time frame: Up to 4.8 years
Population: NOTE: No conclusions should be drawn due to insufficient number of patients randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo | Disease-free Survival | 17 participants with DFS event |
| Group 2: Rosuvastatin | Disease-free Survival | 21 participants with DFS event |
Secondary
Measurements of Relevant Tumor and Blood Markers
This study terminated early. Data on samples was not collected, the relevant analyses were not performed.
Time frame: At randomization
Population: Data on tumors and blood markers were not collected.
Secondary
Overall Survival (OS)
Number of patients with the OS event (death from any cause)
Time frame: Up to 4.8 years
Population: NOTE: No conclusions should be drawn due to insufficient number of patients randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo | Overall Survival (OS) | 1 participants with OS event |
| Group 2: Rosuvastatin | Overall Survival (OS) | 4 participants with OS event |
Secondary
Recurrence-free Interval (RFI)
Number of patients with the RFI event (First recurrence of colon cancer)
Time frame: Up to 4.8 years
Population: NOTE: No conclusions should be drawn due to insufficient number of patients randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo | Recurrence-free Interval (RFI) | 12 participants with RFI event |
| Group 2: Rosuvastatin | Recurrence-free Interval (RFI) | 14 participants with RFI event |
Secondary
Second Non-colorectal Primary Cancer-free Interval
Number of patients with the first occurrence of non-colorectal primary cancer
Time frame: Up to 4.8 years
Population: NOTE: No conclusions should be drawn due to insufficient number of patients randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo | Second Non-colorectal Primary Cancer-free Interval | 4 participants non-colorectal primary cx |
| Group 2: Rosuvastatin | Second Non-colorectal Primary Cancer-free Interval | 7 participants non-colorectal primary cx |
Secondary
Size of Colorectal Adenomas, Including Advanced Adenomas
The histologic size (diameter of adenoma into the wall of the colon; as per AJCC staging) of the largest adenoma among patients who have at least one adenoma detected. If histologic size was not available, the endoscopic size was provided.
Time frame: Up to 4.8 years
Population: Patients who have at least one adenoma detected. NOTE: No conclusions should be drawn due to insufficient number of patients randomized to the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Placebo | Size of Colorectal Adenomas, Including Advanced Adenomas | 0.4 centimeters |
| Group 2: Rosuvastatin | Size of Colorectal Adenomas, Including Advanced Adenomas | 0.4 centimeters |
Secondary
Toxicity Assessed by Adverse Events
Percentage of patients with at least one grade 2 or higher adverse event reported.
Time frame: Up to 4.8 years
Population: Patients with available adverse event information. NOTE: No conclusions should be drawn due to insufficient number of patients randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Placebo | Toxicity Assessed by Adverse Events | 41.4 percentage of patients |
| Group 2: Rosuvastatin | Toxicity Assessed by Adverse Events | 45.4 percentage of patients |