Precancerous/Nonmalignant Condition, Prostate Cancer
Conditions
Keywords
prostate cancer, high grade prostatic intraepithelial neoplasia
Brief summary
RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development of cancer. The use of selenium may be an effective way to prevent prostate cancer in patients who have neoplasia of the prostate. PURPOSE: Randomized phase III trial to study the effectiveness of selenium in preventing prostate cancer in patients who have neoplasia of the prostate.
Detailed description
OBJECTIVES: * Compare the effects of selenium versus placebo on the 3-year incidence rate of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia. * Compare the toxicity of these regimens in these patients. * Compare the effects of these regimens on the rate of increase in prostate-specific antigen (PSA) in these patients. * Compare the effects of these regimens on prostatic cellular proliferation and apoptosis, degradation of basal cell integrity of prostatic ducts, and changes in nuclear chromatin patterns in these patients. OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to age (40-60 vs 61 and over), race (African American vs other), baseline PSA (less than 4 ng/mL vs 4-10 ng/mL), concurrent vitamin E supplementation (yes vs no), and cores obtained from initial biopsy (10 or more vs less than 10). Patients are randomized to 1 of 2 arms. * Arm I: Patients receive oral selenium once daily. * Arm II: Patients receive oral placebo once daily. Treatment in both arms continues for 3 years in the absence of progression to prostate cancer or unacceptable toxicity. Patients are followed every 6 months for 2 years and then annually for 8 years. PROJECTED ACCRUAL: A total of 465 patients will be randomized for this study.
Interventions
Randomization between active L-selenomethionine and placebo
DRUGL-selenomethionine placebo
Randomization between active L-selenomethionine and placebo
Sponsors
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
Cancer and Leukemia Group B
SWOG Cancer Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of high-grade prostatic intraepithelial neoplasia with no evidence of cancer * Documented by a digital rectal exam and biopsy of the prostate with transrectal ultrasound guidance (required if fewer than 6 cores obtained in biopsy) meeting one of the following conditions: * Biopsy yielded fewer than 10 cores within the past 24 months OR yielded more than 10 cores 6-24 months before study * Biopsy yielded 10 or more cores within the past 6 months * PSA ≤ 10 ng/mL (≤ 5 ng/mL for patients who have received finasteride or other androgen suppressor within the past 2 months) * American Urological Association symptom score of less than 20 PATIENT CHARACTERISTICS: Age: * 40 and over Performance status: * SWOG 0-1 Life expectancy: * Not specified Hematopoietic: * Not specified Hepatic: * Not specified Renal: * Not specified Other: * No malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or adequately treated stage I or II cancer that is in complete remission PRIOR CONCURRENT THERAPY: Biologic therapy * Not specified Chemotherapy * Not specified Endocrine therapy * See Disease Characteristics * No concurrent finasteride or any other androgen suppressor Radiotherapy * Not specified Surgery * Not specified Other * At least 30 days since prior daily dietary supplements containing 50 micrograms or more of selenium * No concurrent daily dietary supplements containing more than 50 micrograms of selenium
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Presence of Carcinoma of the Prostate as Measured by Biopsy | 3 years | The primary endpoint is biopsy-proven presence/absence of carcinoma of the prostate within 3 years after randomization to treatment. An end-of-study biopsy at 3 years after randomization will be used to determine presence/absence of prostate carcinoma in those patients not previously diagnosed with prostate carcinoma on study. Biopsies performed within ± 90 days of the 3-year anniversary will be considered end-of-study biopsies. Pathologically confirmed presence of prostate carcinoma may be determined at any time during the 3 years and 90 days after randomization, but absence can only be determined by the end-of-study biopsy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | 3 months after randomization and then every 3 months for 3 years | Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Selenium Patients receive oral selenium once daily for 3 years | 212 |
| Placebo Patients receive oral placebo once daily for 3 years | 211 |
| Total | 423 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Initial Registration | Ineligible | 167 | 0 | 0 |
| Randomization | Adverse Event | 0 | 11 | 7 |
| Randomization | Death | 0 | 1 | 3 |
| Randomization | Ineligible | 0 | 15 | 14 |
| Randomization | Other | 0 | 36 | 33 |
| Randomization | Progression/Relapse | 0 | 22 | 21 |
| Randomization | Refusal Unrelated to Adverse Event | 0 | 16 | 10 |
Baseline characteristics
| Characteristic | Selenium | Placebo | Total |
|---|---|---|---|
| Age 50-54 years | 20 participants | 20 participants | 40 participants |
| Age <50 years | 9 participants | 7 participants | 16 participants |
| Age 55-60 years | 28 participants | 35 participants | 63 participants |
| Age 61-70 years | 96 participants | 98 participants | 194 participants |
| Age >70 years | 59 participants | 51 participants | 110 participants |
| Age Continuous | 65.90 years | 65.30 years | 65.65 years |
| Baseline Prostate-Specific Antigen (PSA) - reported by site 4-10 ng/mL | 131 participants | 121 participants | 252 participants |
| Baseline Prostate-Specific Antigen (PSA) - reported by site <4 ng/mL | 81 participants | 90 participants | 171 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 13 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 195 Participants | 187 Participants | 382 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants | 11 Participants | 24 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 5 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 26 Participants | 26 Participants | 52 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) White | 180 Participants | 173 Participants | 353 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 212 Participants | 211 Participants | 423 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 54 / 203 | 57 / 202 |
| serious Total, serious adverse events | 9 / 203 | 4 / 202 |
Outcome results
Primary
Presence of Carcinoma of the Prostate as Measured by Biopsy
The primary endpoint is biopsy-proven presence/absence of carcinoma of the prostate within 3 years after randomization to treatment. An end-of-study biopsy at 3 years after randomization will be used to determine presence/absence of prostate carcinoma in those patients not previously diagnosed with prostate carcinoma on study. Biopsies performed within ± 90 days of the 3-year anniversary will be considered end-of-study biopsies. Pathologically confirmed presence of prostate carcinoma may be determined at any time during the 3 years and 90 days after randomization, but absence can only be determined by the end-of-study biopsy.
Time frame: 3 years
Population: All eligible randomized patients who started treatment and have prostate cancer known through an interim biopsy or a biopsy taken at +/- 90 days of the end of study were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selenium | Presence of Carcinoma of the Prostate as Measured by Biopsy | 48 participants |
| Placebo | Presence of Carcinoma of the Prostate as Measured by Biopsy | 49 participants |
Comparison: With target sample size of 466 randomized patients (233 per arm), there is a 90% of power to detect a one-third reduction in the three-year incidence rate of prostate cancer. The alpha level is set at 0.025, one-sided.p-value: 0.73Regression, Logistic
Secondary
Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug
Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.
Time frame: 3 months after randomization and then every 3 months for 3 years
Population: Eligible patients who had received any treatment were included in the adverse event summaries. Any CTCAE 3.0 event of Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal) which deemed to be related to protocol treatment are included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Selenium | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Cardiac ischemia/infarction | 0 Participants |
| Selenium | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Rash/desquamation | 1 Participants |
| Selenium | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | GI-other | 0 Participants |
| Selenium | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Urinary frequency/urgency | 0 Participants |
| Placebo | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Urinary frequency/urgency | 1 Participants |
| Placebo | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Cardiac ischemia/infarction | 1 Participants |
| Placebo | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | GI-other | 1 Participants |
| Placebo | Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Rash/desquamation | 0 Participants |