Prostate Cancer
Conditions
Keywords
adenocarcinoma of the prostate, stage I prostate cancer, stage IIB prostate cancer, stage IIA prostate cancer
Brief summary
RATIONALE: Radiation therapy (RT) uses high-energy x-rays to damage tumor cells. Androgens can stimulate the growth of prostate cancer cells. Hormone therapy using flutamide, goserelin, and leuprolide may fight prostate cancer by reducing the production of androgens. It is not yet known which regimen of antiandrogen therapy is most effective for prostate cancer. PURPOSE: Randomized phase III trial to study the effectiveness of radiation therapy with or without antiandrogen therapy in treating patients who have stage I or stage II prostate cancer.
Detailed description
OBJECTIVES: Primary: To evaluate whether a combination of Zoladex and flutamide used as cytoreductive agents prior to and during definitive radiation therapy improves overall survival over radiation therapy alone in locally confined carcinomas of the prostate; Secondary: To compare the rates of disease-specific survival, clinical relapse (local progression and/or distant failure), freedom from prostate-specific antigen (PSA) failure, freedom from second clinical relapse, freedom from second PSA relapse, and disease-free survival; To compare the prostate re-biopsy at two years; To measure the effect on sexual function. OUTLINE: This is a randomized, multicenter study. Patients were stratified by PSA level (less than 4 vs 4-20), tumor differentiation (well vs moderate vs poor), nodal status (N0 \[nodes evaluated by surgical sampling\] vs NX \[nodes evaluated negative by imaging methods only\]), and participating center. Patients are randomized to one of two treatment arms. Arm I: Patients receive oral flutamide 3 times a day and goserelin subcutaneously once every 4 weeks, or once as a time release injection (intramuscular leuprolide may be substituted for goserelin), beginning 2 months prior to radiotherapy and continuing until completion of radiotherapy. Patients undergo radiotherapy daily 4-5 days per week for almost 8 weeks. Arm II: Patients undergo radiotherapy only, as in arm I. Patients are followed every 3 months for the remainder of the first year, every 4 months for the second year, every 6 months for the third through fifth years, and then annually thereafter. PROJECTED ACCRUAL: A total of 1980 patients within 5 years.
Interventions
DRUGflutamide
Two 125 mg capsules (t.i.d., p.o.) beginning two months before RT and continuing until RT is completed.
DRUGZoladex
3.6 mg s.c. monthly x 4 beginning two months before RT and continuing until RT is completed. The 3-month preparation may be used instead of three separate monthly injections.
DRUGLupron
7.5 mg IM (intramuscular) monthly x 4 beginning two months before RT and continuing until RT is completed. The 3-month preparation may be used instead of three separate monthly injections.
RADIATIONradiation therapy
46.8 Gy (1.8 Gy/day four to five times a week \[26 fx\]) to regional lymphatics followed by 19.8 Gy (1.8 Gy/day x 11 fx) for a total of 66.6 Gy to the prostate. Prostate only may be treated in defined circumstances.
Sponsors
National Cancer Institute (NCI)
Radiation Therapy Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed locally confined adenocarcinoma of the prostate with primary tumors confined to the prostate, clinical stage T1b,1c, 2a or 2b. * Negative nodes evaluated by imaging methods (classified in the study as NX) or by surgical sampling (classified in the study as N0). * Karnofsky performance status ≥ 70. * PSA is mandatory, must be ≤ 20) * No prior hormonal therapy, radiation or chemotherapy. * Prior finasteride for prostate hypertrophy allowed if discontinued at least 60 days prior to randomization. * Prior testosterone administration allowed if at least 90 days elapsed since last administration. * No evidence of distant metastasis or other synchronous primary. Patients with prior invasive malignancy who were disease free for at least 5 years could be eligible with pre-randomization approval by the study chairman. * Treatment begins within 21 days after randomization. * Patients signs a study-specific informed consent form. * Alanine Aminotransferase (ALT) within 2x upper normal limits.
Exclusion criteria
* Stage T1a or ≥ T2c disease. * Lymph node involvement (N1 - N3). * Evidence of distant metastasis. (M1) * PSA \> 20. * Radical surgery or cryosurgery for carcinoma of the prostate, previous irradiation, antiandrogen therapy or chemotherapy. * Previous or concurrent cancers other than basal cell or squamous cell skin carcinoma. Patients with squamous cell carcinomas required to be NED (no evidence of disease) for a minimum of two years prior to study entry. * Major medical or psychiatric illness which, in the investigator's opinion, would prevent completion of treatment and would interfere with follow-up. * Karnofsky performance status of \< 70.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival Rate (10-year) | From date of randomization to 10 years | Overall survival (OS) was calculated from randomization to the date of death from any cause and overall survival rates were estimated by the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Local Progression Rate (10 Years) | From registration to 10 years | Local progression defined as documented local progression as determined by clinical exam . Failure rates were estimated by means of cumulative incidence functions. |
| Distant Failure Rate (10 Years) | From registration to 10 years | Failure is defined as documented metastatic disease. Failure rates were estimated by means of cumulative incidence functions. |
| Biochemical Failure Rate (10 Years) | From registration to 10 years | The Phoenix definition of biochemical failure was used - an increase in the prostate-specific antigen (PSA) level of \>2 ng per milliliter above the nadir. Failure rates were estimated by means of cumulative incidence functions. |
| Disease-specific Survival Rate (10 Years) | From registration to 10 years | Disease-specific failure is defined as death certified as due to prostate cancer (by central review), death due to complications of treatment (irrespective of malignancy status), death from unknown causes with active malignancy, or death from unknown causes with previously documented relapse (either clinical or biochemical). Survival rates were estimated by means of cumulative incidence functions. |
| Second Biochemical Relapse Rate (10 Years) | From registration to 10 years | Second biochemical relapse is as defined as follows (after initiation of salvage hormone therapy): A rise in PSA on at least two consecutive cases above the nadir (after initiation of salvage hormone therapy), with the rises in PSA exceeding 1 ng/ml above the nadir; or failure to reach 4 ng/L or less at 18 months. The rates of second biochemical relapse were estimated by means of cumulative incidence functions. |
| Disease-free Survival Rate (10 Years) | From registration to 10 years | Disease-free failure is defined as documentation of progression (local progression, distant failure, and biochemical failure) or death from any cause. Disease-free survival rates were estimated by the Kaplan-Meier method. |
| Positive Re-biopsy Rate at Two Years | From registration to two years | The rate of prostate rebiopsy at two years is defined as the proportion of patients whose results are positive among all eligible patients who had a repeat biopsy at two years. The rate was estimated separately in each arm. |
| Clinical Relapse Rate (10 Years) | From registration to 10 years | Clinical relapse is defined as local progression or distant metastases. Failure rates were estimated by means of cumulative incidence functions. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hormone Therapy + Radiation Therapy Neoadjuvant total androgen suppression (TAS) - Flutamide and Zoladex or Lupron - two months before and during radiation therapy. | 987 |
| Radiation Therapy Alone Radiation therapy alone | 992 |
| Total | 1,979 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 19 | 17 |
| Overall Study | Withdrawal by Subject | 7 | 6 |
Baseline characteristics
| Characteristic | Total | Hormone Therapy + Radiation Therapy | Radiation Therapy Alone |
|---|---|---|---|
| Age, Continuous | 71 years | 70 years | 71 years |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1979 Participants | 987 Participants | 992 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 975 / 1,003 | 955 / 1,003 |
| serious Total, serious adverse events | 33 / 1,003 | 16 / 1,003 |
Outcome results
Primary
Overall Survival Rate (10-year)
Overall survival (OS) was calculated from randomization to the date of death from any cause and overall survival rates were estimated by the Kaplan-Meier method.
Time frame: From date of randomization to 10 years
Population: All eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormone Therapy + Radiation Therapy | Overall Survival Rate (10-year) | 61.9 percentage of patients |
| Radiation Therapy Alone | Overall Survival Rate (10-year) | 56.8 percentage of patients |
Comparison: Null hypothesis: 8-year OS rate of 60% radiation therapy (RT) alone vs. 67% with hormone therapy. The study was designed with 90% power to detect a 7-percentage- point absolute difference in the 8-year survival rate, with the use of a one-sided log-rank test at the 0.025 significance level, requiring 1980 patients and 716 deaths for definitive analysis.p-value: 0.030995% CI: [1.01, 1.35]Log Rank
Secondary
Biochemical Failure Rate (10 Years)
The Phoenix definition of biochemical failure was used - an increase in the prostate-specific antigen (PSA) level of \>2 ng per milliliter above the nadir. Failure rates were estimated by means of cumulative incidence functions.
Time frame: From registration to 10 years
Population: All eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormone Therapy + Radiation Therapy | Biochemical Failure Rate (10 Years) | 26.3 percentage of participants |
| Radiation Therapy Alone | Biochemical Failure Rate (10 Years) | 41.1 percentage of participants |
Comparison: Gray's test was used to compare cumulative incidence between treatment arms (1-sided significance level of 0.025) and the Fine-Gray model was used to calculate hazard ratios.p-value: <0.00195% CI: [1.48, 2.04]Gray's test
Secondary
Clinical Relapse Rate (10 Years)
Clinical relapse is defined as local progression or distant metastases. Failure rates were estimated by means of cumulative incidence functions.
Time frame: From registration to 10 years
Population: All eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormone Therapy + Radiation Therapy | Clinical Relapse Rate (10 Years) | 15.0 percentage of participants |
| Radiation Therapy Alone | Clinical Relapse Rate (10 Years) | 21.7 percentage of participants |
Comparison: Gray's test was used to compare cumulative incidence between treatment arms (1-sided significance level of 0.025) and the Fine-Gray model was used to calculate hazard ratios.p-value: <0.00195% CI: [1.21, 1.85]Gray's test
Secondary
Disease-free Survival Rate (10 Years)
Disease-free failure is defined as documentation of progression (local progression, distant failure, and biochemical failure) or death from any cause. Disease-free survival rates were estimated by the Kaplan-Meier method.
Time frame: From registration to 10 years
Population: All eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormone Therapy + Radiation Therapy | Disease-free Survival Rate (10 Years) | 51.7 percentage of participants |
| Radiation Therapy Alone | Disease-free Survival Rate (10 Years) | 39.5 percentage of participants |
Comparison: Treatment arms were compared using the log-rank test (one-sided significance level of 0.025).p-value: <0.00195% CI: [1.22, 1.56]Log Rank
Secondary
Disease-specific Survival Rate (10 Years)
Disease-specific failure is defined as death certified as due to prostate cancer (by central review), death due to complications of treatment (irrespective of malignancy status), death from unknown causes with active malignancy, or death from unknown causes with previously documented relapse (either clinical or biochemical). Survival rates were estimated by means of cumulative incidence functions.
Time frame: From registration to 10 years
Population: All eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormone Therapy + Radiation Therapy | Disease-specific Survival Rate (10 Years) | 95.7 percentage of participants |
| Radiation Therapy Alone | Disease-specific Survival Rate (10 Years) | 92.6 percentage of participants |
Comparison: Gray's test was used to compare cumulative incidence between treatment arms (1-sided significance level of 0.025) and the Fine-Gray model was used to calculate hazard ratios.p-value: 0.00195% CI: [1.27, 2.74]Gray's test
Secondary
Distant Failure Rate (10 Years)
Failure is defined as documented metastatic disease. Failure rates were estimated by means of cumulative incidence functions.
Time frame: From registration to 10 years
Population: All eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormone Therapy + Radiation Therapy | Distant Failure Rate (10 Years) | 5.5 percentage of participants |
| Radiation Therapy Alone | Distant Failure Rate (10 Years) | 8.0 percentage of participants |
Comparison: Gray's test was used to compare cumulative incidence between treatment arms (1-sided significance level of 0.025) and the Fine-Gray model was used to calculate hazard ratios.p-value: 0.03595% CI: [1.03, 2.06]Gray's test
Secondary
Local Progression Rate (10 Years)
Local progression defined as documented local progression as determined by clinical exam . Failure rates were estimated by means of cumulative incidence functions.
Time frame: From registration to 10 years
Population: All eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormone Therapy + Radiation Therapy | Local Progression Rate (10 Years) | 10.9 percentage of participants |
| Radiation Therapy Alone | Local Progression Rate (10 Years) | 16.1 percentage of participants |
Comparison: Gray's test was used to compare cumulative incidence between treatment arms (1-sided significance level of 0.025) and the Fine-Gray model was used to calculate hazard ratios.p-value: 0.001395% CI: [1.17, 1.93]Gray's test
Secondary
Positive Re-biopsy Rate at Two Years
The rate of prostate rebiopsy at two years is defined as the proportion of patients whose results are positive among all eligible patients who had a repeat biopsy at two years. The rate was estimated separately in each arm.
Time frame: From registration to two years
Population: All eligible patients who had a repeat biopsy at 2 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormone Therapy + Radiation Therapy | Positive Re-biopsy Rate at Two Years | 20.2 percentage of participants |
| Radiation Therapy Alone | Positive Re-biopsy Rate at Two Years | 38.9 percentage of participants |
p-value: <0.001Chi-squared
Secondary
Second Biochemical Relapse Rate (10 Years)
Second biochemical relapse is as defined as follows (after initiation of salvage hormone therapy): A rise in PSA on at least two consecutive cases above the nadir (after initiation of salvage hormone therapy), with the rises in PSA exceeding 1 ng/ml above the nadir; or failure to reach 4 ng/L or less at 18 months. The rates of second biochemical relapse were estimated by means of cumulative incidence functions.
Time frame: From registration to 10 years
Population: All eligible patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormone Therapy + Radiation Therapy | Second Biochemical Relapse Rate (10 Years) | 2.7 percentage of participants |
| Radiation Therapy Alone | Second Biochemical Relapse Rate (10 Years) | 6.1 percentage of participants |
Comparison: Gray's test was used to compare cumulative incidence between treatment arms (1-sided significance level of 0.025) and the Fine-Gray model was used to calculate hazard ratios.p-value: <0.00195% CI: [1.34, 3.16]Gray's test