Prostate Cancer
Conditions
Keywords
adenocarcinoma of the prostate, stage IV prostate cancer, recurrent prostate cancer
Brief summary
RATIONALE: Testosterone can stimulate the growth of prostate cancer cells. Hormone therapy may be effective treatment for prostate cancer. It is not yet known which regimen of hormone therapy is most effective for stage IV prostate cancer. PURPOSE: This randomized phase III trial is studying two different regimens of hormone therapy and comparing how well they work in treating men with stage IV prostate cancer.
Detailed description
OBJECTIVES: Primary * Compare the survival of patients with metastatic stage IV prostate cancer responsive to combined androgen-deprivation therapy (CAD) treated with intermittent vs continuous CAD. * Compare the effects of these treatment regimens on impotence, libido, and vitality/fatigue as well as the physical and emotional well-being of these patients. Secondary * Compare general symptoms, role functioning, global perception of quality of life, and social functioning of patients treated with these regimens. * Assess prostate-specific antigen (PSA) levels after continuous CAD administered before randomization and evaluate PSA changes throughout randomized treatment of these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to SWOG performance status (0-1 vs 2), severity of disease (minimal vs extensive), and prior hormonal therapy (neoadjuvant hormonal therapy vs finasteride vs neither). * Induction therapy: Patients receive combined androgen-deprivation (CAD) therapy comprising goserelin subcutaneously once a month and oral bicalutamide once daily for 8 courses (7 months). * Consolidation therapy: Patients are randomized to 1 of 2 consolidation regimens. * Arm I (continuous CAD therapy): Patients continue CAD therapy as in induction therapy. Treatment continues in the absence of disease progression. * Arm II (intermittent CAD therapy): Patients undergo observation in the absence of rising prostate-specific antigen (PSA) or clinical symptoms of progressive disease. Patients with rising PSA or progressive disease begin CAD therapy as in induction therapy. Patients whose PSA normalizes after 8 courses return to observation. Patients whose PSA does not normalize after 8 courses continue CAD therapy. Quality of life is assessed before induction therapy, at 3 months (before consolidation therapy), and then at 9 and 15 months. Patients are followed every 6-12 months for at least 10 years. PROJECTED ACCRUAL: Approximately 1,500 patients will be accrued for this study.
Interventions
DRUGbicalutamide
Given orally
DRUGgoserelin acetate
Given subcutaneously
OTHERclinical observation
Patients undergo observation in the absence of rising prostate-specific antigen (PSA) or clinical symptoms of progressive disease.
Sponsors
National Cancer Institute (NCI)
NCIC Clinical Trials Group
Cancer and Leukemia Group B
Eastern Cooperative Oncology Group
European Organisation for Research and Treatment of Cancer - EORTC
SWOG Cancer Research Network
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
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed adenocarcinoma of the prostate * Metastatic stage IV (stage D2) * Any number of bone metastases by bone scan allowed * Unequivocal visceral organ metastases (liver, brain, or lung) allowed * No suspected second primary tumors unless metastases are histologically confirmed, including special stains (e.g., prostate specific antigen \[PSA\] and prostatic alkaline phosphatase \[PAP\]) * For entry into late induction therapy: * No more than 1 month from the beginning of antiandrogen therapy to the beginning of luteinizing hormone-releasing hormone (LHRH) agonist therapy * No more than 6 months since initiation of current combined androgen-deprivation therapy (LHRH agonist and antiandrogen) * The effectiveness of the current depot LHRH agonist would not extend beyond 8 months after initiation of combined androgen therapy * PSA at least 5 ng/mL * No acute spinal cord compression PATIENT CHARACTERISTICS: Age: * Adult Performance status: * SWOG 0-2 Hematopoietic: * Not specified Hepatic: * Not specified Renal: * Not specified Other: * Recovered from any major infection * No active medical illness that would preclude study or limit survival * No other malignancy within the past 5 years except: * Adequately treated basal cell or squamous cell skin cancer * Adequately treated carcinoma in situ of the bladder * Adequately treated other superficial cancer PRIOR CONCURRENT THERAPY: Biologic therapy: * No concurrent biological response modifier therapy Chemotherapy: * No concurrent chemotherapy Endocrine therapy: * See Disease Characteristics * More than 1 year since any prior neoadjuvant or adjuvant hormonal therapy for a duration of no more than 4 months * Single or combination therapy allowed * More than 1 year since prior finasteride for prostate cancer for a duration of no more than 9 months (less than 6 months for benign prostatic hypertrophy) * Prior or concurrent megestrol for hot flashes allowed * No other concurrent hormonal therapy Radiotherapy: * No concurrent radiotherapy other than palliation of painful bone metastases Surgery: * No prior bilateral orchiectomy * Recovered from any prior major surgery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Erectile Dysfunction | 3 months | This outcome was assessed by having patients report whether they had erectile dysfunction (a score of 1) or no erectile dysfunction (a score of 0). This analysis looks at change from Baseline to 3 Months. |
| Vitality | 3 months | This outcome was scored on a scale of 0 to 100, with higher scores indicating better functioning. This analysis looks at mean change from Baseline score to 3 Months. |
| Overall Survival | Up to 15 years | Non-inferiority test to determine if intermittent combined androgen deprivation (CAD) overall survival is not substantially worse than continuous CAD overall survival. Specifically, the trial is designed for a one-sided test of the hypothesis that the hazard ratio of intermittent CAD to continuous CAD is 1.2. The assumptions used to compute the trial size are an overall type I error rate of 0.05 and a type II error of 0.10 (power = 0.9). |
| Physical Functioning as Measured by the SF-36 | 3 months | This outcome was scored on a scale of 0 to 100, with higher scores indicating better functioning. Change from Baseline in SF-36 Score at 3 Months |
| Emotional Functioning as Measured by the SF-36 Mental Health Inventory | 3 months | This outcome was scored on a scale of 0 to 100, with higher scores indicating better functioning. Change from Baseline in SF-36 Score at 3 Months |
| High Libido | 3 months | This outcome was assessed by having patients report whether their interest in sexual activities was very high, high, or moderate (a score of 1) or low or very low (a score of 0). This outcome measure is reporting a change from baseline in the percentage of participants with High Libido at 3 months. High Libido is defined as very high, high or moderate interest in sexual activities. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Social Functioning | 15 months | Mean of the change in social functioning from randomization |
| Role Functioning | 15 months | Mean of the change in role functioning from randomization |
| General Symptoms | 15 months | — |
| Global Perception of Quality of Life | 15 months | — |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Continuous Hormonal Therapy Patients continue to receive goserelin 3.6 mg subcutaneously once a month and oral bicalutamide 50 mg once daily until progression of disease | 765 |
| Intermittent Hormonal Therapy Patients are cycled between observation periods and Combined Androgen Deprivation (CAD) periods based on PSA results. Patients undergo observation in the absence of rising prostate-specific antigen (PSA) or clinical symptoms of progressive disease. Patients with rising PSA or progressive disease begin CAD therapy (goserelin 3.6 mg subcutaneously once a month and oral bicalutamide 50 mg once daily ). Patients whose PSA normalizes after 8 cycles of CAD treatment return to observation. Patients whose PSA does not normalize after 8 cycles of CAD treatment continue CAD therapy until progression (1 cycle of CAD treatment = 7 months with 8 injections. There are 2 injections in the first month on Days 1 and 29). | 770 |
| Total | 1,535 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Consolidation and Randomization | Adverse Event | 0 | 36 | 14 |
| Consolidation and Randomization | Death | 0 | 38 | 48 |
| Consolidation and Randomization | not eligible | 0 | 102 | 112 |
| Consolidation and Randomization | Other | 0 | 314 | 313 |
| Consolidation and Randomization | Progression/relapse | 0 | 295 | 298 |
| Consolidation and Randomization | Refusal unrelated to adverse event | 0 | 53 | 75 |
| Induction | Adverse Event | 44 | 0 | 0 |
| Induction | Death | 62 | 0 | 0 |
| Induction | not eligible | 90 | 0 | 0 |
| Induction | Other | 823 | 0 | 0 |
| Induction | Progression/relapse | 274 | 0 | 0 |
| Induction | Refusal unrelated to adverse event | 50 | 0 | 0 |
Baseline characteristics
| Characteristic | Intermittent Hormonal Therapy | Total | Continuous Hormonal Therapy |
|---|---|---|---|
| Age, Continuous | 70 years | 70 years | 70 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 40 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 564 Participants | 1135 Participants | 571 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 183 Participants | 360 Participants | 177 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 13 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 94 Participants | 187 Participants | 93 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 144 Participants | 298 Participants | 154 Participants |
| Race (NIH/OMB) White | 519 Participants | 1026 Participants | 507 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 770 Participants | 1535 Participants | 765 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 665 / 732 | 609 / 702 |
| serious Total, serious adverse events | 19 / 732 | 10 / 702 |
Outcome results
Primary
Emotional Functioning as Measured by the SF-36 Mental Health Inventory
This outcome was scored on a scale of 0 to 100, with higher scores indicating better functioning. Change from Baseline in SF-36 Score at 3 Months
Time frame: 3 months
Population: Only eligible patients with a usable form set for SF-36 Mental Health Inventory both at baseline and 3 months were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Consolidation Arm I | Emotional Functioning as Measured by the SF-36 Mental Health Inventory | -0.95 units on a scale | Standard Error 0.6804 |
| Consolidation Arm II | Emotional Functioning as Measured by the SF-36 Mental Health Inventory | 1.92 units on a scale | Standard Error 0.7241 |
p-value: 0.00395% CI: [1, 4.76]t-test, 2 sided
Primary
Erectile Dysfunction
This outcome was assessed by having patients report whether they had erectile dysfunction (a score of 1) or no erectile dysfunction (a score of 0). This analysis looks at change from Baseline to 3 Months.
Time frame: 3 months
Population: Only eligible patients with a usable answers regarding erectile dysfunction both at baseline and 3 months were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Consolidation Arm I | Erectile Dysfunction | 2 percentage of participants |
| Consolidation Arm II | Erectile Dysfunction | -7 percentage of participants |
p-value: <0.00195% CI: [-14, -5]t-test, 2 sided
Primary
High Libido
This outcome was assessed by having patients report whether their interest in sexual activities was very high, high, or moderate (a score of 1) or low or very low (a score of 0). This outcome measure is reporting a change from baseline in the percentage of participants with High Libido at 3 months. High Libido is defined as very high, high or moderate interest in sexual activities.
Time frame: 3 months
Population: Only eligible patients with a usable answers regarding libido both at baseline and 3 months were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Consolidation Arm I | High Libido | -2 percentage of participants |
| Consolidation Arm II | High Libido | 16 percentage of participants |
p-value: 0.0495% CI: [1, 36]t-test, 2 sided
Primary
Overall Survival
Non-inferiority test to determine if intermittent combined androgen deprivation (CAD) overall survival is not substantially worse than continuous CAD overall survival. Specifically, the trial is designed for a one-sided test of the hypothesis that the hazard ratio of intermittent CAD to continuous CAD is 1.2. The assumptions used to compute the trial size are an overall type I error rate of 0.05 and a type II error of 0.10 (power = 0.9).
Time frame: Up to 15 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Consolidation Arm I | Overall Survival | 5.8 years |
| Consolidation Arm II | Overall Survival | 5.1 years |
p-value: 0.1590% CI: [0.99, 1.23]Regression, Cox
Primary
Physical Functioning as Measured by the SF-36
This outcome was scored on a scale of 0 to 100, with higher scores indicating better functioning. Change from Baseline in SF-36 Score at 3 Months
Time frame: 3 months
Population: Only eligible patients with a usable form set for Physical Functioning portion of the SF-36 both at baseline and 3 months were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Consolidation Arm I | Physical Functioning as Measured by the SF-36 | -1.74 units on a scale | Standard Error 0.7366 |
| Consolidation Arm II | Physical Functioning as Measured by the SF-36 | 0.09 units on a scale | Standard Error 0.8084 |
p-value: 0.0995% CI: [-0.31, 3.97]t-test, 2 sided
Primary
Vitality
This outcome was scored on a scale of 0 to 100, with higher scores indicating better functioning. This analysis looks at mean change from Baseline score to 3 Months.
Time frame: 3 months
Population: Only eligible patients with a usable form set for Vitality both at baseline and 3 months were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Consolidation Arm I | Vitality | -1.42 units on a scale | Standard Error 0.7379 |
| Consolidation Arm II | Vitality | -0.11 units on a scale | Standard Error 0.8154 |
p-value: 0.2395% CI: [-0.83, 3.46]t-test, 2 sided
Other Pre-specified
General Symptoms
Time frame: 15 months
Other Pre-specified
Global Perception of Quality of Life
Time frame: 15 months
Other Pre-specified
Role Functioning
Mean of the change in role functioning from randomization
Time frame: 15 months
Other Pre-specified
Social Functioning
Mean of the change in social functioning from randomization
Time frame: 15 months