Prostate Cancer
Conditions
Keywords
stage IIB prostate cancer, stage IIA prostate cancer, stage III prostate cancer, stage IV prostate cancer
Brief summary
RATIONALE: Hormones can stimulate the production of prostate cancer cells. Hormone therapy may fight prostate cancer by reducing the production of androgens. Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether hormone therapy plus radiation therapy is more effective with or without combination chemotherapy for prostate cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of hormone therapy plus radiation therapy with or without combination chemotherapy in treating patients who have prostate cancer.
Detailed description
OBJECTIVES: * Compare the efficacy of androgen suppression and radiotherapy with or without subsequent paclitaxel, estramustine, and etoposide, in terms of overall and disease-free survival, biochemical and local control, and freedom from distant metastasis, in patients with localized high-risk prostate cancer. * Compare the toxic effects of these regimens in these patients. OUTLINE: This is a randomized study. Patients are stratified according to prostate-specific antigen level (≤ 10 ng/mL vs 11-100 ng/mL), tumor stage (T1-2 vs T3-4), Gleason score (7 vs 8-10), and prior hormone use (yes vs no). Patients are randomized to one of two treatment arms. All patients receive androgen suppression comprising a luteinizing hormone-releasing hormone (LHRH) agonist AND bicalutamide OR flutamide for 4 months. Beginning 8 weeks after the initiation of androgen suppression, all patients undergo radiotherapy once daily, 5 days a week, for 7-8 weeks. Patients who received prior androgen suppression therapy count time to radiotherapy from start date of prior hormonal therapy. * Arm I: Patients continue androgen suppression therapy (LHRH agonist only) for approximately 20 more months after radiotherapy is completed. * Arm II: Patients continue therapy as in arm I and receive chemotherapy beginning 28 days after completing radiotherapy. Chemotherapy comprises oral estramustine 3 times daily and oral etoposide twice daily on days 1-14 and paclitaxel IV over 1 hour on day 2. Chemotherapy repeats every 21 days for 4 courses. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 1,440 patients will be accrued for this study within 6 years.
Interventions
DRUGbicalutamide
Administered orally at a dose of one 50mg tablet per day. Begins 8 weeks prior to radiotherapy and continues throughout radiotherapy.
DRUGestramustine phosphate sodium
280 mg three times a day for 14 days and repeated every 3 weeks for 4 cycles
DRUGetoposide
50 mg/m\^2 in divided doses b.i.d. for 14 days and repeated every 3 weeks for 4 cycles
DRUGflutamide
Administered orally at a dose of two 125 mg capsules three times a day for a total daily dose of 750 mg. Begins 8 weeks prior to radiotherapy and continues throughout radiotherapy.
DRUGpaclitaxel
135 mg/m\^2 given as a 1-hour infusion (on day 2 of each cycle) and repeated every 3 weeks for 4 cycles
DRUGLuteinizing hormone releasing hormone [LHRH] agonist
Releasing hormone agonists (such as leuprolide, goserelin, buserelin, triptorelin) will be given for 4 months
RADIATIONRadiation therapy
Radiation will begin 8 weeks following the initiation of hormone administration: 46.8 Gy to the regional lymphatics followed by a 23.4 Gy boost to the prostate to bring the total dose to the prostate to 70.2 Gy. Daily tumor doses will be 1.8 Gy per day, 5 days per week x 7-8 weeks.
DRUGwarfarin
To keep international normalized ratio (INR) \> 1.5 and \< 2.5; begins with the start of chemotherapy and will be given continuously until 4 weeks after the end of the fourth cycle of chemotherapy
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
DISEASE CHARACTERISTICS: * Histologically proven prostate cancer at high risk for relapse as determined by either of the following: * Prostate-specific antigen (PSA) 20-100 ng/mL and Gleason score at least 7 (any T stage) * Clinical stage at least T2, Gleason score at least 8, and PSA no greater than 100 ng/mL * Negative lymph nodes * No metastatic disease PATIENT CHARACTERISTICS: Age: * Over 18 Performance status: * Zubrod 0 or 1 Life expectancy: * Not specified Hematopoietic: * White blood cell (WBC) count of at least 3,000/mm\^3 * Platelet count at least 130,000/mm\^3 * Hemoglobin at least 11.4 g/dL Hepatic: * Aspartate aminotransferase (AST) no greater than 2 times upper limit of normal Renal: * Creatinine no greater than 2.5 mg/dL Other: * No other invasive cancer within the past 5 years except superficial nonmelanomatous skin cancer * No major medical or psychiatric illness that would preclude study participation * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: * Not specified Chemotherapy: * At least 5 years since prior chemotherapy Endocrine therapy: * At least 60 days since prior finasteride for prostatic hypertrophy * At least 90 days since prior testosterone * No more than 30 days since initiation of prior pharmacologic androgen ablation for prostate cancer Radiotherapy: * No prior pelvic radiotherapy * No concurrent intensity-modulated radiotherapy Surgery: * No prior radical prostatectomy * No prior cryosurgery for prostate cancer * No prior orchiectomy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (5-year Rate Reported) | From the date of randomization to the date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. | Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at date of last contact. This analysis was planned to occur when all patients had been potentially followed for 5 years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Biochemical Failure at 5 Years | From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years. | Biochemical failure uses the American Society for Radiation Oncology (ASTRO) definition of prostate-specific antigen (PSA) rises on three consecutive occasions, with biochemical failure date being midway between the last non-rising PSA and the first rise in PSA. Time to biochemical failure is defined as time from randomization to biochemical failure, last known follow-up (censored), or death (competing risk). Biochemical failure rates are estimated using the cumulative incidence method. |
| Rate of Local Progression at 5 Years | From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years. | Local progression is defined as documented clinical local and/or regional progression. Time to local progression is defined as time from randomization to local progression, last known follow-up (censored), or death (competing risk). Local progression rates are estimated using the cumulative incidence method. |
| Rate of Distant Metastasis at Five Years | From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years. | Distant metastasis (DM) is defined as documented metastatic disease. Time to distant metastasis is defined as time from randomization to distant metastatic disease, last known follow-up (censored), or death (competing risk). Distant metastasis rates are estimated using the cumulative incidence method. |
| Disease-free Survival Rate at 5 Years | From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years. | Disease-free survival (DFS) was measured from the date of randomization to the date of documentation of progression (local, distant, biochemical failure), death, or last follow-up (censored). The Kaplan-Meier method was used to estimate DFS rates. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hormones and RT Androgen suppression (AS) (Luteinizing hormone releasing hormone \[LHRH\] agonist and bicalutamide \[Casodex\] or flutamide \[Eulexin\]) x 8 weeks followed by RT to 70.2 Gy with concurrent AS (LHRH agonist and bicalutamide \[Casodex\] or flutamide \[Eulexin\]). AS will continue for a total of 24 months from initiation of all treatment. Oral anti-androgen will be discontinued at the end of radiation therapy (RT). | 197 |
| Hormones and RT Plus Chemotherapy AS (LHRH agonist and bicalutamide \[Casodex\] or flutamide \[Eulexin\]) x 8 weeks followed by RT to 70.2 Gy with concurrent AS (LHRH agonist and bicalutamide \[Casodex\] or flutamide \[Eulexin\]) and estramustine phosphate sodium, etoposide, paclitaxel, and warfarin \[Coumadin®\]. AS will continue for a total of 24 months from initiation all treatment. Oral antiandrogen will be discontinued at the end of RT. | 200 |
| Total | 397 |
Baseline characteristics
| Characteristic | Hormones and RT | Hormones and RT Plus Chemotherapy | Total |
|---|---|---|---|
| Age, Continuous | 65 years | 67 years | 66 years |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 197 Participants | 200 Participants | 397 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 189 / 197 | 198 / 200 |
| serious Total, serious adverse events | 6 / 197 | 70 / 200 |
Outcome results
Primary
Overall Survival (5-year Rate Reported)
Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at date of last contact. This analysis was planned to occur when all patients had been potentially followed for 5 years.
Time frame: From the date of randomization to the date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 5 years.
Population: All randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormones and RT | Overall Survival (5-year Rate Reported) | 84.9 percentage of participants |
| Hormones and RT Plus Chemotherapy | Overall Survival (5-year Rate Reported) | 87.2 percentage of participants |
Comparison: The original target sample size was 1440 patients with a requirement of 340 deaths to test the hypothesis of overall survival (OS) efficacy of the hormones and RT plus chemotherapy arm; the design is based on detecting a 6% absolute improvement in 5-year OS from 79% to 85%, or a 33% relative reduction in the yearly hazard rate, with 90% power and a 2-sided significance level of 0.05.p-value: 0.8195% CI: [0.76, 1.43]Log Rank
Secondary
Disease-free Survival Rate at 5 Years
Disease-free survival (DFS) was measured from the date of randomization to the date of documentation of progression (local, distant, biochemical failure), death, or last follow-up (censored). The Kaplan-Meier method was used to estimate DFS rates.
Time frame: From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years.
Population: All randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormones and RT | Disease-free Survival Rate at 5 Years | 39.1 percentage of participants |
| Hormones and RT Plus Chemotherapy | Disease-free Survival Rate at 5 Years | 42.9 percentage of participants |
p-value: 0.6195% CI: [0.75, 1.19]Log Rank
Secondary
Rate of Biochemical Failure at 5 Years
Biochemical failure uses the American Society for Radiation Oncology (ASTRO) definition of prostate-specific antigen (PSA) rises on three consecutive occasions, with biochemical failure date being midway between the last non-rising PSA and the first rise in PSA. Time to biochemical failure is defined as time from randomization to biochemical failure, last known follow-up (censored), or death (competing risk). Biochemical failure rates are estimated using the cumulative incidence method.
Time frame: From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years.
Population: All randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormones and RT | Rate of Biochemical Failure at 5 Years | 48.0 percentage of participants |
| Hormones and RT Plus Chemotherapy | Rate of Biochemical Failure at 5 Years | 47.9 percentage of participants |
p-value: 0.8295% CI: [0.74, 1.27]Gray's test
Secondary
Rate of Distant Metastasis at Five Years
Distant metastasis (DM) is defined as documented metastatic disease. Time to distant metastasis is defined as time from randomization to distant metastatic disease, last known follow-up (censored), or death (competing risk). Distant metastasis rates are estimated using the cumulative incidence method.
Time frame: From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years.
Population: All randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormones and RT | Rate of Distant Metastasis at Five Years | 10.4 percentage of participants |
| Hormones and RT Plus Chemotherapy | Rate of Distant Metastasis at Five Years | 8.3 percentage of participants |
p-value: 0.4295% CI: [0.48, 1.36]Gray's test
Secondary
Rate of Local Progression at 5 Years
Local progression is defined as documented clinical local and/or regional progression. Time to local progression is defined as time from randomization to local progression, last known follow-up (censored), or death (competing risk). Local progression rates are estimated using the cumulative incidence method.
Time frame: From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years.
Population: All randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hormones and RT | Rate of Local Progression at 5 Years | 5.8 percentage of participants |
| Hormones and RT Plus Chemotherapy | Rate of Local Progression at 5 Years | 4.1 percentage of participants |
p-value: 0.0995% CI: [0.28, 1.1]Gray's test