Prostate Cancer
Conditions
Keywords
adenocarcinoma of the prostate, stage IV prostate cancer, recurrent prostate cancer, Strontium-89, Induction Chemotherapy, Androgen-Independent Prostate Cancer
Brief summary
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radioactive substances such as strontium-89 may relieve bone pain associated with prostate cancer. It is not yet known whether chemotherapy is more effective with or without strontium-89 in treating bone metastases. PURPOSE: This randomized phase III trial is studying giving chemotherapy together with strontium-89 to see how well it works compared to chemotherapy alone in treating patients with prostate cancer that has spread to the bone.
Detailed description
OBJECTIVES: * Compare the effectiveness, in terms of overall survival, of consolidation therapy with or without strontium chloride Sr 89 after induction chemotherapy in patients with androgen-independent prostate cancer. OUTLINE: This is a randomized study. Patients are stratified according to type of induction chemotherapy (KAVE vs prednisone and docetaxel), number of bony metastases (no more than 20 vs more than 20), Eastern Cooperative Oncology (ECOG) performance status (0-1 vs 2-3), and use of zoledronate (yes vs no). * Induction therapy: Patients receive 1 of 2 induction therapy regimens. * Regimen A (KAVE): Patients receive doxorubicin IV over 24 hours on day 1 and oral ketoconazole three times daily on days 1-7 of weeks 1, 3, and 5. Patients receive vinblastine IV over 30 minutes on day 1 and oral estramustine three times daily on days 1-7 of weeks 2, 4, and 6. Patients receive no treatment on weeks 7 and 8. Treatment repeats every 8 weeks for at least 2 courses\* in the absence of disease progression or unacceptable toxicity. NOTE: \*Patients continue to receive oral ketoconazole three times daily until disease progression. * Regimen B (prednisone and docetaxel): Patients receive oral prednisone twice daily on days 1-21 (days 1-14 of course 5 only) and docetaxel IV over 1 hour on day 1. Treatment repeats every 21 days for at least 5 courses in the absence of disease progression or unacceptable toxicity. * Consolidation therapy: Patients with a prostate-specific antigen (PSA) response (at least 50% decline in PSA level from baseline at week 16 OR at least 2 PSA levels decreased at least 50% from baseline) are randomized to 1 of 2 consolidation treatment arms. * Arm I: Patients receive doxorubicin IV over 24 hours once weekly for 6 weeks plus strontium chloride Sr 89 IV once at the beginning of chemotherapy. * Arm II: Patients receive doxorubicin as in arm I. Patients are followed every 4 weeks until PSA progression and then every 3 months thereafter. PROJECTED ACCRUAL: Approximately 480 patients (240 randomized) will be accrued for this study within 48 months.
Interventions
DRUGDocetaxel
75 mg/m2 intravenous piggyback (IVPB) over 1 hour, Day 1, every 3 weeks.
DRUGDoxorubicin hydrochloride
20 mg/m2 IV, day 1 on Weeks 1, 3, 5
DRUGEstramustine phosphate sodium
140 mg orally 3 x day, Days 1 through 7 on Weeks 2, 4, 6
DRUGKetoconazole
400 mg orally (po) 3 x day, Days 1 through 7
DRUGPrednisone
5 mg orally 2 x daily, weeks 1-14
DRUGVinblastine
4 mg/m2 IVPB, Day 1 on Weeks 2, 4, 6
RADIATIONStrontium chloride Sr 89
One dose (4 mCi total dose) IV
DRUGDexamethasone
4 mg is given orally at 12 and 1 hours before and 12 hours after docetaxel.
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
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
1. Rising PSA on at least 2 occasions \>1 week apart (minimum value of 5 ng/ml), accompanied either by bone pain or, if the patient is asymptomatic, by a worsening bone scan with new lesions over a period of \<6 months 2. Patients on antiandrogens should be discontinued from flutamide or nilutamide for at least 4 weeks and bicalutamide for 6 weeks; If progression is documented during this time interval as in inclusion criterion # 1, patients are eligible 3. Osteoblastic metastases on bone scan or CT scan 4. Androgen-independent prostate adenocarcinoma 5. Castrate testosterone level \</= 50 ng/ml; treatment to maintain castrate levels of testosterone must be continued 6. \>/= 18 years of age 7. Life expectancy of greater than or equal to 12 weeks 8. Zubrod performance status \</= 3 9. Patients must have normal organ and marrow function as defined below: Leukocytes greater than 3,000/mcL Absolute neutrophil count greater than 1,500/mcL Platelets greater than 100,000/mcL Total bilirubin less than or equal to 2X institutional upper limit of normal AST(SGOT)/ALT(SGPT) less than or equal to 2X institutional upper limit of normal 10. The patient must have the ability to understand and the willingness to sign a written informed consent document 11. Participating subjects and their female partners agree to the use of adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation
Exclusion criteria
1. History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used on this trial 2. Prior doxorubicin, or vinblastine in the KAVE arm and prior docetaxel in the prednisone plus docetaxel arm. However, previous treatment using other secondary hormonal agents (aminoglutethimide, diethylstilbesterol, estramustine), steroids (dexamethasone, prednisone, hydrocortisone), angiogenesis inhibitors, gene therapy, or immunotherapy are allowed 3. More than one prior cytotoxic treatment 4. Prior Sr-89 or Sm-153 treatment 5. Patients who have had chemotherapy, immunotherapy, or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier 6. Previous vagotomy or other conditions (such as pernicious anemia) associated with achlorhydria. Patients with active peptic ulcer disease who still require regular use of H2 blockers (such as cimetidine \[Tagamet\], ranitidine \[Zantac\], famotidine \[Pepcid\], etc), proton pump inhibitors (omeprazole \[Prilosec\]), or antacids (Mylanta, Maalox, Tums, etc) at week 16 of induction chemotherapy (option 1 only) might not be suitable for randomization 7. Predominant visceral metastases in the liver, lungs, or brain 8. Symptomatic lymphadenopathy (scrotal or pedal edema) or significant local invasive disease (hematuria) 9. Small cell carcinoma 10. Recent history of transient ischemic attacks (TIA) or myocardial infarctions (MI) within 12 months, or active angina or claudication sufficient to limit activity 11. Active or likely to become active second malignancy (other than non-melanoma skin cancer) 12. Uncontrolled inter-current illness: including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival From Randomization | Followed every 4 weeks from randomization until death, up to 7 years. | Overall survival (OS) was computed using the number of months from the date of randomization to the date of death. Participants still alive were censored at the last follow-up date. Kaplan-Meier methodology was used to evaluate OS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival From Registration | Followed every 4 weeks from registration until death, up to 7 years. | Overall survival (OS) was computed using the number of months from the date of registration to the date of death. Participants still alive were censored at the last follow-up date. Kaplan-Meier methodology was used to evaluate OS. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: April 16, 2002 to October 20, 2010 from various hospitals and institutions representing the Community Clinical Oncology Program (CCOP).
Pre-assignment details
Of the 265 participants enrolled - 127 were randomized to either the Sr-89 treatment arm or the no Sr-89 treatment arm and the rest (138 participants) did not qualify for randomization. Of the 138 participants, 5 did not receive any treatment and the rest received only induction treatment. Study was closed prematurely due to issues with accrual.
Participants by arm
| Arm | Count |
|---|---|
| Induction Treatment Induction treatment option 1: Weeks 1,3,5: Doxorubicin 20 mg/m\^2 IV, day 1 and Ketoconazole 400 mg oral 3 x daily, days 1 through 7. Weeks 2,4,6: Vinblastine 4 mg/m\^2 IVPB, day 1 and Estramustine 140 mg oral 3 x daily, days 1 through 7. Weeks 7,8: No treatment. Hydrocortisone 10 mg oral 2 x daily will be administered throughout treatment or Induction treatment option 2: Prednisone 5 mg oral 2 x daily, weeks 1-14 and Docetaxel 75 mg/m\^2 IVPB over 1 hour, every 3 weeks. Dexamethasone 4 mg is given orally at 12 and 1 hours before and 12 hours after docetaxel. | 133 |
| Induction Treatment + Strontium-89 Induction treatment option 1: Weeks 1,3,5: Doxorubicin 20 mg/m\^2 IV, day 1 and Ketoconazole 400 mg oral 3 x daily, days 1 through 7. Weeks 2,4,6: Vinblastine 4 mg/m\^2 IVPB, day 1 and Estramustine 140 mg oral 3 x daily, days 1 through 7. Weeks 7,8: No treatment. Hydrocortisone 10 mg oral 2 x daily will be administered throughout treatment or Induction treatment option 2: Prednisone 5 mg oral 2 x daily, weeks 1-14 and Docetaxel 75 mg/m\^2 IVPB over 1 hour, every 3 weeks. Dexamethasone 4 mg is given orally at 12 and 1 hours before and 12 hours after docetaxel. Randomization: Doxorubicin IV over 24 hours once weekly for 6 weeks + Strontium-89 IV once at beginning of chemotherapy. | 65 |
| Induction Treatment + No Strontium-89 Induction treatment option 1: Weeks 1,3,5: Doxorubicin 20 mg/m\^2 IV, day 1 and Ketoconazole 400 mg oral 3 x daily, days 1 through 7. Weeks 2,4,6: Vinblastine 4 mg/m\^2 IVPB, day 1 and Estramustine 140 mg oral 3 x daily, days 1 through 7. Weeks 7,8: No treatment. Hydrocortisone 10 mg oral 2 x daily will be administered throughout treatment or Induction treatment option 2: Prednisone 5 mg oral 2 x daily, weeks 1-14 and Docetaxel 75 mg/m\^2 IVPB over 1 hour, every 3 weeks. Dexamethasone 4 mg is given orally at 12 and 1 hours before and 12 hours after docetaxel. Randomization: Doxorubicin 20mg/m\^2 IV over 24 hours once weekly for 6 weeks. | 62 |
| Total | 260 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 53 | 47 |
Baseline characteristics
| Characteristic | Induction Treatment + Strontium-89 | Induction Treatment + No Strontium-89 | Induction Treatment | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 43 Participants | 38 Participants | 80 Participants | 161 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 23 Participants | 53 Participants | 98 Participants |
| Age, Continuous | 68 years | 67 years | 67 years | 67 years |
| Region of Enrollment United States | 65 participants | 62 participants | 133 participants | 260 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 65 Participants | 62 Participants | 133 Participants | 260 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 34 / 138 | 12 / 65 | 13 / 62 |
| serious Total, serious adverse events | 77 / 138 | 53 / 65 | 47 / 62 |
Outcome results
Primary
Overall Survival From Randomization
Overall survival (OS) was computed using the number of months from the date of randomization to the date of death. Participants still alive were censored at the last follow-up date. Kaplan-Meier methodology was used to evaluate OS.
Time frame: Followed every 4 weeks from randomization until death, up to 7 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Induction Treatment + Strontium-89 | Overall Survival From Randomization | 24.2 months |
| Induction Treatment + No Strontium-89 | Overall Survival From Randomization | 22.8 months |
Secondary
Overall Survival From Registration
Overall survival (OS) was computed using the number of months from the date of registration to the date of death. Participants still alive were censored at the last follow-up date. Kaplan-Meier methodology was used to evaluate OS.
Time frame: Followed every 4 weeks from registration until death, up to 7 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Induction Treatment + Strontium-89 | Overall Survival From Registration | 27.9 months |
| Induction Treatment + No Strontium-89 | Overall Survival From Registration | 26.6 months |