Hormone Therapy and Radiation Therapy or Hormone Therapy and Radiation Therapy Followed by Docetaxel and Prednisone in Treating Patients With Localized Prostate Cancer

Study Overview
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Brief Summary
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RATIONALE: Androgens can cause the growth of prostate cancer cells. Hormone therapy using drugs, such as leuprolide, goserelin, flutamide, or bicalutamide, may fight prostate cancer by lowering the amount of androgens the body makes. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as docetaxel and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving hormone therapy and radiation therapy together with chemotherapy is more effective than giving hormone therapy together with radiation therapy in treating prostate cancer. PURPOSE: This randomized phase III trial is studying hormone therapy and radiation therapy followed by docetaxel and prednisone to see how well it works compared to hormone therapy and radiation therapy in treating patients with localized prostate cancer.

Detailed Description
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OBJECTIVES: Primary Compare the relative efficacy, in terms of overall survival, of the combination of androgen suppression and radiotherapy versus androgen suppression and radiotherapy followed by docetaxel and prednisone in patients with localized, high-risk prostate cancer. Secondary Compare the disease-free survival and incidence of adverse events in patients treated with these regimens. Compare the biochemical control, local control, and freedom from distant metastases in patients treated with these regimens. Determine the validity of prostate-specific antigen (PSA)-defined endpoints as a surrogate for overall survival of patients treated with these regimens. Compare the time interval between biochemical failure and distant metastases with respect to testosterone level in patients treated with these regimens. OUTLINE: This is an open-label, randomized, multicenter study. Patients are stratified according to risk group. Arm I: Patients receive androgen suppression therapy comprising luteinizing hormone-releasing hormone (LHRH) agonist (e.g., leuprolide acetate, goserelin, buserelin, or triptorelin) and oral antiandrogen (i.e., oral flutamide 3 times daily for 2 months or oral bicalutamide once daily for 2 months). Beginning at week 8, patients undergo radiotherapy 5 days a week for approximately 8 weeks. Antiandrogen therapy is discontinued at completion of radiotherapy, but LHRH agonist therapy continues for 20 months. Arm II: Patients receive androgen suppression therapy and undergo radiotherapy as in arm I. Beginning 4 weeks after completion of radiotherapy, patients receive docetaxel IV over 1 hour on day 1 and oral prednisone daily on days 1-21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients continue LHRH agonist therapy as in arm I. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 600 patients will be accrued for this study.

Official Title
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A Phase III Protocol of Androgen Suppression (AS) and 3DCRT/IMRT Vs AS and 3DCTR/IMRT Followed by Chemotherapy With Docetaxel and Prednisone for Localized, High-Risk, Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Prednisone
* Drug: docetaxel
* Drug: Oral antiandrogen
* Radiation: Radiation therapy
* Drug: LHRH agonist


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed prostate cancer at high-risk for recurrence within the past 180 days as determined by 1 of the following combinations (risk groups): Gleason score ≥ 9, prostate-specific antigen (PSA) ≤ 150 ng/mL, and any T stage Gleason score 8, PSA < 20 ng/mL, and stage ≥ T2 Gleason score 8, PSA 20-150 ng/mL, and any T stage Gleason score 7, PSA 20-150 ng/mL, and any T stage Clinically negative lymph nodes by imaging (pelvic CT scan or pelvic MRI), nodal sampling, or dissection within 90 days prior to study entry Equivocal or questionable lymph nodes ≤ 1.5 cm by imaging allowed Positive lymph nodes by capromab pendetide (ProstaScint^®) scan with a corresponding lymph node ≤ 1.5 cm by CT scan or MRI allowed PSA ≤ 150 ng/mL Cannot have been obtained during any of the following time points: 10-day period after prostate biopsy After initiation of hormonal therapy Within 30 days after discontinuation of finasteride Within 90 days after discontinuation of dutasteride No distant metastases by physical exam and bone scan Equivocal bone scan findings allowed if plain films are negative PATIENT CHARACTERISTICS: Zubrod performance status 0-1 Platelet count ≥ 100,000/mm^3 Absolute neutrophil count ≥ 1,800/mm^3 Hemoglobin ≥ 8 g/dL (transfusion or other intervention allowed) Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN Bilirubin ≤ 1.5 times ULN Fertile patients must use effective contraception during and for at least 3 months after completion of study treatment No prior invasive malignancy, except nonmelanomatous skin cancer or other malignancy, unless disease-free for ≥ 3 years (e.g., carcinoma in situ of the oral cavity or bladder are allowed) No unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months No transmural myocardial infarction within the past 6 months No acute bacterial or fungal infection requiring intravenous antibiotics No AIDS No prior allergic reaction to any study drugs or other drugs formulated with polysorbate 80 No existing peripheral neuropathy ≥ grade 2 PRIOR CONCURRENT THERAPY: At least 60 days since prior 5-alpha reductase inhibitor (e.g., finasteride) for prostatic hypertrophy At least 90 days since prior testosterone Prior pharmacologic androgen ablation for prostate cancer allowed provided androgen ablation was initiated no more than 50 days prior to study entry No prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy No prior systemic chemotherapy for prostate cancer Prior chemotherapy for a different cancer is allowed No prior radiotherapy, including brachytherapy, to the region of prostate cancer that would result in overlap of radiotherapy fields Intensity modulated radiotherapy allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Androgen suppression + Radiation Therapy<br>Androgen suppression (AS; LHRH agonist and oral antiandrogen) for 8 weeks followed by radiation therapy and concurrent AS. LHRH continues for 24 months after initiation of any treatment, oral antiandrogen discontinues at the end of radiation therapy (RT). | Drug: Oral antiandrogen<br>* Oral antiandrogen of treating institution's choice to be given per package instructions for 8 weeks, then concurrent with radiation therapy. Treatment is discontinued at the end of radiation therapy.<br>Radiation: Radiation therapy<br>* 46.8 Gy, using either three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiation therapy (IMRT), will be given to the regional lymphatics followed by a 25.2-28.8 Gy boost to the prostate, to bring the total dose to the prostate to 72.0-75.6 Gy. Daily prescription doses will be 1.8 Gy per day, 5 days per week x 8-8.5 weeks, beginning 8 weeks after the initiation of androgen suppression.<br>* Other names: Intensity-modulated radiation therapy;Drug: LHRH agonist<br>* LHRH agonist of treating institution's choice to be given per package instructions for 8 weeks, then concurrent with radiation therapy, and then until 24 months from initiation of any treatment has been reached.<br>|
| Experimental: Androgen suppression + Radiation Therapy + Chemotherapy<br>Androgen suppression (AS; LHRH agonist and oral antiandrogen) for 8 weeks followed by radiation therapy and concurrent AS. LHRH continues for 24 months after initiation of any treatment, oral antiandrogen discontinues at the end of RT. Following completion of RT, 6 cycles of docetaxel (premedicated with dexamethasone) and prednisone are delivered concurrently with androgen suppression. | Drug: Dexamethasone<br>* Premedication of dexamethasone prior to docetaxel, per institutional standards.<br>Drug: Prednisone<br>* 10 mg orally per day until day 21 of the last cycle of docetaxel, beginning 28 days after the completion of RT.<br>Drug: docetaxel<br>* 75 mg/m2 i.v. over 1 hour (on day 1 of each cycle) every 21 days for 6 cycles, beginning 28 days after the completion of RT.<br>Drug: Oral antiandrogen<br>* Oral antiandrogen of treating institution's choice to be given per package instructions for 8 weeks, then concurrent with radiation therapy. Treatment is discontinued at the end of radiation therapy.<br>Radiation: Radiation therapy<br>* 46.8 Gy, using either three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiation therapy (IMRT), will be given to the regional lymphatics followed by a 25.2-28.8 Gy boost to the prostate, to bring the total dose to the prostate to 72.0-75.6 Gy. Daily prescription doses will be 1.8 Gy per day, 5 days per week x 8-8.5 weeks, beginning 8 weeks after the initiation of androgen suppression.<br>* Other names: Intensity-modulated radiation therapy;Drug: LHRH agonist<br>* LHRH agonist of treating institution's choice to be given per package instructions for 8 weeks, then concurrent with radiation therapy, and then until 24 months from initiation of any treatment has been reached.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Four-year rates are shown. 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 the date of last contact. | From randomization to date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 4 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical Control | Four-year rates are shown (Kaplan-Meier estimates). Biochemical control is defined as freedom from biochemical failure. Biochemical failure was considered as the first of either prostate-specific antigen (PSA) failure or initiation of salvage hormone therapy. PSA failure was defined as a rise of 2 ng/ml over the nadir PSA. Patients who experienced death without biochemical failure, local failure prior to biochemical failure, or development of distant metastases prior to biochemical failure were censored on the date of the competing event. The corresponding outcome time was measured from the date of randomization. | From randomization to date of biochemical failure, death, or last follow-up. Analysis occurs after all patients have been potentially followed for 4 years. | 
| Local Control | Local control is defined as the absence of local failure which is the first of either progression or recurrence within the prostate. Progression of the tumor was considered to have occurred when there was a 25% or greater increase in the product of the two largest perpendicular diameters of the prostate. Recurrence was defined as the reappearance of disease after a complete response. Patients who experienced death without local failure, biochemical failure prior to local failure, and development of distant metastases prior to local failure were censored on the date of the competing event. The corresponding outcome time was measured from the date of randomization. Due to an insufficient number of events (2 in each arm), this endpoint was not statistically compared. Local control rates at 4 years were calculated using the Kaplan-Meier method. | From randomization to date of local failure, death, or last follow-up. Analysis occurs after all patients have been potentially followed for 4 years. | 
| Distant Metastasis | Distant failure was considered when there was evidence of metastatic disease. Patients who experienced death without distant failure, local failure prior to distant failure, and biochemical failure prior to distant failure were censored on the date of the competing event. The corresponding outcome time was measured from the date of randomization. Distant failure rates at 4 year were calculated using the Kaplan-Meier method. | From randomization to date of distant metastasis, death, or last follow-up. Analysis occurs after all patients have been potentially followed for 4 years. | 
| Disease-free Survival | A failure for disease-free survival is the first of the following: biochemical failure, local failure, distant metastases, or death due to any cause. The corresponding outcome time was measured from the date of randomization. Disease-free survival rates at 4 years were calculated using the Kaplan-Meier method. | From randomization to date of progression, death, or last follow-up. Analysis occurs after all patients have been potentially followed for 4 years. | 
| Incidence of Adverse Events | Adverse events are graded using CTCAE v3.0. The worst grade of all adverse events for each patient is counted. | From start of treatment until the end of follow-up | 
| The Time Interval Between Biochemical Failure and Distant Failure Respect to Testosterone Level | Biochemical failure is defined as the first of either prostate-specific antigen (PSA) failure or the initiation of salvage hormone therapy. PSA failure is defined as a rise in PSA of 2 ng/ml over the nadir PSA. Distant failure is defined as the first occurrence of distant metastasis. | From date of biochemical failure to development of distant metastasis. Maximum follow-up was 12.9 years. | 
| Validity of PSA Endpoint as a Surrogate for Overall Survival | Prentice's operational criteria for determining whether determining whether biochemical failure (surrogate endpoint) is a suitable endpoint for overall survival (true endpoint): Treatment is prognostic for true endpoint Treatment is prognostic for surrogate endpoint Surrogate is prognostic for true endpoint The full effect of the treatment on the true endpoint is explained by the surrogate. If any of the criteria are not met, it is concluded that biochemical failure is not a suitable surrogate for overall survival. Therefore, if any of the criteria are met, the other criteria do not do not need to be evaluated. | From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 4 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III prostate cancer, stage IIB prostate cancer, stage IIA prostate cancer, stage IV prostate cancer