Radiation Therapy, Androgen Suppression, and Docetaxel in Treating Patients With High-Risk Prostate Cancer Who Have Undergone Radical Prostatectomy

Study Overview
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Brief Summary
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RATIONALE: Specialized radiation therapy that delivers a high-dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as leuprolide, goserelin, flutamide, or bicalutamide, may lessen the amount of androgens made by the body. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with androgen suppression and docetaxel after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying how well giving radiation therapy together with androgen suppression and docetaxel works in treating patients with high risk prostate cancer who have undergone radical prostatectomy.

Detailed Description
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OBJECTIVES: Primary To assess whether the addition of androgen suppression therapy and docetaxel to adjuvant radiotherapy improves freedom from progression. Secondary To assess freedom from local-regional progression, distant metastases, disease-free survival, prostate cancer specific survival, non-prostate cancer specific survival, overall survival, and time to biochemical (PSA) failure. To evaluate treatment-related acute and late toxicity based on Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0. To correlate genomic and proteomic biomarkers with the primary and secondary clinical endpoints utilizing archival prostatectomy tissue and pretreatment and prospectively collected serum/plasma. OUTLINE: This is a multicenter study. Androgen suppression therapy: Patients receive a luteinizing hormone-releasing hormone (LHRH) agonist (leuprolide or goserelin) as an injection AND an oral antiandrogen (flutamide 3 times daily or bicalutamide once daily) for up to 6 months. Radiotherapy: Beginning 8 weeks after the initiation of androgen suppression therapy, patients undergo 3-dimensional conformal radiotherapy or intensity-modulated radiotherapy once a day 5 days a week for up to approximately 8 weeks. Chemotherapy: Beginning 3-6 weeks after the completion of radiotherapy, patients receive docetaxel IV over 1 hour on day 1. Treatment repeats every 21 days for up to 6 courses. After the completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Official Title
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Adjuvant 3DCRT/IMRT in Combination With Androgen Suppression and Docetaxel for High Risk Prostate Cancer Patients Post-Prostatectomy: A Phase II Trial

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: bicalutamide
* Drug: docetaxel
* Drug: flutamide
* Drug: LHRH agonist
* Radiation: 3-dimensional conformal radiation therapy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Pathologically proven adenocarcinoma of the prostate gland meeting one of the following criteria: Gleason ≥ 7and post-operative PSA nadir > 0.2 ng/ml with any pathologic tumor (pT) classification Gleason ≥ 8, post-operative PSA nadir ≤ 0.2 ng/ml and ≥ pT3a classification Must have undergone radical prostatectomy within the past year PSA must be obtained within 6 weeks (42 days) prior to study registration No lymph node or distant metastases (N0, M0), based upon the following minimum diagnostic workup: History and physical examination within 8 weeks prior to study registration Bone scan and CT or MRI of the pelvis and no evidence of osseous metastases on bone scan within 16 weeks prior to study registration No pelvic lymph nodes > 1.5 cm in greatest dimension on CT scan or MRI of the pelvis within 16 weeks prior to study registration, unless the enlarged lymph node is biopsied and negative PATIENT CHARACTERISTICS: Zubrod performance status 0-1 Absolute neutrophil count (ANC) ≥ 2,000/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention to achieve hemoglobin ≥ 8.0 g/dL is acceptable) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN Total bilirubin ≤ 1.2 times ULN No other invasive malignancy within the past 3 years except non-melanomatous skin cancer No active, severe co-morbidity, including any of the following: Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months Transmural myocardial infarction within the past 6 months Acute bacterial or fungal infection requiring intravenous antibiotics Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy AIDS HIV testing is not required for study entry No prior allergic reaction to the study drug(s) PRIOR CONCURRENT THERAPY: No prior systemic chemotherapy for prostate cancer More than 3 years since prior chemotherapy for a different cancer No prior androgen deprivation for treatment of prostate cancer Prior use of hormonal agents, such as finasteride or dutasteride, for treatment of benign prostatic hypertrophy is allowed No prior radiotherapy to the region of the prostate that would result in overlap of radiotherapy fields

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Androgen suppression + RT + docetaxel<br>LHRH agonist and oral antiandrogen (flutamide or bicalutamide), radiation therapy (RT), and docetaxel | Drug: bicalutamide<br>* 50 mg (one tablet) daily orally for 6 months, starting within 6 months after registration<br>Drug: docetaxel<br>* 75 mg/m2 IV over 1 hour on day 1 of each cycle q21 days for 6 cycles, starting 3-6 weeks after completion of radiation therapy<br>Drug: flutamide<br>* 250 mg (two 125-mg capsules) three times daily (total 750 mg) orally for 6 months, starting within 6 months after registration<br>Drug: LHRH agonist<br>* LHRH agonist (such as leuprolide, goserelin, buserelin, or triptorelin) for 6 months, starting within 6 weeks after registration<br>Radiation: 3-dimensional conformal radiation therapy<br> <br> Radiation: radiation therapy<br>* 66.6 Gy (1.8 Gy per fraction, 5 days per week) to the prostate bed (IMRT or 3DCRT), starting 8 weeks after start of hormones<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Free From Progression at 3 Years | Failure was defined as PSA ≥ 0.4 ng/mL after the end of radiation therapy confirmed by a second higher PSA, non-protocol hormones, local-regional progression, distant metastasis, or death, within 3 years after study registration. Freedom from progression (FFP) rate under null hypothesis was 50%; under alternative hypothesis ≥ 70%. Per Fleming's multiple testing procedure with 3 stages, 69 patients (76 allowing for 10% ineligible) were required for 90% power and type I error 0.025. If ≥ 44 of 69 patients had a FFP event, we would reject 50% FFP rate in favor of ≥ 70%. Analysis was out of 74 patients (not 69), so ≥ 44 was revised to ≥ 46. | From registration to 3 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local-regional Progression (3 Year Rate) | Time from registration to date of local progression (failure), death (competing risk), or last follow-up (censored). Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method. | Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.) | 
| Distant Metastasis (3-year Rate) | Time from registration to date of distant metastasis (failure), death (competing risk), or last follow-up (censored). Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method. | Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.) | 
| Prostate Cancer Death (3-year Rate) | Time from registration to date of distant metastasis (failure), death (competing risk), or last follow-up (censored). Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method. | Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.) | 
| Non-prostate Cancer Death (3-year Rate) | Time from registration to date of death due to other causes (failure), death due to prostate cancer (competing risk), or last follow-up (censored).Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method. | Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.) | 
| Overall Survival (3-year Rate) | Time from registration to date of death (failure) or last follow-up (censored). Three-year rate and 95% confidence interval were estimated by the Kaplan-Meier method. | Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.) | 
| Time to Biochemical (PSA) Failure (3-year Rate) | Failure is defined as PSA ≥ 0.4 ng/mL confirmed by a second higher PSA or initiation of non-protocol hormones. Death is considered a competing risk. Three-year failure rate and 95% confidence interval were estimated by the cumulative incidence method. | Analysis occurs after all patients have been on study for at least 3 years. (Patients are followed from registration to death or study termination whichever occurs first.) | 
| Number of Patients With Acute Adverse Events (Based on CTCAE, v3.0) | The number of patients with at least one grade 3 or higher adverse event (AE) from start of treatment to 90 days after the planned end of treatment (21 days after last docetaxel dose). Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | From start of treatment to 90 days after the planned end of treatment (21 days after last docetaxel dose). Analysis occurs at the time of the primary analysis. (Patients are followed until death or study termination whichever occurs first. | 
| Time to Late Grade 3+ Adverse Events (Based on CTCAE, v3.0) | Two-year rate shown (cumulative incidence method). Adverse events are graded using CTCAE v3.0. Time of first late adverse event occurrence of the Grade 3+ adverse event between 91 days and 730 days from the completion of treatment (3 weeks after the last planned docetaxel dose) calculated. Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | From 91 to 730 days after the planned end of treatment (21 days after last docetaxel dose). Analysis occurs at the time of the primary analysis. (Patients are followed from registration to death or study termination whichever occurs first.) | 
| Prognostic Value of Genomic and Proteomic Markers for the Primary and Secondary Clinical Endpoints |  | Analysis can occur at the same time as the primary endpoint if data is available. | 

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