Prostate Adenocarcinoma TransCutaneous Hormones

Study Overview
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Brief Summary
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RATIONALE: The increasingly prolonged and extended use of androgen deprivation therapy (ADT) in the treatment of prostate cancer, usually achieved through the administration of LHRH agonists, has raised concerns about long-term toxicities, in particular osteoporosis and adverse metabolic changes which may be associated with type II diabetes and increased cardiovascular risk. An alternative approach is to investigate other methods of ADT. Oral oestrogen has been shown to be as effective as LHRH and surgical orchidectomy in achieving castrate levels of testosterone and has equivalent or improved prostate cancer outcomes but is not used routinely as first-line therapy because of the risk of cardiovascular system (CVS) complications. The CVS complications have been attributed to first-pass hepatic metabolism. Administering oestrogen parenterally avoids the entero-hepatic circulation and so is expected to mitigate the risk of CVS toxicity whilst still effectively suppressing testosterone to castrate levels. This hypothesis has been supported by results from the early stages of this trial which have provided sufficient indication of the safety and efficacy of the patches to warrant further investigation of the treatment in this setting, as recommended by the IDMC.. PURPOSE: This randomized phase III trial is studying how well the estrogen skin patch works compared with luteinizing hormone-releasing hormone agonist injections in treating patients with locally advanced or metastatic prostate cancer.

Detailed Description
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OBJECTIVES: Primary Compare the progression-free survival and overall survival of patients with locally advanced or metastatic prostate cancer treated with transcutaneous estrogen patches vs luteinizing hormone-releasing hormone analogues. Secondary Compare the cardiovascular system-related morbidity and mortality in patients treated with these regimens Compare the activity of these treatments, in terms of castrate level of hormones, failure-free survival, and biochemical failure, in these patients. Compare other toxicities, including osteoporosis, hot flushes, gynecomastia, and anemia, in patients treated with these regimens. Compare the quality of life of patients treated with these regimens. OUTLINE: This is a randomized, controlled, multicenter study. Patients are randomized to 1 of 2 treatment arms at 1(control):1 (patch) ratio. Arm I (control): Patients receive luteinizing hormone-releasing hormone agonists as per local practice in the absence of unacceptable toxicity. Arm II (patch): Patients receive 4 transcutaneous estrogen patches, changing twice weekly for 4 weeks. Patients' testosterone levels are measured at week 4. Patients whose testosterone level is > 1.7 nmol/L continue to receive patch as before and have their testosterone level measured every 2 weeks. Patients whose testosterone level is < 1.7 nmol/L at week 4 or any other point receive 3 transcutaneous estrogen patches changed twice weekly in the absence of unacceptable toxicity. Quality of life is assessed at baseline; at weeks 4, 8, and 12; every 3 months for 24 months. After completion of study treatment, patients are followed periodically. Peer Reviewed and Funded or Endorsed by Cancer Research UK PROJECTED ACCRUAL: A total of 2200 patients will be accrued for this study.

Official Title
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A Randomized-Controlled Trial of Transcutaneous Oestrogen Patches Versus LHRH Agonists in Prostate Cancer

Conditions
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Anemia, Cardiovascular Complications, Hot Flashes, Osteoporosis, Prostate Cancer

Intervention / Treatment
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* Drug: Goserelin
* Drug: Estradiol


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Must meet 1 of the following criteria: Newly diagnosed patients with any of the following: Stage T3 or T4, NX, M0 histologically confirmed prostate adenocarcinoma with prostate-specific antigen (PSA) ≥ 20 ng/mL or Gleason score ≥ 6 Any T, N+, M0, or any T, any N, M+ histologically confirmed prostate adenocarcinoma Multiple sclerotic bone metastases with a PSA ≥ 50 ng/mL without histological confirmation Patients with histologically confirmed prostate adenocarcinoma previously treated with radical surgery or radiotherapy who are currently in relapse with on of the following: PSA ≥ 4 ng/mL and rising with doubling time less than 6 months PSA ≥ 20 ng/mL Must have written informed consent Intention to treat with long-term androgen-deprivation therapy Normal testosterone level prior to hormonal treatment PATIENT CHARACTERISTICS: WHO performance status 0-2 No other prior or current malignant disease or cardiovascular system disease that is likely to interfere with study treatment or assessment No cardiovascular disease, including any of the following: History of cerebral ischemia (e.g., stroke or transient ischemic attack) within the past 2 years History of deep vein thrombosis or pulmonary embolism confirmed radiologically History of myocardial infarction (MI) within the past 6 months OR MI more than 6 months ago with evidence of q-wave anterior infarct on ECG ECHO or MUGA required for patients with history of ischemic heart disease Left Ventricular Ejection Fraction ≤ 40% No condition or situation that could preclude protocol treatment or compliance with follow-up schedule PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 12 months since prior adjuvant or neoadjuvant hormonal therapy for localized prostate cancer AND therapy lasted ≤ 12 months in duration No prior systemic therapy for locally advanced or metastatic prostate cancer No concurrent participation in another clinical trial of prostate cancer treatment that would preclude study therapy or outcome measures Concurrent prophylactic radiotherapy to prevent gynecomastia allowed

Ages Eligible for Study
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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: LHRH agonists<br>Patients randomised to the control arm will receive continuous treatment with LHRH agonists as per local practice. Treatment should continue for at least 3 years. LHRH antagonists, such as degarelix, are not allowed on the trial. The recommended anti-flare medication is bicalutamide and should be prescribed according to local practice. Control arm medication should be obtained from the hospital pharmacy or GP as per local practice. | Drug: Goserelin<br>* 3.6mg implant, in pre-filled syringe<br>* Other names: Zoladex;|
| Experimental: Oestrogen Patches<br>Patients randomised to the investigational arm will receive transcutaneous oestrogen patches (100 micrograms/24 hours). Treatment should be planned to continue for at least 3 years. For patients prescribed bicalutamide or flutamide prior to randomisation, this treatment should be discontinued before treatment with the patches can commence (no washout period is needed). | Drug: Estradiol<br>* Each patch contains 3 mg of estradiol hemihydrate in a patch size of 30 cm2, releasing 100 micrograms of estradiol per 24 hours.<br>* Other names: FemSeven;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival |  | Up to 180 months | 
| Overall Survival |  | Up to 180 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hormone activity by castrate levels of hormones |  | Up to 180 months | 
| Other toxicity |  | Up to 180 months | 
| Cardiovascular morbidity |  | Up to 180 months | 
| Cardiovascular mortality |  | Up to 180 months | 
| Quality of Life | will be measured using patient-completed questionnaires, EORTC QLQ-C30 and PR25 which is prostate specific | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hot flashes, anemia, osteoporosis, cardiovascular complications, recurrent prostate cancer, stage III prostate cancer, stage IV prostate cancer, adenocarcinoma of the prostate