Neoadjuvant Estradiol or Androgen Deprivation in Clinically Localized Prostate Cancer (NE2)
Prostate cancer is the most commonly diagnosed cancer among males in the U.S. More than 220,000 men will be diagnosed with prostate cancer in the USA this year and more that 31,000 will die of this disease.
Androgen deprivation, the elimination of testosterone and its active metabolites, remains the single most effective intervention available for the treatment of advanced prostate carcinoma. Androgen deprivation induces an immune response to normal prostate and prostate cancer, which is usually short-lived. Estradiol induces activation of many arms of the immune system and may be a more effective and long lasting means of inducing immunity to prostate tissue.
This study will treat clinically localized prostate cancer patients with either estrogens, or standard androgen deprivation without estrogens, prior to prostatectomy in order more completely to describe immune regulation by estradiol in men. Control tissue from patients who have not been treated with androgen deprivation will be procured from the Northwest Special Projects in Oncology Research Excellence (SPORE) tissue core and used as comparisons against the cancers treated before prostatectomy. Tumors removed at prostatectomy, tissue samples and blood samples will be assessed for immune system changes.
Drug: Leuprolide or goserelin
Drug: Transdermal estradiol
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Neoadjuvant Estradiol or Androgen Deprivation in Clinically Localized Prostate Cancer|
- The primary endpoint of the study is to evaluate the induction of tumor and prostate-specific immunity by androgen deprivation and estradiol administration. [ Time Frame: End of Study ] [ Designated as safety issue: No ]
- Effects of androgen deprivation and estradiol administration on tumor infiltration by T lymphocytes, NK cells, and plasmacytoid dendritic cells [ Time Frame: End of Study ] [ Designated as safety issue: No ]
|Study Start Date:||March 2005|
|Study Completion Date:||December 2006|
|Primary Completion Date:||December 2006 (Final data collection date for primary outcome measure)|
Active Comparator: A
Leuprolide 7.5 mg or Goserelin 3.6 mg
Drug: Leuprolide or goserelin
Leuprolide 7.5 mg (4-week depot) or goserelin 3.6 mg (4-week depot)
Transdermal estradiol 0.6 mg q 3 days
Drug: Transdermal estradiol
Estradiol patches, six at 0.1 mg each, changed every 3-4 days
Estrogens are effective means of treating advanced prostate cancer. In randomized studies estrogens have better cancer control rates than orchiectomy alone, suggesting that estrogen efficacy is not limited to its ability to suppress testosterone. One hypothesis is that estrogens modulate immunity to prostate cancer through direct activation of effector cells and by upregulating cytokines in prostatic stroma. Administration of estrogen in murine models induces infiltration of normal prostate with T lymphocytes even in castrate male animals potentially through induction of autoimmunity to normally cryptic prostate antigens. Estrogens activate multiple immune effectors and autoimmunity in a broad variety of experimental settings, suggesting upregulation of immune recognition on many levels. Pilot data demonstrates that estrogens upregulate expression of interferon regulated genes, major histocompatibility antigens (MHC) on prostate cancer, and increase both number and activation of natural killer (NK) cells. Other groups have shown that standard forms of androgen deprivation also induce immunity against both normal and malignant prostate tissue. We propose to test the hypothesis that administration of estrogen and/or androgen deprivation induces immune recognition of prostate cancer in humans through upregulation of major histocompatibility antigens on tumor and induction of tumor specific immunity. The specificity of estrogen effect will be tested by comparing measures of immunity in patients treated with estradiol, androgen deprivation or no neoadjuvant therapy.
Plan of therapy
The specific aims of this proposal are:
- To treat patients with clinically localized, low to intermediate risk prostate cancer who are candidates for radical prostatectomy with either standard androgen deprivation prior to surgery (neoadjuvant androgen deprivation) or neoadjuvant transdermal estradiol. Patients will undergo radical prostatectomy 21 days after initiation of treatment.
- To evaluate radical prostatectomy specimens obtained from these patients for expression of MHC class I and II, and NK ligands MICA and MICB in prostate carcinoma and adjacent prostate by immunohistochemistry (IHC) and Western analysis.
- To evaluate tumor tissue for infiltration by clonal T lymphocytes, NK cells, and plasmacytoid dendritic cells using IHC and spectratyping of T cell receptor gene rearrangements.
- To evaluate patients for the induction of tumor specific antibodies using patient immunoglobulin collected before and after neoadjuvant therapy (SEREX)
- To evaluate patients for induction of NK cells and upregulation of the NK receptor NKG2D on patient lymphocytes by androgen deprivation and estradiol.
- To evaluate the effects of androgen deprivation and estradiol on induction of plasma and tissue levels of interferon gamma, alpha, beta, IL-4 and GM-CSF by ELISA and ribonuclease protection assay.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00167648
|United States, Washington|
|VA Puget Sound Health Care System|
|Seattle, Washington, United States, 98119|
|University of Washington Medical Center|
|Seattle, Washington, United States, 98195-6158|
|Principal Investigator:||R. Bruce Montgomery, MD||University of Washington; VA Puget Sound Health Care System|