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Neoadjuvant Estradiol or Androgen Deprivation in Clinically Localized Prostate Cancer

Phase 2
18 Years
Not Enrolling
Cancer, Prostate Neoplasms

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Trial Information

Neoadjuvant Estradiol or Androgen Deprivation in Clinically Localized Prostate Cancer

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:

1. 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

2. 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.

3. 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

4. To evaluate patients for the induction of tumor specific antibodies using patient
immunoglobulin collected before and after neoadjuvant therapy (SEREX)

5. To evaluate patients for induction of NK cells and upregulation of the NK receptor
NKG2D on patient lymphocytes by androgen deprivation and estradiol.

6. 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.

Inclusion Criteria:

1. Men 18 years or older with a histologic diagnosis of low to intermediate risk
prostate cancer prior to radical prostatectomy as defined by:

1. Clinical stage T1-T2b

2. PSA < 20

3. Gleason score < 7

Patients who have more than one of the following prognostic factors: T2b, Gleason 7,
PSA 10-20 are not eligible.

2. Patient's tumor must be considered surgically resectable as determined by a urologic

3. ECOG performance status of 0-1

4. Life expectancy greater than 2 years

5. Able to understand and give informed consent

6. Patients must agree not to take dietary phytoestrogens or other estrogen containing

Exclusion Criteria:

1. Patients with locally advanced or high-risk disease as defined above.

2. Patients who have a testosterone less than 280 ng/dL.

3. Patients who have evidence of cerebrovascular accident or ischemia, recent deep
venous thrombosis, pulmonary emboli, unstable angina or clinical congestive heart

4. Patients who are receiving any other investigational therapy.

5. Patients with an active serious infection or other serious underlying medical
condition that would otherwise impair their ability to receive protocol treatment.

6. Dementia or significantly altered mental status that would prohibit the understanding
and/or giving of informed consent.

7. Patients with immunodeficiency or on oral corticosteroids

8. Histologic evidence of small cell carcinoma of the prostate.

9. Patients with a prior history of myocardial infarction, pulmonary embolism, CVA or
atrial fibrillation.

10. Patients with active thrombophlebitis.

11. Patients with evidence of active angina as evidenced by chest pain responsive to
sublingual nitroglycerin or other anginal equivalent.

12. Medical conditions, which, in the opinion of the investigators would jeopardize
either the patient or the integrity of the data obtained

13. Patients who are currently receiving active therapy for other neoplastic disorders
will not be eligible for study.

14. Patients taking any of the following medications who cannot discontinue these
medications for three weeks during administration of androgen deprivation:
aprepitant, bexarotene, clarithromycin, itraconazole, ketoconazole, St. John's wort.

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The primary endpoint of the study is to evaluate the induction of tumor and prostate-specific immunity by androgen deprivation and estradiol administration.

Outcome Time Frame:

End of Study

Safety Issue:


Principal Investigator

R. Bruce Montgomery, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Washington; VA Puget Sound Health Care System


United States: Institutional Review Board

Study ID:

05-5564-V 01



Start Date:

March 2005

Completion Date:

December 2006

Related Keywords:

  • Cancer
  • Prostate Neoplasms
  • Neoplasms
  • Prostatic Neoplasms



University of Washington Medical Center Seattle, Washington  98195-6043
VA Puget Sound Health Care System Seattle, Washington  98101