Maximal Suppression of the Androgen Axis in Clinically Localized Prostate Cancer
| Status: | Completed |
|---|---|
| Conditions: | Prostate Cancer, Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 100 |
| Updated: | 8/11/2018 |
| Start Date: | July 2006 |
| End Date: | January 2014 |
Prostate cancer (CaP) is the most commonly diagnosed cancer among males in the U.S. and the
second leading cause of cancer-related mortality. More than 230,000 men will be diagnosed
with prostate cancer in the USA this year and more than 30,000 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. This is usually achieved by surgical removal of the testes (orchiectomy), by
suppressing production of testosterone (LHRH agonists) and/or by blocking the androgens at
receptor sites (antiandrogens). Unfortunately, androgen suppression does not cure the
disease. Most patients progress within 0-5 years, and all patients ultimately progress if the
cancer is not eliminated during initial therapy (usually prostatectomy or radiation).
Hormone suppression treatment eliminates the detectable levels of testosterone in the blood.
However, the testosterone levels in tissue remain high enough to stimulate androgen
receptors. Overexpression of androgen receptors is present in all cell lines which
demonstrate "androgen independence," i.e., are resistant to androgen-suppressive therapy.
Approximately 95% of testosterone is supplied by the testes, with the remaining 5% supplied
by the adrenal glands. The presumption that standard androgen deprivation achieves the
optimal level of androgen suppression for patients is based on the levels of androgen which
result from orchiectomy. However, because adrenal androgen levels are unaffected by standard
modes of androgen deprivation, 5% of the body's testosterone remains despite hormone therapy.
The hypothesis of this study is that more effective suppression of the androgen axis through
elimination of adrenal androgens and more effective suppression of testosterone metabolites
will lower intraprostatic androgen levels, minimizing activation of the androgen receptor and
augmenting natural cell death (apoptosis). The investigators propose to test this hypothesis
by administering neoadjuvant (pre-surgery) androgen deprivation therapy of different types
before prostatectomy for patients with clinically localized prostate cancer. The
investigators will assay serum and intraprostatic androgen levels, while assessing relative
levels of apoptosis of normal and malignant tissue.
second leading cause of cancer-related mortality. More than 230,000 men will be diagnosed
with prostate cancer in the USA this year and more than 30,000 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. This is usually achieved by surgical removal of the testes (orchiectomy), by
suppressing production of testosterone (LHRH agonists) and/or by blocking the androgens at
receptor sites (antiandrogens). Unfortunately, androgen suppression does not cure the
disease. Most patients progress within 0-5 years, and all patients ultimately progress if the
cancer is not eliminated during initial therapy (usually prostatectomy or radiation).
Hormone suppression treatment eliminates the detectable levels of testosterone in the blood.
However, the testosterone levels in tissue remain high enough to stimulate androgen
receptors. Overexpression of androgen receptors is present in all cell lines which
demonstrate "androgen independence," i.e., are resistant to androgen-suppressive therapy.
Approximately 95% of testosterone is supplied by the testes, with the remaining 5% supplied
by the adrenal glands. The presumption that standard androgen deprivation achieves the
optimal level of androgen suppression for patients is based on the levels of androgen which
result from orchiectomy. However, because adrenal androgen levels are unaffected by standard
modes of androgen deprivation, 5% of the body's testosterone remains despite hormone therapy.
The hypothesis of this study is that more effective suppression of the androgen axis through
elimination of adrenal androgens and more effective suppression of testosterone metabolites
will lower intraprostatic androgen levels, minimizing activation of the androgen receptor and
augmenting natural cell death (apoptosis). The investigators propose to test this hypothesis
by administering neoadjuvant (pre-surgery) androgen deprivation therapy of different types
before prostatectomy for patients with clinically localized prostate cancer. The
investigators will assay serum and intraprostatic androgen levels, while assessing relative
levels of apoptosis of normal and malignant tissue.
Androgen deprivation has been the principal means of controlling advanced prostate cancer,
but does not cure the disease and all patients ultimately progress if the tumor is not
eliminated with definitive local therapy. It has been demonstrated that despite androgen
deprivation with LHRH agonists or orchiectomy, prostate tissue and prostate cancer maintain
levels of androgens which are more than adequate to stimulate the androgen receptor. These
levels of androgen may continue to stimulate the receptor and allow both survival of tumor
cells and induction of resistance by overexpression of the receptor. The presumption that
standard androgen deprivation achieves the optimal level of androgen suppression for patients
is based on the levels of androgen achieved with castration, which achieves relatively short
term control of cancer in the majority of patients. The hypothesis of this study is that more
effective suppression of the androgen axis through elimination of adrenal androgens and more
effective suppression of conversion to dihydrotestosterone will lower intraprostatic androgen
levels, minimizing activation of the androgen receptor and augmenting apoptosis. We propose
to test this hypothesis in a prospective, randomized trial, administering neoadjuvant
androgen deprivation therapy of different types prior to radical prostatectomy for patients
with clinically localized prostate cancer for 3 months.
Plan of therapy
Patients with clinically localized (cT1-T2) prostate cancer, at intermediate-high risk for
relapse who are candidates for radical prostatectomy will be treated with one of three
regimens:
- Goserelin with dutasteride
- Goserelin with bicalutamide and dutasteride
- Goserelin with bicalutamide and dutasteride and ketoconazole
Patients will undergo radical prostatectomy 3 months after initiation of treatment.
Preoperative and intraoperative biopsies of the prostate gland will be utilized for analysis
of prostatic hormones, gene expression and apoptosis.
but does not cure the disease and all patients ultimately progress if the tumor is not
eliminated with definitive local therapy. It has been demonstrated that despite androgen
deprivation with LHRH agonists or orchiectomy, prostate tissue and prostate cancer maintain
levels of androgens which are more than adequate to stimulate the androgen receptor. These
levels of androgen may continue to stimulate the receptor and allow both survival of tumor
cells and induction of resistance by overexpression of the receptor. The presumption that
standard androgen deprivation achieves the optimal level of androgen suppression for patients
is based on the levels of androgen achieved with castration, which achieves relatively short
term control of cancer in the majority of patients. The hypothesis of this study is that more
effective suppression of the androgen axis through elimination of adrenal androgens and more
effective suppression of conversion to dihydrotestosterone will lower intraprostatic androgen
levels, minimizing activation of the androgen receptor and augmenting apoptosis. We propose
to test this hypothesis in a prospective, randomized trial, administering neoadjuvant
androgen deprivation therapy of different types prior to radical prostatectomy for patients
with clinically localized prostate cancer for 3 months.
Plan of therapy
Patients with clinically localized (cT1-T2) prostate cancer, at intermediate-high risk for
relapse who are candidates for radical prostatectomy will be treated with one of three
regimens:
- Goserelin with dutasteride
- Goserelin with bicalutamide and dutasteride
- Goserelin with bicalutamide and dutasteride and ketoconazole
Patients will undergo radical prostatectomy 3 months after initiation of treatment.
Preoperative and intraoperative biopsies of the prostate gland will be utilized for analysis
of prostatic hormones, gene expression and apoptosis.
Inclusion Criteria:
1. Men 18 years or older with a histologic diagnosis of clinically localized prostate
cancer prior to radical prostatectomy as defined by:
- Clinical stage T1-T2b
- Prostate specific Antigen (PSA) less than 20
- Gleason score 7-10
2. Patient's tumor must be considered surgically resectable .
3. Eastern Cooperative Group (ECOG) performance status of 0-1.
4. Life expectancy greater than 2 years.
5. Able to understand and give informed consent.
6. Laboratory values must be within specified limits.
Exclusion Criteria:
1. Patients with locally advanced or high risk disease not meeting the criteria defined
above.
2. Patients who have a total testosterone less than 280 ng/dL.
3. Patients who are receiving any other investigational therapy.
4. Patients with an active serious infection or other serious underlying medical
condition.
5. Dementia or significantly altered mental status that would prohibit the understanding
and/or giving of informed consent.
6. Histologic evidence of small cell carcinoma of the prostate.
7. Patients who are currently receiving active therapy for other neoplastic disorders.
8. Patients who are receiving any androgens, estrogens or progestational agents.
9. Patients who are taking drugs or herbal supplements which affect androgen metabolism
(e.g., spironolactone, aprepitant, bexarotene, clarithromycin, itraconazole,
ketoconazole, St. John's wort).
10. Patients who have chronic active hepatitis.
11. Patients taking any of the following medications who cannot discontinue these
medications for three months during administration of ketoconazole; statin cholesterol
medications, cyclosporine, isoniazid, rifampin, terfenadine, triazolam or astemizole.
12. Patients who have history of cerebrovascular accident, deep venous thrombosis,
pulmonary emboli, unstable angina or clinical congestive heart failure.
13. Medical conditions, which, in the opinion of the investigators would jeopardize either
the patient or the integrity of the data obtained.
14. Patients unwilling to use contraceptives while on study.
15. Patients with a risk of nodal involvement of greater than 10% should have received a
bone scan and CT of the pelvis prior to screening for the study as part of standard of
care.
We found this trial at
2
sites
Univ of Washington Founded in 1861 by a private gift of 10 acres in what...
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