Effects of IAS in Men With Localized Biochemical Relapsed Prostate Cancer
Effects of IAS in Men With Localized Biochemical Relapsed Prostate Cancer
This study was a prospective analysis in men with localized prostate cancer who had rising
 Prostate Specific Antigen (PSA) levels after definitive treatment with surgery or radiation.
 Patients received Intermittent Androgen Suppression (IAS) in 9 month cycles until they became
 metastatic, became castrate resistant, or withdrew from the study. Subjects were monitored
 for time to development of Castration Resistant Prostate Cancer (CRPC) and overall survival.
 They were also monitored for the impact of IAS on a variety of neuro-psychiatric assessments
 and on bone density.
The standard first line treatment for men with early stage newly diagnosed localized prostate
 cancer is a surgical removal of the prostate, localized external beam radiation,
 brachytherapy, or a combination of surgery and radiation. In most patients Prostate Specific
 Antigen (PSA) levels will decline after these localized treatments, demonstrating a response
 to these therapies. However despite an initial response to localized treatment, some men will
 go on to later develop a rise in PSA levels, an indicator of Biochemical Relapsed Prostate
 Cancer (BRPC). For BRPC patients who have not yet developed metastasis, the standard
 treatment is Androgen Deprivation Therapy (ADT) to decrease levels of Testosterone,
 subsequently decreasing PSA levels. A low value for the PSA is more desirable as it may
 indicate no tumor growth.

 ADT may be administered as a continuous treatment (Continuous Androgen Suppression, or CAS)
 or as intermittent treatment (Intermittent Androgen Suppression, or IAS). This treatment is
 continued until the development of Castration Resistant Prostate Cancer (CRPC), indicated by
 a rise in PSA despite ADT. Giving the hormone therapy intermittently (in cycles of treatment
 and off treatment periods) appears to delay the change of prostate cancer to a type of
 prostate cancer that resists hormone therapy, prolonging efficacy of ADT monotherapy. IAS may
 also decrease the impact of ADT on mental status.

 This study evaluated the effect of intermittent androgen suppression on time to androgen
 independent progression (the development of castration resistant disease) and overall
 survival in men with localized prostate cancer. Subjects were also evaluated for the effects
 of intermittent androgen suppression on a variety of neuro-psychiatric assessments and on
 bone density.

 The subjects in this study had a rising PSA value after definitive therapy either with
 radical prostatectomy or external beam irradiation for the treatment of prostate cancer. All
 subjects were males at or over the age of 21 years.

 New subjects were introduced to this study protocol (along with other non-study treatment
 options) during a clinic visit with Dr. Higano or another sub-investigator. After informed
 consent was obtained, subjects underwent the following screening procedures before starting
 treatment: Bone density scan (DEXA), Technetium-99 bone scan, CT scan of the chest, abdomen,
 and pelvis, blood draw, and neuro-psychiatric assessments. Subjects then began androgen
 suppression with a two-week lead-in of Flutamide, followed by 9 monthly injections of
 Leuprolide Acetate. During the treatment, they had quarterly clinic visits and blood draws.
 Their PSA levels were monitored monthly, and if their PSA reached the appropriate nadir at by
 month 9, the androgen suppression was interrupted. At the end of each treatment cycle,
 subjects underwent another bone density test, blood draw, problem solving test, and
 neuro-psychiatric assessments.

 During the "off treatment" phase, the subject will again had quarterly clinic visits, blood
 draws, and neuro-psychiatric assessments. PSA and testosterone were be monitored monthly.
 Once the PSA reached the appropriate threshold, the subject performed another set of
 screening procedures and resumed treatment for another 9 months. This cycle continued until
 the patient withdrew from the study, was taken off the study due to toxicities or the
 decision of the investigator, or until the treatment with IAS was no longer effective in
 controlling the prostate cancer. The neuro-psychiatric assessments were only performed during
 the subject's first cycle of treatment (consisting of the 9 months on treatment, and at month
 3 of the off treatment period afterwards).
Inclusion Criteria:

 -  Biochemical relapse (rising PSA) after initial treatment (radiation therapy,
 brachytherapy, or radical prostatectomy) for histologically or cytologically confirmed
 adenocarcinoma of the prostate

 -  Clinical stage A2, B, C, D1

 -  Age: older than 21 years old

 -  Performance status of 0 or 1

 -  Pretreatment serum testosterone, normal range (or no clinical evidence of testosterone
 deficiency).

 -  If less than 30 months since completion of radiation therapy, biopsy of prostate
 suggested within 6 months of study entry. If more than or equal to 30 months since
 completion of radiation therapy, biopsy of prostate suggested within 1 year.

 -  Written informed consent.

 Exclusion Criteria:

 -  Abnormal bone scan suggestive of metastatic osseous disease.

 -  Previous hormonal manipulation including orchiectomy or any medication with
 significant antiandrogenic activity (combined androgen suppression over 9 months,
 monotherapy antiandrogens, estrogens, ketoconazole). *Neoadjuvant androgen suppression
 therapy of less than or equal to 3 months is allowed, if this androgen suppression
 therapy was completed more than or equal to 1 year prior to study enrollment AND if
 the Testosterone level is within the normal ranges.

 -  Any systemic chemotherapy or curative radiotherapy within 6 months.

 -  Hepatic dysfunction:

 -  Total bilirubin greater than 2.0 mg/dl

 -  Aspartate transaminase (AST; SGOT) greater than 3 times the upper limit of normal
 range

 -  Lactate dehydrogenase (LDH) greater than 3 times the upper limit of normal
 range).

 -  Renal dysfunction:

 -  Blood urea nitrogen (BUN) greater than 40 mg/dl

 -  Serum Creatinine greater than 2.0 mg/dl.

 -  History or presence of other malignancy within the last 5 years (except treated
 squamous/basal cell carcinoma of the skin or superficial bladder carcinoma).

 -  Hypersensitivity to flutamide or leuprolide.