Materials and Methods

Study Design. This study was an open-label, historically controlled, single center phase IIa study in which men diagnosed with HG PIN were treated with 60 mg/day oftoremifene for 120 days. The study primary objectives were to determine whether toremifene was able to reduce HG PIN in men with HG PIN, to evaluate its effect on other intermediate endpoints including serum total PSA and % free PSA, as well as its safety and impact on male hormonal status. The effects of toremifene on quality of life issues, i.e., changes in libido, erectile function, and hot flashes were also assessed. Once informed consent was obtained, subjects were referred to the study if any prostate biopsy within the last 6 mo had HG PIN (at least 6 prostate cores were needed to be included in the study). The prostate pathology was re-evaluated to confirm HG PIN. Subjects who had HG PIN and fulfilled all of the eligibility requirements were enrolled in the study. At study day 120, subjects underwent transrectal ultrasound guided biopsies (8 prostate cores).

Exclusion/Inclusion Criteria. Subjects were eligible for the study ifthey met the following criteria: Willing to participate in the study and sign an informed consent, be a > 30 years old male, have a histologically confirmed Grade II and/or III PIN on biopsy; serum PSA < 20 ng/ml, Zubrod performance status < 1, adequate bone marrow, liver, and renal function. Subjects were excluded from the study if they had any of the following: Underwent prior experimental therapy for chemoprevention, evidence of PCA on initial evaluation (local, regional, and/or distant metastasis), active systemic viral, bacterial, or fungal infections requiring treatment, a serious concurrent illness or psychological, familial, sociological, geographical, or other concomitant conditions which did not permit adequate follow-up and compliance with the study protocol, concurrent treatment with other investigational agents, were taking finasteride or T, herbal medicine or dietary supplements for prostate health, and had a history of thromboembolic disease.

Efficacy and Safety Measures. Prostate biopsy and a quality of life questionnaire were evaluated at baseline and at day 120. Serum PSA was evaluated at baseline, days 60 and 120. Final prostate biopsies were obtained under transrectal ultrasound guidance and standardized with 8 total biopsy cores taken from right and left apex, right and left midbase, right and left base, and right and left lateral base. All samples were reviewed by a single pathologist. Investigators questioned subjects on any signs/symptoms experienced since the previous visit to determine whether the subject experienced any adverse event (AE). AEs were assessed using the revised NCI Common Toxicity Criteria.

Statistics. The primary efficacy variable was the determination ofthe response of HG PIN by prostate biopsy. T-tests were performed for serum PSA, hormones, hematology, biochemistry, and quality of life to determine whether changes from baseline were different from zero.

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