Biochemical and pathological effects of 8 months of neoadjuvant androgen withdrawal therapy before radical prostatectomy in patients with clinically confined prostate cancer

Purpose: A prospective, nonrandomized trial was initiated to determine the duration of neoadjuvant therapy required for prostate specific antigen (PSA) to reach its nadir, evaluate the ability of an ultrasensitive assay to measure decreases in PSA less than 0.2 mu g./l., and characterize the effects of 8 months of neoadjuvant therapy on pathological stage, positive margin rates, proliferation and tumor marker immune-staining. Materials and Methods: We evaluated 50 patients with clinically localized prostate cancer treated by 8 months of reversible androgen ablation before radical prostatectomy. Serum PSA and testosterone levels were measured monthly. Results: Serum PSA decreased by 84% after 1 month and by a further 52% between 3 and 8 months. Using an ultrasensitive assay, serum PSA decreased to undetectable levels (less than 0.1 mu g./l.) or reached its nadir in 22% of the cases after 3 months, 42% after 5 months and 84% after 8 months. Overall, the positive margin rate was 4%. Of the cases 68% were organ-confined and 24% were specimen-confined. The positive margin rate was not increased after reevaluation with cytokeratin, PSA and prostatic acid phosphatase immune-staining but of 4 cases initially staged as PO on hematoxylin and eosin evaluation 2 had microscopic foci of cancer with prostatic acid phosphatase staining. Immune-staining with the proliferation markers proliferation cell nuclear antigen and Ki-67 showed decreased staining in surgical specimens relative to pretreatment needle biopsy specimens, which suggests that outgrowth of androgen independent clones does not develop during prolonged neoadjuvant therapy. Conclusions: Eight months of neoadjuvant androgen withdrawal therapy results in low positive margin rates and PSA nadir levels. The initial rapid decrease in PSA results from cessation of androgen regulated PSA synthesis and apoptosis, while the ongoing slower decrease reflects decreasing tumor volume.