Diagnostic Center for Disease

Randomized Comparison of Neoadjuvant Treatment Arms in Organ Confined Prostate Cancer using PSA Nadir as the End Point
Ronald E. Wheeler, Scott Yun, Jonathan Vukovich, Charles Metzger, Ahmad Kassraeian, Bradford Moss, and Victor Ching

Introduction and Objectives: Neoadjuvant therapy has become the state of the art methodology for tumor size reduction (downsizing) and alteration from one stage of disease to another (downstaging). Prostate cancer treatment has been enhanced by the timeliness and efficacy of neoadjuvant therapy. Regardless of the methodology used, the PSA (prostate specific antigen) has served as the biologic marker to gauge effectiveness of treatment response. Thus PSA is a surrogate marker to disease suppression or inactivity in the vast majority of cases. The concept of CAB (combined androgen blockade) is well known. This format remains the gold standard for patients with clinical stage C or stage D disease. The goal of such therapy is to provide stabilization of disease, maintain minimal side effects, provide minimal impact on quality of life issues while allowing patient compliance in a cost effective manner. Based upon the belief that an antiandrogen + Finasteride could reduce disease activity as effectively as standard CAB, a study model was designed to compare the two arms prospectively. In a randomized format, an LHRH-a + Flutamide arm was compared to a Flutamide + Finasteride arm. PSA nadir was the pre-selected end point to disease stabilization prior to definitive therapy. It is generally accepted that physicians recognize a low PSA as a marker representative of decreased cancer activity.

Methods: Seventy-six patients with organ confined prostate cancer were randomized to the LHRH-a + Flutamide arm or the Flutamide + Finasteride arm. Organ confinement was largely left to physician judgement and in concert with recognized diagnostic modalities. The initial PSA at disease verification was recorded prior to the initialization of the neoadjuvant treatment arm. Subsequent PSA testing was recorded weekly starting at week 4. PSA testing continued until the PSA nadired at less than 2 ng/ml. At this point, patients were scheduled to undergo definitive treatments including radical prostatectomy, brachytherapy, external beam radiation therapy, combination radiation therapy, or cryosurgery.

Result: Seventy-six patients representing 6 institutions qualified for the study. Patient selection was based upon organ confined prostate cancer using recognized industry standards to validate within a randomized format. Twenty-nine patients were evaluated on an LHRH-a + Flutamide arm while thirty-five patients entered the Flutamide + Finasteride arm. Patient selection for this study was based on the likelihood that definitive therapy would be carried out. Defined treatment included radical prostatectomy, external beam radiation therapy, brachytherapy, and cryotherapy. The average PSA starting point for the Flutamide/Finasteride arm was 10.95 ng/ml (n=35), while the average PSA starting point in the LHRH-a/Flutamide arm was 9.3 ng/ml. The average PSA nadir was .59 ng/ml in the Flutamide/Finasteride arm while the average PSA nadir in the LHRH-a/Flutamide arm was .45 ng/ml. The average change in PSA in the Flutamide/Finasteride arm was 10.36 ng/ml while the average change in PSA in the LHRH-a/Flutamide arm was 8.85 ng/ml. The average days to nadir on the Flutamide/Finasteride arm were 60.06 while the average days to nadir with the LHRH-a/Flutamide arm were 59.83. Patients who failed to complete the neoadjuvant trial numbered twelve (six in each arm). Reasons given for study withdrawal included urinary retention, a positive bone scan, nausea and diarrhea, heart palpitations, hot flashes, history of previous prostate cancer treatment, triple hormone blockade, excessive medicine expense, inability to nadir the PSA or patient non-compliance.

Conclusion: While no one has criticized the ability of CAB to nadir cancer activity through the use of PSA, the use of an antiandrogen + Finasteride is a novel if not a new approach in the battle for prostate cancer suppression. While economic ramifications of this study are significant, both the physician and patient are given an opportunity to nadir disease activity with a very user friendly and cost effective methodology, heretofore not identified. Additionally, it would appear that the side effect profile would favor the novel Flutamide/Finasteride approach.