Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: Biochemical and pathological effects

Purpose: A prospective phase 3 trial was initiated to determine whether 8 c ompared with 3-month neoadjuvant hormonal therapy reduces prostate specific antigen (PSA) recurrence rates after radical prostatectomy. Our interim an alysis includes secondary end points of differences in biochemistry, pathol ogy and adverse events between the 2 groups. Materials and Methods: Men with clinically confined prostate cancer were ra ndomized to receive 7.5 mg. leuprolide intramuscularly monthly and 250 mg. flutamide orally 3 times daily for 3 or 8 months before radical prostatecto my. Our study was powered to detect a 35% decrease in PSA recurrence, assum ing a 30% recurrence rate in the 3-month arm after 3 years. Results: A total of 547 men were randomized between August 1995 and April 1 998. Men in the 8 and 3-month groups were equally stratified for T stage (2 9% T1c, 70% T2), Gleason grade (68% less than 4, 32% 4 or greater) and pret reatment PSA (63% less than 10, 27% 10 to 20 and 10% greater than 20 mug./l .). Mean pretreatment PSA was slightly higher in the 8-month compared with the 3-month group (11.64 versus 9.95 mug./l., respectively, p = 0.0539). A total of 44 men withdrew from study before surgery and, therefore, were non evaluable. Preoperative PSA nadir was less than 0.1 mug./l. in 43.3% versus 75.1% (p <0.0001), and 0.3 mug./l. or greater in 21% versus 9.2% after 3 v ersus 8 months, respectively (p <0.0006). Mean serum PSA decreased 98% to 0 .12 mug./l. after 3 months, with a further 57% to 0.052 mug./l. from 3 to 8 months. Transrectal ultrasound determined that prostatic volume decreased 37% from a mean of 40.6 to 25.4 cc after 3-month neoadjuvant hormonal thera py (p = 0.0001) and a further 13% to 22.2 cc after 8 months (p 0.03). Mean hemoglobin decreased 15% (148.2 to 125.4 gm./dl.) after 3-month neoadjuvant hormonal therapy but stabilized thereafter. Radical prostatectomy was comp leted in 500 men, while surgery was aborted intraoperatively in 3, Positive margin rates were significantly lower in the 8 than 3-month group (12% ver sus 23%, respectively, p = 0.0106). There were no fatal adverse events and no differences between the 2 groups in the severity or causality (p = 0.287 , 0.0564) of adverse events, or incidence of increased liver enzymes or dia rrhea (p = 0.691, 0.288, respectively). However, men in the 8-month group n oticed a higher number of newly reported adverse events (4.5 versus 2.9, p <0.0001) and higher incidence of hot flushes than the 3-month group (87% ve rsus 72%, respectively, p <0.0001). Conclusions: Ongoing biochemical and pathological regression of prostate tu mors occurs between 3 and 8 months of neoadjuvant hormonal therapy, suggest ing that the optimal duration of neoadjuvant hormonal therapy is longer tha n 3 months. Longer followup is needed to determine whether longer therapy a lters PSA recurrence rates.