Gleave M E, Goldenberg S L, Chin J L, Warner J, Saad F, Klotz L H, Jewett M, Kassabian V, Chetner M, Dupont C, Van Rensselaer S
Vancouver Hospital and Health Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada.
J Urol. 2001 Aug;166(2):500-6; discussion 506-7.
A prospective phase 3 trial was initiated to determine whether 8 compared with 3-month neoadjuvant hormonal therapy reduces prostate specific antigen (PSA) recurrence rates after radical prostatectomy. Our interim analysis includes secondary end points of differences in biochemistry, pathology and adverse events between the 2 groups.
Men with clinically confined prostate cancer were randomized to receive 7.5 mg. leuprolide intramuscularly monthly and 250 mg. flutamide orally 3 times daily for 3 or 8 months before radical prostatectomy. Our study was powered to detect a 35% decrease in PSA recurrence, assuming a 30% recurrence rate in the 3-month arm after 3 years.
A total of 547 men were randomized between August 1995 and April 1998. Men in the 8 and 3-month groups were equally stratified for T stage (29% T1c, 70% T2), Gleason grade (68% less than 4, 32% 4 or greater) and pretreatment PSA (63% less than 10, 27% 10 to 20 and 10% greater than 20 microg./l.). Mean pretreatment PSA was slightly higher in the 8-month compared with the 3-month group (11.64 versus 9.95 microg./l., respectively, p = 0.0539). A total of 44 men withdrew from study before surgery and, therefore, were nonevaluable. Preoperative PSA nadir was less than 0.1 microg./l. in 43.3% versus 75.1% (p <0.0001), and 0.3 microg./l. or greater in 21% versus 9.2% after 3 versus 8 months, respectively (p <0.0006). Mean serum PSA decreased 98% to 0.12 microg./l. after 3 months, with a further 57% to 0.052 microg./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 therapy (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 completed in 500 men, while surgery was aborted intraoperatively in 3. Positive margin rates were significantly lower in the 8 than 3-month group (12% versus 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 diarrhea (p = 0.691, 0.288, respectively). However, men in the 8-month group noticed 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% versus 72%, respectively, p <0.0001).
Ongoing biochemical and pathological regression of prostate tumors occurs between 3 and 8 months of neoadjuvant hormonal therapy, suggesting that the optimal duration of neoadjuvant hormonal therapy is longer than 3 months. Longer followup is needed to determine whether longer therapy alters PSA recurrence rates.
开展一项前瞻性3期试验，以确定与3个月新辅助激素治疗相比，8个月新辅助激素治疗能否降低根治性前列腺切除术后前列腺特异性抗原（PSA）复发率。我们的中期分析包括两组在生化、病理及不良事件方面差异的次要终点。
临床局限性前列腺癌男性患者在根治性前列腺切除术前行随机分组，分别接受每月7.5mg亮丙瑞林肌肉注射及每日口服250mg氟他胺3次，疗程为3个月或8个月。假设3个月疗程组在3年后复发率为30%，我们的研究旨在检测出PSA复发率降低35%。
1995年8月至1998年4月间共有547名男性患者被随机分组。8个月疗程组与3个月疗程组在T分期（29%为T1c，70%为T2）、Gleason分级（68%小于4级，32%为4级或更高）及术前PSA水平（63%小于10μg/L，27%为10至20μg/L，10%大于20μg/L）方面分层均衡。8个月疗程组的平均术前PSA略高于3个月疗程组（分别为11.64μg/L和9.95μg/L，p = 0.0539）。共有44名男性患者在手术前退出研究，因此无法进行评估。术前PSA最低点小于0.1μg/L的比例在3个月疗程组为43.3%，8个月疗程组为75.1%（p <0.0001）；术前PSA最低点大于或等于0.3μg/L的比例在3个月疗程组为21%，8个月疗程组为9.2%（p <0.0006）。3个月后平均血清PSA下降98%至0.12μg/L，3至8个月间进一步下降57%至0.052μg/L。经直肠超声检查显示，3个月新辅助激素治疗后前列腺体积从平均40.6cc降至25.4cc，下降37%（p = 0.0001），8个月后进一步降至22.2cc，下降13%（p = 0.03）。3个月新辅助激素治疗后平均血红蛋白下降15%（从148.2g/dl降至125.4g/dl），此后保持稳定。500名男性患者完成了根治性前列腺切除术，3名患者手术中中止。8个月疗程组的切缘阳性率显著低于3个月疗程组（分别为12%和23%，p = 0.0106）。无致命不良事件发生，两组在不良事件的严重程度或因果关系方面无差异（p = 0.287，0.0564），在肝酶升高或腹泻发生率方面也无差异（分别为p = 0.691，0.288）。然而，8个月疗程组新报告的不良事件数量更多（分别为4.5起和2.9起，p <0.0001），潮热发生率高于3个月疗程组（分别为87%和72%，p <0.0001）。
新辅助激素治疗3至8个月期间前列腺肿瘤持续发生生化及病理消退，提示新辅助激素治疗的最佳疗程长于3个月。需要更长时间的随访来确定更长疗程的治疗是否会改变PSA复发率。
