雄激素拮抗剂和前列腺癌.ppt
去势治疗（去势治疗（Castration）雄激素拮抗剂（雄激素拮抗剂（Anti-androgen）全雄阻断（全雄阻断（TAB）最大雄激素阻断（最大雄激素阻断（MAB）联合激素治疗（联合激素治疗（CAB）testosterone enters the cell and is reduced to 5dihydrotestosterone(DHT)by 5-reductase.DHT binds to the androgen receptor,and the complex moves into the nucleus,where transcription control of Androgen dependent genes occurs.竞争细胞内雄激素（DHT-睾酮）受体位点，同时作为一种孕激素，可以直接抑制垂体LH的产生，降低睾酮的产生。代表药物：醋酸氯羟甲基孕酮（醋酸色普龙，CPA）仅有竞争细胞内雄激素（DHT-睾酮）受体位点的作用，同时可以竞争性的抑制下丘脑的负反馈抑制作用，因此引起继发性的下丘脑GnRH及LH的分泌增加，从而刺激睾酮的分泌。代表药物：氟他胺（福至尔）、尼鲁米特和比卡鲁胺（康士得）。作用结果单纯雄激素拮抗剂类固醇雄激素拮抗剂血浆睾酮（T）双氢睾酮（DHT）促黄体生成素（LH）雌二醇（E2）前列腺体积乳房肿大 方式血睾酮（ng/ml）达到最低点时间参考文献正常血睾水平5.72 1.35 ng/mLCoffey（1992）(19.8 4.7 nmol/L)手术去势正常水平5108.6 3.2hLin et al(1994)0.2(0.2nmol/)LHRH类似物0.2(0.2nmol/)34weekCampbells urol(8th)乙烯雌酚1mg/day0.8第7天测定Maclder et al(1972)0.75第4周测定Sheaver et al(1973)3mg/day0.2-0.538.3 15.5daysLin et al(1994)flutamide 正常水平的1.5倍Campbells urol(8th)CPA正常水平的25%Campbells urol(8th)DES：3mg/d.NSAAs包括氟他胺 750mg/d、康士得50mg/d、100mg/d、150mg/d.Antiandrogens包括 NSAAs以及cyproterone(类固醇雄激素拮抗剂）cyproterone is not superior to nonsteroidal antiandrogens.一、单纯雄激素拮抗剂与类固醇雄激素拮抗剂相比，患者的生存率无差别No trials directly compared different nonsteroidal antiandrogens.The meta-analysis found a hazard ratio compared with orchiectomy of 1.2027(CI,0.973 to 1.487)for bicalutamide and 1.9583(CI,0.369 to 10.394)for flutamide.二、没有康士德和氟他胺数据的直接对比，如果分别与手术去势相比，康士德的hazard ratio 是1.2027，而氟他胺是1.953。These results suggest that no treatment is better than orchiectomy and that some treatments seem to be less effective.一、所有的治疗中手术去势的效果依然是最佳的，是前列腺癌激素治疗的“金标准”。DES and LHRH agonists as a class are essentially equivalent to rchiectomy 二、乙烯雌酚（3mg/day）与LHRH类似物的治疗效果与手术去势的治疗效果基本等同。patients treated with nonsteroidal*and steroidal antiandrogens seem to have lower survival rates.三、单纯雄激素拮抗剂或类固醇雄激素拮抗剂与手术去势相比，患者（2年）生存率较低。（nonsteroidal包括氟他胺 750mg/d、康士得50mg/d、100mg/d、150mg/d）Most trials that compared an antiandrogen with DES or orchiectomy favored the control arm or found no significant difference.四、大多数的研究显示雄激素拮抗剂的治疗失败时间与手术去势和乙烯雌酚相比无明显统计学差异。多数研究并不支持单独应用雄激素拮抗剂治疗前列腺癌。研究康士得50mg/d、100mg/d、150mg/d的剂量分别与去势治疗相对比的文献，有如下结论：1、康士得50mg或100mg/日治疗前列腺癌的效果不如去势治疗。2、对于M0期的前列腺癌康士得150mg/日 可以达到与去势治疗相同的生存率（随访4年-200周）。3、对于M1期前列腺癌康士得150mg/日的效果不如去势治疗。Urology.1998 Mar;51(3):389-96.Eur Urol.1998;33(5):447-56.Fujikawa对手术去势或药物去势的前列腺癌复发患者，加用氟他胺，结果表明：那些在手术或药物去势治疗后，PSA水平降至4ng/ml水平的前列腺癌患者，前列腺癌复发后加用氟他胺有效。Fujikawa K，Prostate-specific antigen levels and clinical response to flutamide as the second hormone therapy for hormone-refractory prostate carcinoma.Eur Urol.2000 Feb;37(2):218-22.同样，Kucuk在对44名手术去势或药物去势的前列腺癌复发患者加用康士得后，9名（20）患者出现PSA下降50或者更多。Kucuk O,Urology.2001 Jul;58(1):53-8.Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed:a Southwest Oncology Group study(SWOG 9235).1、Maximal androgen blockade for patients with metastatic prostate cancer:outcome of a controlled trial of bicalutamide versus flutamide,each in combination with luteinizing hormone-releasing hormone analogue therapy.Casodex Combination Study Group.Urology.1996 Jan;47(1A Suppl):54-60;discussion 80-4.2、Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma:final report of a double-blind,randomized,multicenter trial.Casodex Combination Study Group.Urology.1997 Sep;50(3):330-6.3、A controlled trial of bicalutamide versus flutamide,each in combination with luteinizing hormone-releasing hormone analogue therapy,in patients with advanced prostate cancer.Casodex Combination Study Group.Urology.1995 May;45(5):745-52.4、A controlled trial of Casodex(bicalutamide)vs.flutamide,each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer.Casodex Combination Study Group.Eur Urol.1996;29 Suppl 2:105-9.1993年Scher和Kelly最早观察到应用氟他胺以达到最大雄激素阻断后出现病情恶化的患者中，约40%撤除氟他胺后，患者病情从生化或临床上出现缓解。这种缓解以撤停缓退瘤后血浆PSA水平下降50%为特征，并可能持续1年以上。该现象术语称之为氟他胺撤停综合征。以后的研究有发现，在停用康士得或非类固醇雄激素拮抗剂的患者中约20%也会发生这一综合征。因此，现在我们称这种现象为：雄激素撤退综合征（antiandrogen withdrawal syndrome 或antiandrogen rebound）.可能机制之一是具有突变的雄激素受体肿瘤细胞没有被清除而引起克隆繁殖。也有解释为氟他胺或其它雄激素拮抗剂能引起突变的前列腺癌细胞系（例如LNCaP）刺激性增生的结果。1、campbells urology(8th)2、Small EJ,J Clin Oncol.1997 Jan;15(1):382-8.Prostate specific antigen decreases after withdrawal of antiandrogen therapy with bicalutamide or flutamide in patients receiving combined androgen blockade.那么在撤去氟他胺或康士得多久会出现PSA水平的下降？Schellhammere的研究认为在撤去氟他胺几天内（a few days)，患者PSA就会下降；而康士得需要撤去48周，患者的PSA才会下降。J Urol.1997 May;157(5):1731-5.因此Paul建议，应该在氟他胺停用4周，康士得停用8周时，患者还没有出现血PSA下降，才能够除外雄激素撤退综合征。1、Small EJ,J Clin Oncol.1997 Jan;15(1):382-8.Prostate specific antigen decreases after withdrawal of antiandrogen therapy with bicalutamide or flutamide in patients receiving combined androgen blockade.2、SchellhammerePF,J Urol.1997 May;157(5):1731-5.Prostate specific antigen decreases after withdrawal of antiandrogen therapy with bicalutamide or flutamide in patients receiving combined androgen blockade.3、pau
