Kirby R, Robertson C, Turkes A, Griffiths K, Denis L J, Boyle P, Altwein J, Schröder F
Department of Urology, St. George's Hospital, Tooting, United Kingdom.
Prostate. 1999 Jul 1;40(2):105-14. doi: 10.1002/(sici)1097-0045(19990701)40:2<105::aid-pros6>3.0.co;2-9.
It was very reasonable to consider that the combination of the 5alpha-reductase, finasteride, and a pure antiandrogen such as flutamide should provide an effective form of maximal androgen blockade (MAB). Finasteride decreases intraprostatic levels of 5alpha-dihydrotestosterone (DHT), and the antiandrogen would restrain the biological action of the residual DHT by interfering with its association with androgen receptor. This form of MAB should sustain the concentration of testosterone in plasma, thereby maintaining sexual function and reasonable quality of life. In order to investigate this, a randomized multicenter phase II clinical trial of patients with untreated M1 cancer of the prostate was developed and undertaken.
Patients were randomly allocated to one of three treatment schedules: 1) goserelin, 3.6 mg, s.c., monthly in combination with flutamide, 250 mg., t.i.d. and a placebo, daily, in the image of 2 x 5 mg finasteride; 2) goserelin, 3.6 mg., s.c., monthly in combination with finasteride, 10 mg (2 x 5 mg, daily) and a placebo (t.i.d.) in the image of flutamide; and 3) finasteride, 10 mg (2 x 5 mg, daily) in combination with flutamide (250 mg, t.i.d.). The reduction in concentration of serum PSA at 24 weeks was the endpoint of interest.
Baseline prostate-specific antigen (PSA) levels of the patients in the three groups were very similar. There was a substantial decrease in levels of PSA in the three groups prior to the end of the study, the percent decrease in the groups being: 1) goserelin and flutamide combination, 99.1% (95% Confidence interval (CI), 97.7, 99.6); 2) goserelin and finasteride combination, 98.75% (95% CI, 97.1, 99.5); and 3) finasteride and flutamide combination, 97.6%, 95% CI, 94.5, 98.9). In the Generalized linear model (GLM) analysis, there was no center by treatment group interaction (P = 20), and there were no significant differences between centers (P = 0.059) nor among the three treatment groups (P = 0.16).
The decrease in levels of PSA in such a group of patients with M1 cancer of the prostate over a 24-week period was surprisingly large, and the differences in these decreased levels between the three treatment arms were remarkably small. There were no apparent differences in bone scan scores, World Health Organization (WHO) performance status, and pain scores between the arms. With regard to sexual function associated with quality of life, there were the understandable difficulties of data collection from patients treated with goserelin.
认为5α-还原酶抑制剂非那雄胺与氟他胺等纯抗雄激素药物联合应用应能提供一种有效的最大雄激素阻断（MAB）形式，这是非常合理的。非那雄胺可降低前列腺内5α-双氢睾酮（DHT）水平，而抗雄激素药物会通过干扰其与雄激素受体的结合来抑制残余DHT的生物学作用。这种MAB形式应能维持血浆中睾酮的浓度，从而维持性功能和合理的生活质量。为了对此进行研究，开展并实施了一项针对未经治疗的前列腺M1期癌患者的随机多中心II期临床试验。
患者被随机分配至三种治疗方案之一：1）戈舍瑞林3.6毫克，皮下注射，每月一次，联合氟他胺250毫克，每日三次，以及安慰剂，每日一次，模拟2×5毫克非那雄胺；2）戈舍瑞林3.6毫克，皮下注射，每月一次，联合非那雄胺10毫克（每日2×5毫克）以及安慰剂（每日三次），模拟氟他胺；3）非那雄胺10毫克（每日2×5毫克）联合氟他胺（250毫克，每日三次）。24周时血清PSA浓度的降低是感兴趣的终点。
三组患者的基线前列腺特异性抗原（PSA）水平非常相似。在研究结束前，三组患者的PSA水平均大幅下降，各组下降百分比分别为：1）戈舍瑞林与氟他胺联合组，99.1%（95%置信区间（CI），97.7，99.6）；2）戈舍瑞林与非那雄胺联合组，98.75%（95%CI，97.1，99.5）；3）非那雄胺与氟他胺联合组，97.6%，95%CI，94.5，98.9）。在广义线性模型（GLM）分析中，治疗组与中心之间无交互作用（P = 0.20），各中心之间（P = 0.059）以及三个治疗组之间（P = 0.16）均无显著差异。
在24周期间，此类前列腺M1期癌患者的PSA水平下降幅度惊人地大，且三个治疗组之间这些下降水平的差异非常小。各组之间在骨扫描评分、世界卫生组织（WHO）表现状态和疼痛评分方面无明显差异。关于与生活质量相关的性功能，从接受戈舍瑞林治疗的患者中收集数据存在可理解的困难。
