Armstrong Andrew J, Garrett-Mayer Elizabeth, Ou Yang Yi-Chun, Carducci Michael A, Tannock Ian, de Wit Ronald, Eisenberger Mario
Duke Comprehensive Cancer Center, Durham, NC 27710, USA.
J Clin Oncol. 2007 Sep 1;25(25):3965-70. doi: 10.1200/JCO.2007.11.4769.
It is currently unclear if early prostate-specific antigen (PSA) or pain improvements are adequate surrogates for overall survival in men with metastatic hormone-refractory prostate cancer (HRPC). Here we examined various degrees of PSA decline and pain response as surrogates for the survival benefit observed in the TAX327 trial.
In the TAX327 trial, 1,006 men with HRPC were randomly assigned to receive docetaxel in two schedules, or mitoxantrone, each with prednisone: 989 men provided data on 3-month PSA decline. Surrogacy was examined for post-treatment changes in PSA and pain response using Cox proportional hazards models to calculate the proportion of treatment effect (PTE) explained by each potential surrogate.
A > or = 30% PSA decline within 3 months of treatment initiation provides the highest degree of surrogacy, with a PTE of 0.66 (95% CI, 0.23 to 1.0), and was associated with a hazard ratio (HR) of 0.50 (95% CI, 0.43 to 0.58) for overall survival after adjusting for treatment effect. Introduction of a > or = 30% PSA decline is predictive of survival regardless of treatment arm. Other changes in PSA or PSA kinetics, PSA normalization, and pain responses were highly prognostic but weaker surrogates for survival.
In the TAX327 trial, a PSA decline of > or = 30% within 3 months of chemotherapy initiation had the highest degree of surrogacy for overall survival, confirming data from the Southwest Oncology Group 9916 trial. However, given the wide CIs around the estimate of this moderate surrogate effect, overall survival should remain the preferred end point for phase III trials of cytotoxic agents in HRPC.
目前尚不清楚早期前列腺特异性抗原（PSA）下降或疼痛改善是否足以作为转移性激素难治性前列腺癌（HRPC）男性患者总生存期的替代指标。在此，我们研究了不同程度的PSA下降和疼痛反应，作为TAX327试验中观察到的生存获益的替代指标。
在TAX327试验中，1006例HRPC男性患者被随机分配接受两种多西他赛给药方案或米托蒽醌治疗，均联合泼尼松：989例患者提供了3个月时PSA下降的数据。使用Cox比例风险模型检查PSA和疼痛反应的治疗后变化的替代指标，以计算每个潜在替代指标所解释的治疗效果比例（PTE）。
治疗开始后3个月内PSA下降≥30%具有最高程度的替代指标作用，PTE为0.66（95%CI，0.23至1.0），在调整治疗效果后，其总生存期的风险比（HR）为0.50（95%CI，0.43至0.58）。无论治疗组如何，PSA下降≥30%均能预测生存情况。PSA或PSA动力学的其他变化、PSA正常化以及疼痛反应均具有高度预后价值，但作为生存替代指标的作用较弱。
在TAX327试验中，化疗开始后3个月内PSA下降≥30%对总生存期具有最高程度的替代指标作用，这证实了西南肿瘤协作组9916试验的数据。然而，鉴于该中度替代效应估计值的置信区间较宽，总生存期仍应作为HRPC细胞毒性药物III期试验的首选终点。
