Petrylak Daniel P, Ankerst Donna Pauler, Jiang Caroline S, Tangen Catherine M, Hussain Maha H A, Lara Primo N, Jones Jeffrey A, Taplin Mary Ellen, Burch Patrick A, Kohli Manish, Benson Mitchell C, Small Eric J, Raghavan Derek, Crawford E David
Columbia University, New York, NY 10032, USA.
J Natl Cancer Inst. 2006 Apr 19;98(8):516-21. doi: 10.1093/jnci/djj129.
The identification of surrogate endpoints that can replace true outcome endpoints is crucial to the rapid evaluation of new cancer drugs. Retrospective analyses of phase II and III trials in metastatic androgen-independent prostate cancer have shown associations between declines in serum prostate-specific antigen (PSA) levels and survival. We evaluated PSA changes as potential surrogate markers for survival by using data from a clinical trial.
Men with androgen-independent prostate cancer were randomly assigned to either docetaxel/estramustine (D/E) or mitoxantrone/prednisone (M/P) treatment on Southwest Oncology Group Protocol 99-16. Of 674 eligible patients, 551 had a baseline PSA measurement and at least one PSA measurement during the first 3 months on protocol. PSA level declines of 5%-90% and PSA velocity at 1, 2, and 3 months were tested for surrogacy by using three statistical criteria: Prentice's criteria, the proportion of treatment effect explained, and the proportion of variation explained. All statistical tests were two-sided.
Three-month PSA level declines of 20%-40%, a 2-month PSA decline of 30%, and PSA velocity at 2 and 3 months met all three surrogacy criteria. For example, a 3-month PSA decline of at least 30% was associated with a more than 50% decrease in the risk of death compared with the lack of such a decline (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.34 to 0.55; P < .001), and the increased risk of death for men treated with M/P compared with D/E (HR = 1.24, 95% CI = 1.02 to 1.51; P = .032) lost statistical significance after adjustment for this surrogate, whereas the decrease in risk of death associated with a 3-month 30% PSA decline remained statistically significant after adjustment for treatment. PSA level declines of 50%, commonly reported in clinical trials, did not meet the criteria for surrogacy.
Several PSA measures satisfied the surrogacy criteria for survival in a retrospective analysis of data from SWOG 99-16. However, these measures await prospective validation in future clinical trials of chemotherapy in men with androgen-independent prostate cancer.
识别可替代真实结局终点的替代终点对于新癌症药物的快速评估至关重要。转移性去势抵抗性前列腺癌的II期和III期试验的回顾性分析显示，血清前列腺特异性抗原（PSA）水平下降与生存率之间存在关联。我们通过一项临床试验的数据评估PSA变化作为生存的潜在替代标志物。
根据西南肿瘤协作组方案99 - 16，将去势抵抗性前列腺癌男性患者随机分配至多西他赛/雌莫司汀（D/E）或米托蒽醌/泼尼松（M/P）治疗组。在674例符合条件的患者中，551例在方案治疗的前3个月有基线PSA测量值且至少有一次PSA测量值。使用三种统计标准（Prentice标准、治疗效果解释比例和变异解释比例）对5% - 90%的PSA水平下降以及1、2和3个月时的PSA速度进行替代指标检测。所有统计检验均为双侧检验。
3个月时PSA水平下降20% - 40%、2个月时PSA下降30%以及2和3个月时的PSA速度符合所有三项替代指标标准。例如，与无此类下降相比，3个月时PSA至少下降30%与死亡风险降低超过50%相关（风险比[HR] = 0.43，95%置信区间[CI] = 0.34至0.55；P <.001），并且与D/E治疗相比，M/P治疗男性的死亡风险增加（HR = 1.24，95% CI = 1.02至1.51；P =.032）在根据该替代指标进行调整后失去统计学意义，而与3个月时PSA下降30%相关的死亡风险降低在根据治疗进行调整后仍具有统计学意义。临床试验中常见的PSA水平下降50%不符合替代指标标准。
在对SWOG 99 - 16数据的回顾性分析中，几种PSA测量方法符合生存替代指标标准。然而，这些测量方法有待在未来去势抵抗性前列腺癌男性化疗临床试验中进行前瞻性验证。
