Division of Biostatistics, Dana-Farber Cancer Institute, Boston, MA.
International Drug Development Institute, Louvain la Neuve, Belgium.
J Clin Oncol. 2020 Sep 10;38(26):3032-3041. doi: 10.1200/JCO.19.03114. Epub 2020 Jun 18.
Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion.
EFS was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate-ICECaP-database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an ≥ 0.7.
Data for 10,350 patients were analyzed from 15 radiation therapy-based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall's tau from a copula model. At the trial level, the was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS.
EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials.
最近，我们已经证明，无转移生存是中高危局限性前列腺癌患者总生存（OS）的有力替代指标，并能加速新辅助（neo）治疗的评估。事件无进展生存（EFS），一种更早的基于前列腺特异性抗原（PSA）的复合终点，可能进一步加快试验完成速度。
EFS 定义为从随机分组到首次出现疾病复发证据的时间，包括生化失败、局部或区域复发、远处转移或任何原因死亡，或在最后一次 PSA 评估时截尾。从中立临床终点前列腺癌国际协作组（ICECaP）数据库中的试验中分析了可评估 PSA 和疾病随访数据的个体患者数据。我们通过确定 EFS 与 OS（患者水平）的相关性和治疗效果（危险比[HR]）对 EFS 和 OS（试验水平）的相关性，使用两阶段荟萃分析验证模型来评估 EFS 对 OS 的替代作用。预先定义了一个临床相关的替代物，即 ≥0.7。
从 1987 年至 2011 年期间进行的 15 项基于放射治疗的试验中分析了 10350 名患者的数据，中位随访时间为 10 年。在患者水平上，EFS 与 OS 的相关性为 0.43（95%CI，0.42 至 0.44），这是通过来自Copula 模型的 Kendall's tau 测量的。在试验水平上，来自 log(HR)-OS 对 log(HR)-EFS 的加权线性回归的 =0.35（95%CI，0.01 至 0.60）。
EFS 是 OS 的弱替代指标，不适合作为替代 OS 的中期临床终点，以加速原发性放射治疗试验的前列腺癌治疗的 III 期（neo）辅助试验。
