Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
Lancet Oncol. 2021 Mar;22(3):402-410. doi: 10.1016/S1470-2045(20)30730-0.
The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer.
For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R was 0·7 or greater.
75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R 0·28 [0·0045-0·65]), and local failure (R 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R 0·78 [0·59-0·89]) correlated strongly.
Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date.
Prostate Cancer Foundation and National Institutes of Health.
国际前列腺癌临床终点工作组已经确定无转移生存是局部前列腺癌的总生存的替代终点，这是基于 19 项主要基于放疗的试验的结果。我们试图全面评估局部前列腺癌所有随机试验中常用中间临床终点的综合试验水平表现。
在这项荟萃分析中，我们在 1970 年 1 月 1 日至 2020 年 1 月 15 日期间，在 PubMed 上搜索了所有局部或生化复发前列腺癌的试验。合格的试验必须是随机的、治疗性的，报告总生存和至少一个中间临床终点，并且样本量至少为 70 例。排除转移性疾病的试验。中间临床终点包括生化失败、局部失败、远处转移、生化失败无进展生存、无进展生存和无转移生存。使用中间临床终点对数风险比的倒数加权的 R 值评估替代关系的第二个条件（即中间临床终点与总生存的治疗效果的相关性），以确定候选替代关系。如果 R 值为 0.7 或更大，则认为中间临床终点是总生存的替代终点。
我们的分析纳入了 75 项试验（53631 例患者）。中位随访时间为 9.1 年（IQR 5.7-10.6）。生化失败（R 0.38 [95%CI 0.11-0.64]）、生化失败无进展生存（R 0.12 [0.0030-0.33]）、生化失败和临床失败（R 0.28 [0.0045-0.65]）和局部失败（R 0.085 [0.00-0.37]）与总生存相关性较差。无进展生存（R 0.46 [95%CI 0.22-0.67]）与总生存呈中度相关，而无转移生存（R 0.78 [0.59-0.89]）与总生存呈高度相关。
基于生化和局部失败的中间临床终点不符合荟萃分析方法的第二个条件，不能作为局部前列腺癌的总生存替代终点。我们的发现验证了无转移生存是迄今为止唯一确定的总生存替代终点。
前列腺癌基金会和美国国立卫生研究院。
