Department of Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Lancet Oncol. 2022 Oct;23(10):1332-1342. doi: 10.1016/S1470-2045(22)00506-X. Epub 2022 Sep 1.
Recurrence-free survival has been used as a surrogate endpoint for overall survival in trials involving patients with resected colorectal liver metastases. We aimed to assess the correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases to determine the adequacy of this surrogate endpoint.
In this retrospective study and meta-analysis, we compiled an institutional cohort of consecutive patients who had complete resection of colorectal liver metastases from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) prospective database. Patients were eligible for inclusion if they were aged 18 years or older, and underwent hepatectomy, with or without operative ablation, between Jan 1, 1991, and April 30, 2019. We estimated overall survival and recurrence-free survival probabilities at various timepoints using the Kaplan-Meier method, and we assessed pairwise associations between these endpoints using Spearman's rank correlation. We also did a meta-analysis of adjuvant phase 3 clinical trials for colorectal liver metastases to assess the correlation between hazard ratios (HRs) for recurrence-free survival and overall survival. We searched MEDLINE for articles of phase 3 randomised controlled trials analysing adjuvant treatment strategies for resected colorectal metastases from database inception to Jan 1, 2022. The titles and abstracts of identified studies were screened before full-text screening and summary data were either recalculated or extracted manually from the published Kaplan-Meier curves (depending on data availability).
Data were available for 3299 patients in the institutional database, of whom 2983 were eligible for inclusion in our cohort. Median follow-up was 8·4 years (95% CI 7·9-9·1) , during which time there were 1995 (67%) disease recurrences and 1684 (56%) deaths. Median recurrence-free survival was 1·3 years (95% CI 1·3-1·4) and median overall survival was 5·2 years (95% CI 5·0-5·5). 1428 (85%) of 1684 deaths were preceded by recurrence, and median time from recurrence to death was 2·0 years (IQR 1·0-3·4). Pairwise correlations between recurrence-free survival and overall survival were low to moderate, with a correlation estimate ranging from 0·30 (SD 0·17) to 0·56 (0·13). In the meta-analysis of adjuvant clinical trials, the Spearman's correlation coefficient between recurrence-free survival HR and overall survival HR was r=0·20 (p=0·71).
We found a minimal correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases. Recurrence-free survival is an inadequate surrogate endpoint for overall survival in this disease setting.
US National Cancer Institute.
在涉及结直肠肝转移切除患者的试验中，无复发生存已被用作总生存的替代终点。我们旨在评估结直肠肝转移切除后无复发生存与总生存之间的相关性，以确定该替代终点的充分性。
在这项回顾性研究和荟萃分析中，我们从 Memorial Sloan Kettering Cancer Center（美国纽约州纽约市）前瞻性数据库中汇编了连续接受结直肠肝转移完全切除术的机构队列患者。如果患者年龄在 18 岁或以上，并且在 1991 年 1 月 1 日至 2019 年 4 月 30 日期间接受了肝切除术，无论是否联合手术消融，则有资格入组。我们使用 Kaplan-Meier 方法估算各个时间点的总生存和无复发生存概率，并使用 Spearman 秩相关评估这些终点之间的两两关联。我们还对结直肠肝转移的辅助 III 期临床试验进行了荟萃分析，以评估无复发生存的危险比（HR）与总生存的相关性。我们在 MEDLINE 中搜索了从数据库创建到 2022 年 1 月 1 日的 III 期随机对照试验分析辅助治疗策略的文章。在进行全文筛选之前，对研究的标题和摘要进行了筛选，如果数据可用，则从已发表的 Kaplan-Meier 曲线中重新计算或手动提取汇总数据（取决于数据可用性）。
在机构数据库中，有 3299 名患者的数据可用，其中 2983 名符合我们队列的纳入标准。中位随访时间为 8.4 年（95%CI 7.9-9.1），在此期间，有 1995 名（67%）患者发生疾病复发，1684 名（56%）患者死亡。中位无复发生存时间为 1.3 年（95%CI 1.3-1.4），中位总生存时间为 5.2 年（95%CI 5.0-5.5）。1684 例死亡中有 1428 例（85%）发生在复发之前，复发至死亡的中位时间为 2.0 年（IQR 1.0-3.4）。无复发生存与总生存之间的两两相关性为低到中度，相关估计值范围为 0.30（SD 0.17）至 0.56（0.13）。在辅助临床试验的荟萃分析中，无复发生存 HR 和总生存 HR 之间的 Spearman 相关系数为 r=0.20（p=0.71）。
我们发现结直肠肝转移切除后无复发生存与总生存之间存在最小相关性。在这种疾病环境下，无复发生存是总生存的一个不充分替代终点。
美国国家癌症研究所。
