Blondeaux Eva, Xie Wanling, Carmisciano Luca, Mura Silvia, Sanna Valeria, De Laurentiis Michelino, Caputo Roberta, Turletti Anna, Durando Antonio, De Placido Sabino, De Angelis Carmine, Bisagni Giancarlo, Gasparini Elisa, Rimanti Anita, Puglisi Fabio, Mansutti Mauro, Landucci Elisabetta, Fabi Alessandra, Arecco Luca, Perachino Marta, Bruzzone Marco, Boni Luca, Lambertini Matteo, Del Mastro Lucia, Regan Meredith M
U.O. Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Division of Biostatistics, Dana-Farber Cancer Institute, Boston, USA.
EClinicalMedicine. 2024 Mar 20;70:102501. doi: 10.1016/j.eclinm.2024.102501. eCollection 2024 Apr.
Intermediate clinical endpoints (ICEs) are frequently used as primary endpoint in randomised trials (RCTs). We aim to assess whether changes in different ICEs can be used to predict changes in overall survival (OS) in adjuvant breast cancer trials.
Individual patient level data from adjuvant phase III RCTs conducted by the Gruppo Italiano Mammella (GIM) and Mammella Intergruppo (MIG) study groups were used. ICEs were computed according to STEEP criteria. Using a two-stage meta-analytic model, we assessed the surrogacy of each ICE at both the outcome (i.e., OS and ICE are correlated irrespective of treatment) and trial (i.e., treatment effects on ICE and treatment effect on OS are correlated) levels. The following ICEs were considered as potential surrogate endpoints of OS: disease-free survival (DFS), distant disease-free survival (DDFS), distant relapse-free survival (DRFS), recurrence-free survival (RFS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), breast cancer-free interval (BCFI), and invasive breast cancer-free survival (IBCFS). The estimates of the degree of correlation were obtained by copula models and weighted linear regression. Kendall's τ and R ≥ 0.70 were considered as indicators of a clinically relevant surrogacy.
Among the 12,397 patients enrolled from November 1992 to July 2012 in six RCTs, median age at enrolment was 57 years (interquartile range (IQR) 49-65). After a median follow-up of 10.3 years (IQR 6.4-14.5), 2131 (17.2%) OS events were observed, with 1390 (65.2%) attributed to breast cancer. At the outcome-level, Kendall's τ ranged from 0.69 for BCFI to 0.84 for DRFS. For DFS, DDFS, DRFS, RFS, RFI, DRFI, BCFI, and IBCFS endpoints, over 95% of the 8-year OS variability was attributable to the variation of the 5-year ICE. At the trial-level, treatment effects for the different ICEs and OS were strongly correlated, with the highest correlation for RFS and DRFS and the lowest for BCFI.
Our results provide evidence supporting the use of DFS, DDFS, DRFS, RFS, RFI, DRFI, and IBCFS as primary endpoint in breast cancer adjuvant trials.
This analysis was supported by the Italian Association for Cancer Research ("Associazione Italiana per la Ricerca sul Cancro", AIRC; IG 2017/20760) and by Italian Ministry of Health-5 × 1000 funds (years 2021-2022).
中间临床终点（ICEs）在随机试验（RCTs）中常被用作主要终点。我们旨在评估在辅助性乳腺癌试验中，不同ICEs的变化是否可用于预测总生存期（OS）的变化。
使用了意大利乳腺研究组（GIM）和乳腺组间研究组（MIG）进行的辅助性III期RCTs的个体患者水平数据。ICEs根据STEEP标准计算。使用两阶段荟萃分析模型，我们在结局（即无论治疗如何，OS和ICE都相关）和试验（即治疗对ICE的效果与治疗对OS的效果相关）两个层面评估了每个ICE的替代指标性质。以下ICEs被视为OS的潜在替代终点：无病生存期（DFS）、远处无病生存期（DDFS）、远处无复发生存期（DRFS）、无复发生存期（RFS）、无复发间期（RFI）、远处无复发间期（DRFI）、无乳腺癌间期（BCFI）和无浸润性乳腺癌生存期（IBCFS）。相关性程度的估计通过copula模型和加权线性回归获得。肯德尔τ系数和R≥0.70被视为具有临床相关性替代指标性质的指标。
在1992年11月至2012年7月纳入六项RCTs的12397例患者中，入组时的中位年龄为57岁（四分位间距（IQR）49 - 65）。中位随访10.3年（IQR 6.4 - 14.5）后，观察到2131例（17.2%）OS事件，其中1390例（65.2%）归因于乳腺癌。在结局层面，肯德尔τ系数范围从BCFI的0.69到DRFS的0.84。对于DFS、DDFS、DRFS、RFS、RFI、DRFI、BCFI和IBCFS终点，8年OS变异性的95%以上可归因于5年ICE的变化。在试验层面，不同ICEs和OS的治疗效果高度相关，RFS和DRFS的相关性最高，BCFI的相关性最低。
我们的结果提供了证据，支持将DFS、DDFS、DRFS、RFS、RFI、DRFI和IBCFS用作乳腺癌辅助试验的主要终点。
本分析得到了意大利癌症研究协会（“Associazione Italiana per la Ricerca sul Cancro”，AIRC；IG 2017/20760）和意大利卫生部5×1000基金（2021 - 2022年）的支持。
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