Yang Yin, Wang Jianyang, Wang Wenqing, Zhang Tao, Zhao Jingjing, Wang Yu, Li Yexiong, Wang Luhua, Bi Nan
Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.
Front Oncol. 2022 Jan 28;12:810580. doi: 10.3389/fonc.2022.810580. eCollection 2022.
To investigate whether progression-free survival (PFS) or time to progression (TTP) could be a valid surrogate endpoint for overall survival (OS) in patients with limited-stage small-cell lung cancer (LS-SCLC) receiving combined chemoradiotherapy.
Literature searching was performed in PubMed, Embase, and The Cochrane Library up to 2021. Prediction models were firstly established using data from phase III randomized controlled trials (RCTs) and then externally validated in phase II and retrospective studies. Correlation analysis was evaluated by a weighted linear regression model at both trial and arm levels. Cross-validation was performed to assess the consistency and robustness of the established models.
37 studies, including 15 phase III RCTs, 12 phase II studies, and 10 retrospective studies, were selected in the final analysis. In trial-level surrogacy, a very good correlation was observed between hazard ratios (HRs) of PFS/TTP and OS (R = 0.783, 95% CI 0.771-0.794). In arm-level surrogacy, very good correlations were also observed between 2-year (R = 0.823, 95% CI 0.814-0.832), 3-year (R = 0.843, 95% CI 0.833-0.850), 5-year (R = 0.852, 95% CI 0.843-0.859) PFS/TTP, and 5-year OS. An excellent correlation was observed between 4-year PFS/TTP and 5-year OS (R = 0.906, 95% CI 0.901-0.910). Cross-validation demonstrated reasonable overall consistency. External validation in phase II and retrospective studies showed good agreement (R, 0.728-0.824).
PFS/TTP was a valid surrogate endpoint for OS in patients with LS-SCLC receiving combined chemoradiotherapy. The finding provides high-level evidence to support PFS/TTP as the primary endpoint in clinical trials so as to speed up introducing novel agents to the treatment of LS-SCLC.
探讨无进展生存期（PFS）或疾病进展时间（TTP）能否作为局限期小细胞肺癌（LS-SCLC）患者接受放化疗时总生存期（OS）的有效替代终点。
截至2021年，在PubMed、Embase和Cochrane图书馆进行文献检索。首先使用III期随机对照试验（RCT）的数据建立预测模型，然后在II期和回顾性研究中进行外部验证。通过加权线性回归模型在试验和组水平评估相关性分析。进行交叉验证以评估所建立模型的一致性和稳健性。
最终分析纳入37项研究，包括15项III期RCT、12项II期研究和10项回顾性研究。在试验水平的替代指标分析中，观察到PFS/TTP与OS的风险比（HR）之间具有非常好的相关性（R = 0.783，95%CI 0.771-0.794）。在组水平的替代指标分析中，也观察到2年（R = 0.823，95%CI 0.814-0.832）、3年（R = 0.843，95%CI 0.833-0.850）、5年（R = 0.852，95%CI 0.843-0.859）PFS/TTP与5年OS之间具有非常好的相关性。观察到4年PFS/TTP与5年OS之间具有极好的相关性（R = 0.906，95%CI 0.901-0.910）。交叉验证显示总体一致性合理。II期和回顾性研究中的外部验证显示出良好的一致性（R，0.728-0.824）。
PFS/TTP是接受放化疗的LS-SCLC患者OS的有效替代终点。这一发现为支持将PFS/TTP作为临床试验的主要终点提供了高级别证据，从而加速新型药物引入LS-SCLC的治疗。
