Validation of Progression-Free Survival as a Surrogate Endpoint for Overall Survival in Malignant Mesothelioma: Analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) Trials

Oncologist. 2017 Feb;22(2):189-198. doi: 10.1634/theoncologist.2016-0121. Epub 2017 Feb 10.


Purpose: The aim of this study was to investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma.

Materials and methods: Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual-level surrogacy was assessed by Kendall's tau through a Clayton bivariate Copula survival (CBCS) model. Summary-level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)-log HROS and log HRPFS-measured in R2 from a weighted least-square (WLS) regression model and the CBCS model.

Results: The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8-3.5 months) and the median OS was 7.2 months (95% CI, 6.5-8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall's tau ranging from 0.46 to 0.47. The summary-level surrogacy varied among risk factors. The Copula R2 ranged from 0.51 for PS to 0.78 for histology. The WLS R2 ranged from 0.26 for EORTC and PS to 0.67 for age.

Conclusions: The analyses demonstrated low to moderate individual-level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma. The Oncologist 2017;22:189-198Implications for Practice: For better disease management and for more efficient clinical trial designs, it is important to know if progression-free survival (PFS) is a good surrogate endpoint for overall survival in malignant mesothelioma. With a relatively large database of 17 phase II trials and 716 patients from Cancer and Leukemia Group B and North Central Cancer Treatment Group, we conducted statistical analyses and found that there is no evidence to suggest that PFS is a valid surrogate endpoint for OS for malignant mesothelioma. Future research work is needed to find alternative surrogate endpoints for OS.


目的. 本研究的目的是考察无进展生存期(PFS)能否替代总生存期(OS)作为恶性间皮瘤研究的终点。

材料和方法. 从癌症和白血病工作组B的15项II期临床试验(615例患者)和中北部癌症治疗组的2项II期临床试验(101例患者)中收集个体数据。本分析以OS和PFS的5种风险因素作为效应, 其中包括年龄、组织学、体能状态(PS)、白细胞计数和欧洲癌症研究与治疗组织(EORTC)风险评分。采用Clayton Copula二元生存(CBCS)模型, 通过Kendall tau在个体水平评估替代的可行性。通过加权最小二乘(WLS)回归模型和CBCS模型中的R2衡量对数风险比(log HR)log HROS与log HRPFS之间的相关性, 从而在总体水平评价替代的可行性。

结果. 所有患者的中位PFS为3.0个月[95%置信区间(CI):2.8‐3.5个月], 中位OS为7.2个月(95% CI:6.5‐8.0个月)。就所有风险因素而言, 在个体水平上观察到PFS与OS中度相关(Kendall tau介于0.46‐0.47之间), 而总体水平上的替代可行性各不相同。Copula R2由0.51(PS)至0.78(组织学)不等。WLS R2由0.26(EORTC)至0.67(年龄)不等。

结论. 分析表明, 在个体水平上, PFS替代OS的可行性为低至中等。在总体水平上, PFS替代OS的可行性随风险因素的不同而存在显著差异。恶性间皮瘤进展后的生存期较短且PFS与OS中度相关, 故没有证据表明PFS可作为OS的有效替代终点。 The Oncologist 2017;22:189–198

对临床实践的提示:为了提高恶性间皮瘤的疾病管理水平和临床试验设计效率, 有必要了解无进展生存期(PFS)能否作为总生存期的有效替代终点。基于癌症和白血病工作组B以及中北部癌症治疗组开展的17项II期临床试验(共计716例患者)构建了一个规模相对较大的数据库, 据此进行统计分析, 结果发现对于恶性间皮瘤而言, 没有证据表明PFS是OS的有效替代终点。需要通过进一步研究来探索OS的其他替代终点。

Keywords: Malignant mesothelioma; Overall survival; Progression‐free survival; Risk factors; Surrogate endpoint.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Disease-Free Survival
  • Female
  • Humans
  • Lung Neoplasms / mortality*
  • Lung Neoplasms / pathology
  • Male
  • Mesothelioma / mortality*
  • Mesothelioma / pathology
  • Mesothelioma, Malignant
  • Middle Aged
  • Survival Analysis
  • Young Adult