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

Our plain-English summary of 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, by X. Wang, X. Wang, L. Hodgson, et al (The Oncologist, 2017).

The study

• Authors: X. Wang, X. Wang, L. Hodgson, S.L. George, D.J. Sargent, N.R. Foster, A.K. Ganti, T.E. Stinchcombe, J. Crawford, R. Kratzke, A.A. Adjei, H.L. Kindler, E.E. Vokes, H. Pang
• Journal: The Oncologist
• Published: 2017;22(2):189-198
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© AlphaMed Press 2017.

In plain English

This study pooled data on 716 patients from 17 phase II treatment trials in malignant mesothelioma run by the Cancer and Leukemia Group B and North Central Cancer Treatment Group between 1984 and 2009. It asked whether progression-free survival (time until the cancer worsened or the patient died) could stand in for overall survival. It did not study asbestos exposure. Because most trials had one treatment arm, the authors compared how the two outcomes differed between patient groups defined by five risk factors (age, histology, performance status, white blood cell count and EORTC risk score). Median progression-free survival was 3.0 months (95% CI 2.8 to 3.5) and median overall survival 7.2 months (95% CI 6.5 to 8.0). Within patients, the two measures were moderately linked (Kendall's tau 0.45 to 0.47). How closely the group differences in the two outcomes agreed varied, with R-squared from 0.51 to 0.78 in one model and 0.26 to 0.67 in another. The authors noted the trials were small, mostly single-arm, and none used pemetrexed. They concluded that, pending more definitive studies, they could not recommend progression-free survival as a surrogate for overall survival.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Pooled statistical analysis of individual patient data from 17 phase II clinical trials (15 single-arm, 2 two-arm randomized), testing progression-free survival as a surrogate endpoint for overall survival
• Who was studied: 716 patients with malignant mesothelioma enrolled in 15 Cancer and Leukemia Group B trials and 2 North Central Cancer Treatment Group trials conducted between 1984 and 2009. Median age was 65 years and 81% were male.
• Exposure: Asbestos exposure was not studied. The analysis compared groups defined by risk factors: age, histology (nonepithelial vs epithelial), ECOG performance status, white blood cell count and EORTC risk score. Patients in the trials received various chemotherapy and targeted agents.
• Main results:
  • For all 716 patients, median progression-free survival was 3.0 months (95% CI, 2.8 to 3.5 months) and median overall survival was 7.2 months (95% CI, 6.5 to 8.0 months).
  • For the poor vs good EORTC prognosis groups, hazard ratios were 1.36 for progression-free survival (95% CI, 1.15 to 1.6) and 1.67 for overall survival (95% CI, 1.41 to 1.97).
  • At the individual patient level, Kendall's tau between progression-free and overall survival ranged from 0.45 to 0.47 across risk factors. The authors described this as only a moderate correlation.
  • At the summary level, Copula R-squared ranged from 0.51 for age to 0.78 for histology.
  • In the weighted least-squares model, R-squared ranged from 0.26 (lowest, for EORTC risk score and performance status) to 0.67 (highest, for age).
  • In an exploratory analysis that artificially paired trial arms, individual-level tau was 0.46, Copula R-squared was 0.77 and weighted least-squares R-squared was 0.52. The authors described this as moderate surrogacy.
  • A sensitivity analysis limited to patients without prior chemotherapy gave similar results.
• The authors' conclusion: The authors concluded that progression-free survival is associated with overall survival, but not strongly enough to be used as a surrogate. They said they would refrain from a definitive conclusion that it is not valid in future trials, and that, pending more definitive studies, they cannot recommend it as a surrogate endpoint in malignant mesothelioma trials.
• Limitations the authors state:
  • Most trials had a single treatment arm, and treatments differed between trials. Risk-factor groups were used in place of treatment comparisons. The authors noted that baseline factors may not cause survival differences, and that the validity of this approach needs further confirmation.
  • The trials were small (10 to 67 patients), which increased errors in summary-level estimates.
  • None of the trials included pemetrexed. Active agents could affect the correlation in ways that could not be assessed with these data.
  • Summary-level correlation is fundamentally different from trial-level correlation, which could not be estimated from these data.
  • Most of the investigational therapies were negative, which may limit how widely the findings apply.
  • Response and progression in the trials were assessed by investigator review.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Progression-Free Survival, Overall Survival, Malignant Mesothelioma, Histology, Performance Status, Hazard Ratio, confidence interval, Clinical Trial.

Related studies

• Progression free survival rate at 9 and 18 weeks predict overall survival in patients with malignant pleural mesothelioma: an individual patient pooled analysis of 10 European Organisation for Research and Treatment of Cancer Lung Cancer Group studies and an independent study validation — B. Hasan, L. Greillier, et al. (2014)
• Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052) — M.E. O'Brien, R.M. Gaafar, et al. (2013)
• Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107) — T. Jahan, L. Gu, et al. (2012)
• Prognostic factors for progression-free and overall survival in malignant pleural mesothelioma — J. Guzmán-Casta, S. Carrasco-CaraChards, et al. (2021)
• Phase II study of dasatinib in patients with previously treated malignant mesothelioma (cancer and leukemia group B 30601): a brief report — A.Z. Dudek, H. Pang, et al. (2012)
• Aberrant expression of cell cycle regulatory genes predicts overall and disease free survival in malignant pleural mesothelioma patients — A.A. Bahnassy, A.R. Zekri, et al. (2012)

Browse more research in The Oncologist, or return to medical research.