Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer

A re-analysis of meta-analyses of individual patients' data

Audrey Mauguen, Jean Pierre Pignon, Sarah Burdett, Caroline Domerg, David Fisher, Rebecca Paulus, Samithra J. Mandrekar, Chandra Belani, Frances A. Shepherd, Tim Eisen, Herbert Pang, Laurence Collette, William T. Sause, Suzanne E. Dahlberg, Jeffrey Crawford, Mary O'Brien, Steven E. Schild, Mahesh Parmar, Jayne F. Tierney, Cécile Le Pechoux & 1 others Stefan Michiels

Research output: Contribution to journalArticle

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Abstract

Background: The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. Methods: We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. Findings: In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2=0·83, 95% CI 0·83-0·83 in trials without radiotherapy, and 0·87, 0·87-0·87 in trials with radiotherapy) and excellent at trial level (R2=0·92, 95% CI 0·88-0·95 in trials without radiotherapy and 0·99, 0·98-1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77-0·85, dependent on the regimen being assessed) and trial level (R2 range 0·89-0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2=0·71, 95% CI 0·71-0·71 for concurrent chemotherapy and ρ2=0·61, 0·61-0·61 for modified vs standard radiotherapy) and trial-level correlations very good (R2=0·85, 95% CI 0·77-0·92 for concurrent chemotherapy and R2=0·95, 0·91-0·98 for modified vs standard radiotherapy). Interpretation: We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. Funding: Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis.

Original languageEnglish (US)
Pages (from-to)619-626
Number of pages8
JournalThe Lancet Oncology
Volume14
Issue number7
DOIs
StatePublished - Jun 1 2013

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Meta-Analysis
Lung Neoplasms
Radiotherapy
Biomarkers
Drug Therapy
Disease-Free Survival
Survival
Adjuvant Chemotherapy
Non-Small Cell Lung Carcinoma
Random Allocation
Biomedical Research
Randomized Controlled Trials
Clinical Trials
Recurrence
Therapeutics
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Mauguen, Audrey ; Pignon, Jean Pierre ; Burdett, Sarah ; Domerg, Caroline ; Fisher, David ; Paulus, Rebecca ; Mandrekar, Samithra J. ; Belani, Chandra ; Shepherd, Frances A. ; Eisen, Tim ; Pang, Herbert ; Collette, Laurence ; Sause, William T. ; Dahlberg, Suzanne E. ; Crawford, Jeffrey ; O'Brien, Mary ; Schild, Steven E. ; Parmar, Mahesh ; Tierney, Jayne F. ; Pechoux, Cécile Le ; Michiels, Stefan. / Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer : A re-analysis of meta-analyses of individual patients' data. In: The Lancet Oncology. 2013 ; Vol. 14, No. 7. pp. 619-626.
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title = "Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: A re-analysis of meta-analyses of individual patients' data",
abstract = "Background: The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. Methods: We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. Findings: In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2=0·83, 95{\%} CI 0·83-0·83 in trials without radiotherapy, and 0·87, 0·87-0·87 in trials with radiotherapy) and excellent at trial level (R2=0·92, 95{\%} CI 0·88-0·95 in trials without radiotherapy and 0·99, 0·98-1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77-0·85, dependent on the regimen being assessed) and trial level (R2 range 0·89-0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2=0·71, 95{\%} CI 0·71-0·71 for concurrent chemotherapy and ρ2=0·61, 0·61-0·61 for modified vs standard radiotherapy) and trial-level correlations very good (R2=0·85, 95{\%} CI 0·77-0·92 for concurrent chemotherapy and R2=0·95, 0·91-0·98 for modified vs standard radiotherapy). Interpretation: We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. Funding: Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis.",
author = "Audrey Mauguen and Pignon, {Jean Pierre} and Sarah Burdett and Caroline Domerg and David Fisher and Rebecca Paulus and Mandrekar, {Samithra J.} and Chandra Belani and Shepherd, {Frances A.} and Tim Eisen and Herbert Pang and Laurence Collette and Sause, {William T.} and Dahlberg, {Suzanne E.} and Jeffrey Crawford and Mary O'Brien and Schild, {Steven E.} and Mahesh Parmar and Tierney, {Jayne F.} and Pechoux, {C{\'e}cile Le} and Stefan Michiels",
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Mauguen, A, Pignon, JP, Burdett, S, Domerg, C, Fisher, D, Paulus, R, Mandrekar, SJ, Belani, C, Shepherd, FA, Eisen, T, Pang, H, Collette, L, Sause, WT, Dahlberg, SE, Crawford, J, O'Brien, M, Schild, SE, Parmar, M, Tierney, JF, Pechoux, CL & Michiels, S 2013, 'Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: A re-analysis of meta-analyses of individual patients' data', The Lancet Oncology, vol. 14, no. 7, pp. 619-626. https://doi.org/10.1016/S1470-2045(13)70158-X

Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer : A re-analysis of meta-analyses of individual patients' data. / Mauguen, Audrey; Pignon, Jean Pierre; Burdett, Sarah; Domerg, Caroline; Fisher, David; Paulus, Rebecca; Mandrekar, Samithra J.; Belani, Chandra; Shepherd, Frances A.; Eisen, Tim; Pang, Herbert; Collette, Laurence; Sause, William T.; Dahlberg, Suzanne E.; Crawford, Jeffrey; O'Brien, Mary; Schild, Steven E.; Parmar, Mahesh; Tierney, Jayne F.; Pechoux, Cécile Le; Michiels, Stefan.

In: The Lancet Oncology, Vol. 14, No. 7, 01.06.2013, p. 619-626.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer

T2 - A re-analysis of meta-analyses of individual patients' data

AU - Mauguen, Audrey

AU - Pignon, Jean Pierre

AU - Burdett, Sarah

AU - Domerg, Caroline

AU - Fisher, David

AU - Paulus, Rebecca

AU - Mandrekar, Samithra J.

AU - Belani, Chandra

AU - Shepherd, Frances A.

AU - Eisen, Tim

AU - Pang, Herbert

AU - Collette, Laurence

AU - Sause, William T.

AU - Dahlberg, Suzanne E.

AU - Crawford, Jeffrey

AU - O'Brien, Mary

AU - Schild, Steven E.

AU - Parmar, Mahesh

AU - Tierney, Jayne F.

AU - Pechoux, Cécile Le

AU - Michiels, Stefan

PY - 2013/6/1

Y1 - 2013/6/1

N2 - Background: The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. Methods: We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. Findings: In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2=0·83, 95% CI 0·83-0·83 in trials without radiotherapy, and 0·87, 0·87-0·87 in trials with radiotherapy) and excellent at trial level (R2=0·92, 95% CI 0·88-0·95 in trials without radiotherapy and 0·99, 0·98-1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77-0·85, dependent on the regimen being assessed) and trial level (R2 range 0·89-0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2=0·71, 95% CI 0·71-0·71 for concurrent chemotherapy and ρ2=0·61, 0·61-0·61 for modified vs standard radiotherapy) and trial-level correlations very good (R2=0·85, 95% CI 0·77-0·92 for concurrent chemotherapy and R2=0·95, 0·91-0·98 for modified vs standard radiotherapy). Interpretation: We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. Funding: Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis.

AB - Background: The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. Methods: We analysed individual patients' data from 15 071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small-cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. Findings: In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (ρ2=0·83, 95% CI 0·83-0·83 in trials without radiotherapy, and 0·87, 0·87-0·87 in trials with radiotherapy) and excellent at trial level (R2=0·92, 95% CI 0·88-0·95 in trials without radiotherapy and 0·99, 0·98-1·00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (ρ2 range 0·77-0·85, dependent on the regimen being assessed) and trial level (R2 range 0·89-0·97). In studies with data on locoregional control, individual-level correlations were good (ρ2=0·71, 95% CI 0·71-0·71 for concurrent chemotherapy and ρ2=0·61, 0·61-0·61 for modified vs standard radiotherapy) and trial-level correlations very good (R2=0·85, 95% CI 0·77-0·92 for concurrent chemotherapy and R2=0·95, 0·91-0·98 for modified vs standard radiotherapy). Interpretation: We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. Funding: Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi-Aventis.

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