Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the digestive system database

TY - JOUR

T1 - Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the digestive system database

AU - Shi, Qian

AU - de Gramont, Aimery

AU - Grothey, Axel

AU - Zalcberg, John

AU - Chibaudel, Benoist

AU - Schmoll, Hans-Joachim

AU - Seymour, Matthew T

AU - Adams, Richard

AU - Saltz, Leonard

AU - Goldberg, Richard M

AU - Punt, Cornelis J A

AU - Douillard, Jean-Yves

AU - Hoff, Paulo M

AU - Hecht, Joel Randolph

AU - Hurwitz, Herbert

AU - Díaz-Rubio, Eduardo

AU - Porschen, Rainer

AU - Tebbutt, Niall C

AU - Fuchs, Charles

AU - Souglakos, John

AU - Falcone, Alfredo

AU - Tournigand, Christophe

AU - Kabbinavar, Fairooz F

AU - Heinemann, Volker

AU - Van Cutsem, Eric

AU - Bokemeyer, Carsten

AU - Buyse, Marc

AU - Sargent, Daniel J

N1 - © 2014 by American Society of Clinical Oncology.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - PURPOSE: Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination.METHODS: Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti-epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R(2) statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models.RESULTS: Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R(2), 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy.CONCLUSION: In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.

AB - PURPOSE: Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination.METHODS: Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti-epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R(2) statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models.RESULTS: Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R(2), 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy.CONCLUSION: In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.

U2 - 10.1200/JCO.2014.56.5887

DO - 10.1200/JCO.2014.56.5887

M3 - SCORING: Journal article

C2 - 25385741

VL - 33

SP - 22

EP - 28

JO - J CLIN ONCOL

JF - J CLIN ONCOL

SN - 0732-183X

IS - 1

ER -