Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer

Tomasz Burzykowski, Elisabeth Coart, Everardo D. Saad, Qian Shi, Dirkje W. Sommeijer, Carsten Bokemeyer, Eduardo Díaz-Rubio, Jean-Yves Douillard, Alfredo Falcone, Charles S. Fuchs, Richard M. Goldberg, J. Randolph Hecht, Paulo M. Hoff, Herbert Hurwitz, Fairooz F. Kabbinavar, Miriam Koopman, Timothy S. Maughan, Cornelis J. A. Punt, Leonard Saltz, Hans-Joachim Schmoll & 8 others Matthew T. Seymour, Niall C. Tebbutt, Christophe Tournigand, Eric van Cutsem, Aimery de Gramont, John R. Zalcberg, Marc Buyse, Aide et Recherche en Cancerologie Digestive Group

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Importance: Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS). Objective: To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer. Design, Setting, and Participants: Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti-epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer. Main Outcomes and Measures: Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size-weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS. Results: For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95% CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R2 were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 anti-epidermal growth factor receptor comparisons (2684 patients), corresponding values of R2 were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78). Conclusions and Relevance: In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer.
Original languageEnglish
Pages (from-to)e1911750
JournalJAMA network open
Volume2
Issue number9
DOIs
Publication statusPublished - 4 Sep 2019
Externally publishedYes

Cite this

Burzykowski, Tomasz ; Coart, Elisabeth ; Saad, Everardo D. ; Shi, Qian ; Sommeijer, Dirkje W. ; Bokemeyer, Carsten ; Díaz-Rubio, Eduardo ; Douillard, Jean-Yves ; Falcone, Alfredo ; Fuchs, Charles S. ; Goldberg, Richard M. ; Hecht, J. Randolph ; Hoff, Paulo M. ; Hurwitz, Herbert ; Kabbinavar, Fairooz F. ; Koopman, Miriam ; Maughan, Timothy S. ; Punt, Cornelis J. A. ; Saltz, Leonard ; Schmoll, Hans-Joachim ; Seymour, Matthew T. ; Tebbutt, Niall C. ; Tournigand, Christophe ; van Cutsem, Eric ; de Gramont, Aimery ; Zalcberg, John R. ; Buyse, Marc ; Aide et Recherche en Cancerologie Digestive Group. / Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer. In: JAMA network open. 2019 ; Vol. 2, No. 9. pp. e1911750.
@article{46ac108fcfd349e092017bde4ce775bb,
title = "Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer",
abstract = "Importance: Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS). Objective: To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer. Design, Setting, and Participants: Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti-epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer. Main Outcomes and Measures: Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size-weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS. Results: For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95{\%} CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95{\%} CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R2 were 0.25 (95{\%} CI, 0-0.72) and 0.06 (95{\%} CI, 0-0.35). For 8 anti-epidermal growth factor receptor comparisons (2684 patients), corresponding values of R2 were 0.24 (95{\%} CI, 0-0.83) and 0.21 (95{\%} CI, 0-0.78). Conclusions and Relevance: In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer.",
author = "Tomasz Burzykowski and Elisabeth Coart and Saad, {Everardo D.} and Qian Shi and Sommeijer, {Dirkje W.} and Carsten Bokemeyer and Eduardo D{\'i}az-Rubio and Jean-Yves Douillard and Alfredo Falcone and Fuchs, {Charles S.} and Goldberg, {Richard M.} and Hecht, {J. Randolph} and Hoff, {Paulo M.} and Herbert Hurwitz and Kabbinavar, {Fairooz F.} and Miriam Koopman and Maughan, {Timothy S.} and Punt, {Cornelis J. A.} and Leonard Saltz and Hans-Joachim Schmoll and Seymour, {Matthew T.} and Tebbutt, {Niall C.} and Christophe Tournigand and {van Cutsem}, Eric and {de Gramont}, Aimery and Zalcberg, {John R.} and Marc Buyse and {Aide et Recherche en Cancerologie Digestive Group}",
year = "2019",
month = "9",
day = "4",
doi = "10.1001/jamanetworkopen.2019.11750",
language = "English",
volume = "2",
pages = "e1911750",
journal = "JAMA network open",
issn = "2574-3805",
number = "9",

}

Burzykowski, T, Coart, E, Saad, ED, Shi, Q, Sommeijer, DW, Bokemeyer, C, Díaz-Rubio, E, Douillard, J-Y, Falcone, A, Fuchs, CS, Goldberg, RM, Hecht, JR, Hoff, PM, Hurwitz, H, Kabbinavar, FF, Koopman, M, Maughan, TS, Punt, CJA, Saltz, L, Schmoll, H-J, Seymour, MT, Tebbutt, NC, Tournigand, C, van Cutsem, E, de Gramont, A, Zalcberg, JR, Buyse, M & Aide et Recherche en Cancerologie Digestive Group 2019, 'Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer' JAMA network open, vol. 2, no. 9, pp. e1911750. https://doi.org/10.1001/jamanetworkopen.2019.11750

Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer. / Burzykowski, Tomasz; Coart, Elisabeth; Saad, Everardo D.; Shi, Qian; Sommeijer, Dirkje W.; Bokemeyer, Carsten; Díaz-Rubio, Eduardo; Douillard, Jean-Yves; Falcone, Alfredo; Fuchs, Charles S.; Goldberg, Richard M.; Hecht, J. Randolph; Hoff, Paulo M.; Hurwitz, Herbert; Kabbinavar, Fairooz F.; Koopman, Miriam; Maughan, Timothy S.; Punt, Cornelis J. A.; Saltz, Leonard; Schmoll, Hans-Joachim; Seymour, Matthew T.; Tebbutt, Niall C.; Tournigand, Christophe; van Cutsem, Eric; de Gramont, Aimery; Zalcberg, John R.; Buyse, Marc; Aide et Recherche en Cancerologie Digestive Group.

In: JAMA network open, Vol. 2, No. 9, 04.09.2019, p. e1911750.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer

AU - Burzykowski, Tomasz

AU - Coart, Elisabeth

AU - Saad, Everardo D.

AU - Shi, Qian

AU - Sommeijer, Dirkje W.

AU - Bokemeyer, Carsten

AU - Díaz-Rubio, Eduardo

AU - Douillard, Jean-Yves

AU - Falcone, Alfredo

AU - Fuchs, Charles S.

AU - Goldberg, Richard M.

AU - Hecht, J. Randolph

AU - Hoff, Paulo M.

AU - Hurwitz, Herbert

AU - Kabbinavar, Fairooz F.

AU - Koopman, Miriam

AU - Maughan, Timothy S.

AU - Punt, Cornelis J. A.

AU - Saltz, Leonard

AU - Schmoll, Hans-Joachim

AU - Seymour, Matthew T.

AU - Tebbutt, Niall C.

AU - Tournigand, Christophe

AU - van Cutsem, Eric

AU - de Gramont, Aimery

AU - Zalcberg, John R.

AU - Buyse, Marc

AU - Aide et Recherche en Cancerologie Digestive Group

PY - 2019/9/4

Y1 - 2019/9/4

N2 - Importance: Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS). Objective: To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer. Design, Setting, and Participants: Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti-epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer. Main Outcomes and Measures: Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size-weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS. Results: For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95% CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R2 were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 anti-epidermal growth factor receptor comparisons (2684 patients), corresponding values of R2 were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78). Conclusions and Relevance: In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer.

AB - Importance: Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS). Objective: To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer. Design, Setting, and Participants: Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti-epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer. Main Outcomes and Measures: Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size-weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS. Results: For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95% CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R2 were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 anti-epidermal growth factor receptor comparisons (2684 patients), corresponding values of R2 were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78). Conclusions and Relevance: In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85072369799&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31539075

U2 - 10.1001/jamanetworkopen.2019.11750

DO - 10.1001/jamanetworkopen.2019.11750

M3 - Article

VL - 2

SP - e1911750

JO - JAMA network open

JF - JAMA network open

SN - 2574-3805

IS - 9

ER -