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Surrogate marker analysis in cancer clinical trials through time-to-event mediation techniques

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Abstract
The meta-analytic approach is the gold standard for validation of surrogate markers, but has the drawback of requiring data from several trials. We refine modern mediation analysis techniques for time-to-event endpoints and apply them to investigate whether pathological complete response can be used as a surrogate marker for disease-free survival in the EORTC 10994/BIG 1-00 randomised phase 3 trial in which locally advanced breast cancer patients were randomised to either taxane or anthracycline based neoadjuvant chemotherapy. In the mediation analysis, the treatment effect is decomposed into an indirect effect via pathological complete response and the remaining direct effect. It shows that only 4.2% of the treatment effect on disease-free survival after five years is mediated by the treatment effect on pathological complete response. There is thus no evidence from our analysis that pathological complete response is a valuable surrogate marker to evaluate the effect of taxane versus anthracycline based chemotherapies on progression free survival of locally advanced breast cancer patients. The proposed analysis strategy is broadly applicable to mediation analyses of time-to-event endpoints, is easy to apply and outperforms existing strategies in terms of precision as well as robustness against model misspecification.
Keywords
Time-to-event outcomes, mediation analysis, natural direct and indirect effects, cancer, clinical trials, surrogate marker, EORTC 10994/BIG 1-00, BREAST-CANCER, NEOADJUVANT CHEMOTHERAPY, CAUSAL-INFERENCE, PHASE-3 TRIAL, END-POINTS, SURVIVAL, COLLAPSIBILITY, INTERVENTIONS, COX

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MLA
Vandenberghe, Sjouke, Luc Duchateau, Leen Slaets, et al. “Surrogate Marker Analysis in Cancer Clinical Trials Through Time-to-event Mediation Techniques.” STATISTICAL METHODS IN MEDICAL RESEARCH 27.11 (2017): 3367–3385. Print.
APA
Vandenberghe, Sjouke, Duchateau, L., Slaets, L., Bogaerts, J., & Vansteelandt, S. (2017). Surrogate marker analysis in cancer clinical trials through time-to-event mediation techniques. STATISTICAL METHODS IN MEDICAL RESEARCH, 27(11), 3367–3385.
Chicago author-date
Vandenberghe, Sjouke, Luc Duchateau, Leen Slaets, Jan Bogaerts, and Stijn Vansteelandt. 2017. “Surrogate Marker Analysis in Cancer Clinical Trials Through Time-to-event Mediation Techniques.” Statistical Methods in Medical Research 27 (11): 3367–3385.
Chicago author-date (all authors)
Vandenberghe, Sjouke, Luc Duchateau, Leen Slaets, Jan Bogaerts, and Stijn Vansteelandt. 2017. “Surrogate Marker Analysis in Cancer Clinical Trials Through Time-to-event Mediation Techniques.” Statistical Methods in Medical Research 27 (11): 3367–3385.
Vancouver
1.
Vandenberghe S, Duchateau L, Slaets L, Bogaerts J, Vansteelandt S. Surrogate marker analysis in cancer clinical trials through time-to-event mediation techniques. STATISTICAL METHODS IN MEDICAL RESEARCH. 2017;27(11):3367–85.
IEEE
[1]
S. Vandenberghe, L. Duchateau, L. Slaets, J. Bogaerts, and S. Vansteelandt, “Surrogate marker analysis in cancer clinical trials through time-to-event mediation techniques,” STATISTICAL METHODS IN MEDICAL RESEARCH, vol. 27, no. 11, pp. 3367–3385, 2017.
@article{8579644,
  abstract     = {The meta-analytic approach is the gold standard for validation of surrogate markers, but has the drawback of requiring data from several trials. We refine modern mediation analysis techniques for time-to-event endpoints and apply them to investigate whether pathological complete response can be used as a surrogate marker for disease-free survival in the EORTC 10994/BIG 1-00 randomised phase 3 trial in which locally advanced breast cancer patients were randomised to either taxane or anthracycline based neoadjuvant chemotherapy. In the mediation analysis, the treatment effect is decomposed into an indirect effect via pathological complete response and the remaining direct effect. It shows that only 4.2% of the treatment effect on disease-free survival after five years is mediated by the treatment effect on pathological complete response. There is thus no evidence from our analysis that pathological complete response is a valuable surrogate marker to evaluate the effect of taxane versus anthracycline based chemotherapies on progression free survival of locally advanced breast cancer patients. The proposed analysis strategy is broadly applicable to mediation analyses of time-to-event endpoints, is easy to apply and outperforms existing strategies in terms of precision as well as robustness against model misspecification.},
  author       = {Vandenberghe, Sjouke and Duchateau, Luc and Slaets, Leen and Bogaerts, Jan and Vansteelandt, Stijn},
  issn         = {0962-2802},
  journal      = {STATISTICAL METHODS IN MEDICAL RESEARCH},
  keywords     = {Time-to-event outcomes,mediation analysis,natural direct and indirect effects,cancer,clinical trials,surrogate marker,EORTC 10994/BIG 1-00,BREAST-CANCER,NEOADJUVANT CHEMOTHERAPY,CAUSAL-INFERENCE,PHASE-3 TRIAL,END-POINTS,SURVIVAL,COLLAPSIBILITY,INTERVENTIONS,COX},
  language     = {eng},
  number       = {11},
  pages        = {3367--3385},
  title        = {Surrogate marker analysis in cancer clinical trials through time-to-event mediation techniques},
  url          = {http://dx.doi.org/10.1177/0962280217702179},
  volume       = {27},
  year         = {2017},
}

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