Landmark Mediation Survival Analysis Using Longitudinal Surrogate

Authors

Jie Zhou
Xun Jiang
H Amy Xia
Brian P Hobbs
Peng Wei

Publication Date

1-1-2022

Journal

Frontiers in Oncology

Abstract

Clinical cancer trials are designed to collect radiographic measurements of each patient's baseline and residual tumor burden at regular intervals over the course of study. For solid tumors, the extent of reduction in tumor size following treatment is used as a measure of a drug's antitumor activity. Statistical estimation of treatment efficacy routinely reduce the longitudinal assessment of tumor burden to a binary outcome describing the presence versus absence of an objective tumor response as defined by RECIST criteria. The objective response rate (ORR) is the predominate method for evaluating an experimental therapy in a single-arm trial. Additionally, ORR is routinely compared against a control therapy in phase III randomized controlled trials. The longitudinal assessments of tumor burden are seldom integrated into a formal statistical model, nor integrated into mediation analysis to characterize the relationships among treatment, residual tumor burden, and survival. This article presents a frameworkfor landmark mediation survival analyses devised to incorporate longitudinal assessment of tumor burden. R 2 effect-size measures are developed to quantify the survival treatment mediation effects using longitudinal predictors. Analyses are demonstrated with applications to two colorectal cancer trials. Survival prediction is compared in the presence versus absence of longitudinal analysis. Simulation studies elucidate settings wherein patterns of tumor burden dynamics require longitudinal analysis.

Keywords

RECIST, functional principal component analysis, landmark analysis, longitudinal analysis, mediation analysis, oncology

DOI

10.3389/fonc.2022.999324

PMID

36733365

PMCID

PMC9887328

PubMedCentral® Posted Date

1-17-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes