A Causal Framework for Making Individualized Treatment Decisions in Oncology.

Abstract

Simple SummaryPhysicians routinely make individualized treatment decisions by accounting for the joint effects of patient prognostic covariates and treatments on clinical outcomes. Ideally, this is performed using historical randomized clinical trial (RCT) data. Randomization ensures that unbiased estimates of causal treatment effect parameters can be obtained from the historical RCT data and used to predict each new patient’s outcome based on the joint effect of their baseline covariates and each treatment being considered. However, this process becomes problematic if a patient seen in the clinic is very different from the patients who were enrolled in the RCT. That is, if a new patient does not satisfy the entry criteria of the RCT, then the patient does not belong to the population represented by the patients who were studied in the RCT. In such settings, it still may be possible to utilize the RCT data to help choose a new patient’s treatment. This may be achieved by combining the RCT data with data from other clinical trials, or possibly preclinical experiments, and using the combined dataset to predict the patient’s expected outcome for each treatment being considered. In such settings, combining data from multiple sources in a way that is statistically reliable is not entirely straightforward, and correctly identifying and estimating the effects of treatments and patient covariates on clinical outcomes can be complex. Causal diagrams provide a rational basis to guide this process. The first step is to construct a causal diagram that reflects the plausible relationships between treatment variables, patient covariates, and clinical outcomes. If the diagram is correct, it can be used to determine what additional data may be needed, how to combine data from multiple sources, how to formulate a statistical model for clinical outcomes as a function of treatment and covariates, and how to compute an unbiased treatment effect estimate for each new patient. We use adjuvant therapy of renal cell carcinoma to illustrate how causal diagrams may be used to guide these steps.We discuss how causal diagrams can be used by clinicians to make better individualized treatment decisions. Causal diagrams can distinguish between settings where clinical decisions can rely on a conventional additive regression model fit to data from a historical randomized clinical trial (RCT) to estimate treatment effects and settings where a different approach is needed. This may be because a new patient does not meet the RCT’s entry criteria, or a treatment’s effect is modified by biomarkers or other variables that act as mediators between treatment and outcome. In some settings, the problem can be addressed simply by including treatment–covariate interaction terms in the statistical regression model used to analyze the RCT dataset. However, if the RCT entry criteria exclude a new patient seen in the clinic, it may be necessary to combine the RCT data with external data from other RCTs, single-arm trials, or preclinical experiments evaluating biological treatment effects. For example, external data may show that treatment effects differ between histological subgroups not recorded in an RCT. A causal diagram may be used to decide whether external observational or experimental data should be obtained and combined with RCT data to compute statistical estimates for making individualized treatment decisions. We use adjuvant treatment of renal cell carcinoma as our motivating example to illustrate how to construct causal diagrams and apply them to guide clinical decisions.