Potential mechanisms of the fatigue-reducing effect of cognitive-behavioral therapy in cancer survivors: Three randomized controlled trials

Objective: Fatigue is a common symptom among cancer survivors that can be successfully treated with cognitive-behavioral therapy (CBT). Insights into the working mechanisms of CBT are currently limited. The aim of this study was to investigate whether improvements in targeted cognitive-behavioral variables and reduced depressive symptoms mediate the fatigue-reducing effect of CBT. Methods: We pooled data from three randomized controlled trials that tested the efficacy of CBT to reduce severe fatigue. In all three trials, fatigue severity (checklist individual strength) decreased significantly following CBT. Assessments were conducted pre-treatment and 6 months later. Classical mediation analysis testing a pre-specified model was conducted and its results compared to those of causal discovery, an explorative data-driven approach testing all possible causal associations and retaining the most likely model. Results: Data from 250 cancer survivors (n = 129 CBT, n = 121 waitlist) were analyzed. Classical mediation analysis suggests that increased self-efficacy and decreased fatigue catastrophizing, focusing on symptoms, perceived problems with activity and depressive symptoms mediate the reduction of fatigue brought by CBT. Conversely, causal discovery and post-hoc analyses indicate that fatigue acts as mediator, not outcome, of changes in cognitions, sleep disturbance and depressive symptoms. Conclusions: Cognitions, sleep disturbance and depressive symptoms improve during CBT. When assessed pre- and post-treatment, fatigue acts as a mediator, not outcome, of these improvements. It seems likely that the working mechanism of CBT is not a one-way causal effect but a dynamic reciprocal process. Trials integrating intermittent assessments are needed to shed light on these mechanisms and inform optimization of CBT.