Resistance Exercise and Inflammation in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy: Mediation Analysis From a Randomized, Controlled Intervention Trial

Abstract

To explore the mediating role of inflammatory parameters in the development of fatigue, pain, and potentially related depressive symptoms during radiation therapy for breast cancer and its mitigation by resistance exercise. Breast cancer patients scheduled for adjuvant radiation therapy were randomized to 12-week progressive resistance exercise training (EX) or a relaxation control group. Interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were measured in serum samples collected before, at the end, and 6 weeks after radiation therapy from 103 chemotherapy-naïve participants. Fatigue was assessed with the multidimensional Fatigue Assessment Questionnaire, pain with the European Organization for Research and Treatment of Cancer QLQ-C30, and depressive symptoms with the Center for Epidemiologic Studies Depression Scale. Analysis of covariance models, partial correlations, Freedman-Schatzkin tests, and R(2) effect-size measures for mediation were calculated. The analysis of covariance models revealed a significant intervention effect on IL-6 (P=.010) and the IL-6/IL-1ra ratio (P=.018), characterized by a marked increase during radiation therapy among controls, but no significant change in EX. Interleukin-1 receptor antagonist did not change significantly in either group (P=.88). Increased IL-6 and IL-6/IL-1ra levels at the end of radiation therapy were significantly associated with increased physical fatigue and pain 6 weeks after radiation. We observed significant partial mediation by IL-6 and IL-6/IL-1ra of the effect of resistance exercise on physical fatigue (Freedman-Schatzkin P=.023 and P<.001) and pain (both P<.001). Hereby IL-6 and IL-6/IL-1ra mediated between 15% and 24% of the variance of physical fatigue and pain explained by the intervention. This randomized, controlled trial showed a significantly increased proinflammatory cytokine level after adjuvant radiation therapy in breast cancer patients. This effect was counteracted by progressive resistance exercise training. Interleukin-6 and the IL-6/IL-1ra ratio seemed to mediate the beneficial effect of exercise on physical fatigue and pain but only to a small extent.