title: Resistance Exercise and Inflammation in Breast Cancer Patients Undergoing Adjuvant Radiation Therapy: Mediation Analysis From a Randomized, Controlled Intervention Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany. Electronic address: m.schmidt@dkfz.de.
authors: Martina E
authors: ME
authors: Schmidt
authors: Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors: Anna
authors: A
authors: Meynköhn
authors: Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors: Nina
authors: N
authors: Habermann
authors: Division of Medical Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg, Germany.
authors: Joachim
authors: J
authors: Wiskemann
authors: Department of Radiation Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg, Germany.
authors: Jan
authors: J
authors: Oelmann
authors: Department of Radiation Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg, Germany.
authors: Holger
authors: H
authors: Hof
authors: Department of Radiation Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg, Germany.
authors: Sabine
authors: S
authors: Wessels
authors: Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors: Oliver
authors: O
authors: Klassen
authors: Department of Radiation Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg, Germany.
authors: Jürgen
authors: J
authors: Debus
authors: Department of Radiation Oncology, National Center for Tumor Diseases and University Hospital, Heidelberg, Germany.
authors: Karin
authors: K
authors: Potthoff
authors: Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors: Karen
authors: K
authors: Steindorf
authors: Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors: Cornelia M
authors: CM
authors: Ulrich
mesh_terms: D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D003863:Depression / Q000209:etiology / Q000628:therapy*; D005221:Fatigue / Q000209:etiology / Q000628:therapy*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008875:Middle Aged; D010146:Pain / Q000209:etiology; D059408:Pain Management / Q000379:methods*; D011446:Prospective Studies; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors*; D055070:Resistance Training
chemical_list: D015850:Interleukin-6; D053573:Receptors, Interleukin-1 Type I