title: Impact of a combined multimodal-aerobic and multimodal intervention compared to standard aerobic treatment in breast cancer survivors with chronic cancer-related fatigue - results of a three-armed pragmatic trial in a comprehensive cohort design.
abstract: Cancer-related fatigue (CRF) and insomnia are major complaints in breast cancer survivors (BC). Aerobic training (AT), the standard therapy for CRF in BC, shows only minor to moderate treatment effects. Other evidence-based treatments include cognitive behavioral therapy, e.g., sleep education/restriction (SE) and mindfulness-based therapies. We investigated the effectiveness of a 10-week multimodal program (MT) consisting of SE, psycho-education, eurythmy- and painting-therapy, administered separately or in combination with AT (CT) and compared both arms to AT alone.
  
  
  
  In a pragmatic comprehensive cohort study BC with chronic CRF were allocated randomly or by patient preference to (a) MT, (b) CT (MT + AT) or (c) AT alone. Primary endpoint was a composite score of the Pittsburgh Sleep Quality Index and the Cancer Fatigue Scale after 10 weeks of intervention (T1); a second endpoint was a follow-up assessment 6 months later (T2). The primary hypothesis stated superiority of CT and non-inferiority of MT vs. AT at T1. A closed testing procedure preserved the global α-level. The intention-to-treat analysis included propensity scores for the mode of allocation and for the preferred treatment, respectively.
  
  
  
  Altogether 126 BC were recruited: 65 were randomized and 61 allocated by preference; 105 started the intervention. Socio-demographic parameters were generally balanced at baseline. Non-inferiority of MT to AT at T1 was confirmed (p < 0.05), yet the confirmative analysis stopped as it was not possible to confirm superiority of CT vs. AT (p = 0.119). In consecutive exploratory analyses MT and CT were superior to AT at T1 and T2 (MT) or T2 alone (CT), respectively.
  
  
  
  The multimodal CRF-therapy was found to be confirmatively non-inferior to standard therapy and even yielded exploratively sustained superiority. A randomized controlled trial including a larger sample size and a longer follow-up to evaluate multimodal CRF-therapy is highly warranted.
  
  
  
  DRKS-ID: DRKS00003736 . Recruitment period June 2011 to March 2013. Date of registering 19 June 2012.
authors.affiliation: Department of Internal Medicine, Havelhöhe Hospital, Kladower Damm 221, D-14089, Berlin, Germany. mkroez@havelhoehe.de.|Research Institute Havelhöhe, Kladower Damm 221, Berlin, D-14089, Germany. mkroez@havelhoehe.de.|Institute for Social Medicine, Epidemiology and Health Economics, Charité Universitätsmedizin Berlin, Charité CCM, Berlin, 10098 Berlin, Germany. mkroez@havelhoehe.de.|Institute for Integrative Medicine, University of Witten/Herdecke, Gerhard-Kienle-Weg 4, Herdecke, 58313, Germany. mkroez@havelhoehe.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kröz
authors.affiliation: Society for Clinical Research, Hardenbergstraße 20, Berlin, 10623, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Reif
authors.affiliation: Research Institute Havelhöhe, Kladower Damm 221, Berlin, D-14089, Germany.
authors.forename: Augustina
authors.initials: A
authors.lastname: Glinz
authors.affiliation: Institute for Integrative Medicine, University of Witten/Herdecke, Gerhard-Kienle-Weg 4, Herdecke, 58313, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Berger
authors.affiliation: Clinic for Rehabilitative Medicine, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover, 30625, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Nikolaou
authors.affiliation: Department of Internal Medicine, Havelhöhe Hospital, Kladower Damm 221, D-14089, Berlin, Germany.|Research Institute Havelhöhe, Kladower Damm 221, Berlin, D-14089, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Zerm
authors.affiliation: Institute for Social Medicine, Epidemiology and Health Economics, Charité Universitätsmedizin Berlin, Charité CCM, Berlin, 10098 Berlin, Germany.
authors.forename: Benno
authors.initials: B
authors.lastname: Brinkhaus
authors.affiliation: Department of Internal Medicine, Havelhöhe Hospital, Kladower Damm 221, D-14089, Berlin, Germany.|Research Institute Havelhöhe, Kladower Damm 221, Berlin, D-14089, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Girke
authors.affiliation: Institute for Integrative Medicine, University of Witten/Herdecke, Gerhard-Kienle-Weg 4, Herdecke, 58313, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Büssing
authors.affiliation: Clinic for Rehabilitative Medicine, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover, 30625, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Gutenbrunner
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000150:complications* / Q000523:psychology; D000073116:Cancer Survivors / Q000523:psychology*; D015928:Cognitive Behavioral Therapy; D015331:Cohort Studies; D003131:Combined Modality Therapy / Q000379:methods*; D005081:Exercise Therapy / Q000379:methods*; D005221:Fatigue / Q000209:etiology / Q000523:psychology / Q000628:therapy*; D005260:Female; D006801:Humans; D008875:Middle Aged; D064866:Mindfulness; D010151:Paintings; D011446:Prospective Studies; D011897:Random Allocation; D012107:Research Design; D012890:Sleep; D007319:Sleep Initiation and Maintenance Disorders / Q000209:etiology / Q000523:psychology / Q000628:therapy*; D016896:Treatment Outcome; D055815:Young Adult
keywords: Aerobic training; Anthroposophic medicine; Breast cancer; Cancer-related fatigue; Cognitive behavior therapy; Eurythmy therapy; Multimodal intervention; Painting therapy; Sleep education; Sleep restriction