Entwicklung und Evaluation eines bewegungstherapeutischen Modulsystems für die Behandlung von Krebspatienten vor, während und nach allogener hämatopoetischer Stammzelltransplantation

Die allogene hämatopoetische Stammzelltransplantation (allo-HSCT) stellt eines der komplexesten und risikoreichsten medizinischen Behandlungsverfahren der heutigen Zeit dar. Gleichzeitig bietet sie jedoch Patienten mit austherapierten oder hämatologischen Krebserkrankungen mit ungünstigen Risikokonstellationen die letzte Chance auf vollständige Genesung und somit Heilung. Vor, während und nach allo-HSCT unterliegen die betroffenen Patienten mitunter starken biopsychosozialen Beeinträchtigungen, welche durch die Grunderkrankung an sich als auch durch die medizinische Therapie verursacht werden. Sport-/Bewegungstherapeutische Maßnahmen haben das Potential im Rahmen der Transplantation einen wichtigen Beitrag zur Behandlung zahlreicher therapie- und krankheitsbedingten Nebenwirkungen (bspw. Fatiguesymptomatik) zu leisten. Aus diesem Grund wurde in der vorliegenden Dissertation, im Rahmen einer randomisierten und kontrollierten Studie, die Durchführbarkeit und differenzielle Wirksamkeit eines bewegungstherapeutischen Interventionsprogramms (körperliches Kraft- und Ausdauertraining) untersucht, welches als behandlungsphasenübergreifendes Konzept entwickelt wurde und die Patienten im Sinne der integrativen Versorgung vor, während und nach allogener Stammzelltransplantation betreute. Insgesamt konnten 112 Patienten in die Studie eingeschlossen werden, von denen 106 Patienten der allogenen Stammzelltransplantation zugeführt wurden. Das theoriegeleitet konzipierte Trainingsprogramm war in jeder Studienphase praktikabel und erzielte zum Teil Adherence-Werte über 90%. Die interventionsinduzierten Effekte waren dabei multidimensional. So konnte eine hohe Wirksamkeit im Bezug auf die körperliche Leistungsfähigkeit der trainierenden Patienten während und nach der Transplantation gezeigt werden. Die im Gruppenvergleich gefundenen mittleren bis großen Effektstärken sprechen eindeutig für den Bedarf eines gezielten körperlichen Trainings im Kontext der allogenen HSCT, als auch für die Wirksamkeit der durchgeführten Intervention. Im gleichen Zeitraum ließen sich zudem eine signifikant positive Beeinflussung der Lebensqualität und erstmalig eine relevante Einflussnahme auf die Fatiguesymptomatik (häufigste nicht-letale, jedoch stark einschränkende Komplikation nach allo-HSCT) darlegen. Weitere Befunde zur positiven Beeinflussung des subjektiven Stressempfindens sowie zu emotionalen/kognitiven Komponenten erweitern das erfreuliche Therapieoutcome. Auf körperlicher Ebene zeigte sich zudem während des stationären Studienabschnittes eine signifikant geringere Häufigkeit an hypertonen Phasen für die Experimentalgruppe und ein besserer Karnofsky-Index zum Ende der Intervention. Keine statistisch signifikante Beeinflussung konnte hingegen für immuno- oder hämatologische Parameter festgestellt werden, wobei positive Tendenzen zu Gunsten der körperlich Trainierenden mit Blick auf die stationäre Substitutionsbedürftigkeit, die Hämoglobin- und Thrombozytenwerte sowie die BMI-Entwicklung nach stationärer Entlassung deskriptiv sichtbar waren. Zahlreiche Effekte wiesen darüber hinaus eine adäquate Nachhaltigkeit bis zum Ende des Beobachtungszeitraumes 6 Monate nach stationärer Entlassung auf. Zusammenfassend beurteilt ist der Nutzen des untersuchten bewegungstherapeutischen Interventionskonzeptes im Rahmen der allogenen hämatopoetischen Stammzelltransplantation als hoch einzuschätzen, da zahlreiche Nebenwirkungen und Komplikationen der Behandlung abgemildert oder verhindert werden konnten. Somit ist, unter Beachtung spezieller Kontraindikationen, ein entsprechendes körperliches Training für jeden betroffenen allo-HSCT Patienten zu empfehlen

Exploring the organisational structure of networks for exercise oncology provision: a social network analysis of OnkoAktiv

Background: Structured exercise programs provide considerable health benefits for cancer patients. Therefore, various OnkoAktiv (OA) networks were established in Germany with the aim to connect cancer patients with certified exercise programs. However, knowledge about the integration of exercise networks into cancer care systems and conditions of interorganisational collaboration is lacking. The aim of this work was to analyse the OA networks to guide further network development and implementation work. Methods: We used methods of social network analysis within a cross-sectional study design. Network characteristics were analysed such as node and tie attributes, cohesion and centrality. We classified all networks into their level of organisational form in integrated care. Results: We analysed 11 OA networks with 26 actors and 216 ties on average. The smallest network counted 12 actors/56 ties, the largest 52/530. 76% of all actors operated within the medical/exercise sector, serving 19 different medical professions. In smaller “linkage” networks, several individual professionals were linked “from service to service”, whereas the more integrated networks revealed a core-periphery-structure. Discussion: Collaborative networks enable the involvement of professional actors from different operational fields. This study provides an in-depth understanding of underlying organisational structures that provides information for further development of exercise oncology provision. Trial registration: Not applicable, as no health care intervention was performed

Worse or even better than expected? Outcome expectancies and behavioral experiences in the context of physical activity among cancer patients

Expectancies of cancer patients regarding their physical activity before they took part in a behavior change intervention were compared with their experiences during the intervention period. A total of 66 cancer patients completed either a randomly assigned 4-week physical activity or a stress-management counseling intervention. On average, participants had positive expectancies toward physical activity. Outcome expectancies predicted outcomes (e.g. physical activity) at a 10-week follow-up. Outcome realization (discrepancy between expectancies and experiences) further increased explained variance in self-efficacy and physical activity enjoyment. In conclusion, not only initial outcome expectancies but also their realizations seem to be important for subsequent behavior and cognitions

Physical Exercise Training versus Relaxation in Allogeneic stem cell transplantation (PETRA Study) – Rationale and design of a randomized trial to evaluate a yearlong exercise intervention on overall survival and side-effects after allogeneic stem cell transplantation

Background: Allogeneic stem cell transplantation (allo-HCT) is associated with high treatment-related mortality and innumerable physical and psychosocial complications and side-effects, such as high fatigue levels, loss of physical performance, infections, graft-versus-host disease (GvHD) and distress. This leads to a reduced quality of life, not only during and after transplantation, but also in the long term. Exercise interventions have been shown to be beneficial in allo-HCT patients. However, to date, no study has focused on long-term effects and survival. Previous exercise studies used ‘usual care’ control groups, leaving it unclear to what extent the observed effects are based on the physical effects of exercise itself, or rather on psychosocial factors such as personal attention. Furthermore, effects of exercise on and severity of GvHD have not been examined so far. We therefore aim to investigate the effects and biological mechanisms of exercise on side-effects, complications and survival in allo-HCT patients during and after transplantation. Methods/design: The PETRA study is a randomized, controlled intervention trial investigating the effects of a yearlong partly supervised mixed exercise intervention (endurance and resistance exercises, 3–5 times per week) in 256 patients during and after allogeneic stem cell transplantation. Patients in the control group perform progressive muscle relaxation training (Jacobsen method) with the same frequency. Main inclusion criterion is planned allo-HCT. Main exclusion criteria are increased fracture risk, no walking capability or severe cardiorespiratory problems. Primary endpoint is overall survival after two years; secondary endpoints are non-relapse mortality, median survival, patient reported outcomes including cancer related fatigue and quality of life, physical performance, body composition, haematological/immunological reconstitution, inflammatory parameters, severity of complications and side-effects (e.g. GvHD and infections), and cognitive capacity. Discussion: The PETRA study will contribute to a better understanding of the physiological and psychological effects of exercise training and their biological mechanisms in cancer patients after allo-HCT. The ultimate goal is the implementation of optimized intervention programs to reduce side-effects and improve quality of life and potentially prognosis after allogeneic stem cell transplantation. Trial registration: ClinicalTrials.gov Identifier: NCT0137439

Factors influencing participation in a randomized controlled resistance exercise intervention study in breast cancer patients during radiotherapy

Background: Over the past years knowledge about benefits of physical activity after cancer is evolving from randomized exercise intervention trials. However, it has been argued that results may be biased by selective participation. Therefore, we investigated factors influencing participation in a randomized exercise intervention trial for breast cancer patients. Methods: Non-metastatic breast cancer patients were systematically screened for a randomized exercise intervention trial on cancer-related fatigue. Participants and nonparticipants were compared concerning sociodemographic characteristics (age, marital status, living status, travel time to the training facility), clinical data (body-mass-index, tumor stage, tumor size and lymph node status, comorbidities, chemotherapy), fatigue, and physical activity. Reasons for participation or declination were recorded. Results 117 patients (52 participants, 65 nonparticipants) were evaluable for analysis. Multiple regression analyses revealed significantly higher odds to decline participation among patients with longer travel time (p = 0.0012), living alone (p = 0.039), with more comorbidities (0.031), previous chemotherapy (p = 0.0066), of age ≥ 70 years (p = 0.025), or being free of fatigue (p = 0.0007). No associations were found with BMI or physical activity. By far the most frequently reported reason for declination of participation was too long commuting time to the training facility. Conclusions: Willingness of breast cancer patients to participate in a randomized exercise intervention study differed by sociodemographic factors and health status. Neither current physical activity level nor BMI appeared to be selective for participation. Reduction of personal inconveniences and time effort, e.g. by decentralized training facilities or flexible training schedules, seem most promising for enhancing participation in exercise intervention trials. Trial registration: Registered at ClinicalTrials.gov: NCT01468766 (October 2011)

Can Exercise Enhance the Efficacy of Checkpoint Inhibition by Modulating Anti-Tumor Immunity?

Immune checkpoint inhibition (ICI) has revolutionized cancer therapy. However, response to ICI is often limited to selected subsets of patients or not durable. Tumors that are non-responsive to checkpoint inhibition are characterized by low anti-tumoral immune cell infiltration and a highly immunosuppressive tumor microenvironment. Exercise is known to promote immune cell circulation and improve immunosurveillance. Results of recent studies indicate that physical activity can induce mobilization and redistribution of immune cells towards the tumor microenvironment (TME) and therefore enhance anti-tumor immunity. This suggests a favorable impact of exercise on the efficacy of ICI. Our review delivers insight into possible molecular mechanisms of the crosstalk between muscle, tumor, and immune cells. It summarizes current data on exercise-induced effects on anti-tumor immunity and ICI in mice and men. We consider preclinical and clinical study design challenges and discuss the role of cancer type, exercise frequency, intensity, time, and type (FITT) and immune sensitivity as critical factors for exercise-induced impact on cancer immunosurveillance

Differentiated resistance training of the paravertebral muscles in patients with unstable spinal bone metastasis under concomitant radiotherapy: study protocol for a randomized pilot trial

Background: Metastatic bone disease is a common and severe complication in patients with advanced cancer. Radiotherapy (RT) has long been established as an effective local treatment for metastatic bone disorder. This study assesses the effects of RT combined with muscle-training exercises in patients with unstable bone metastases of the spinal column from solid tumors. The primary goal of this study is to evaluate the feasibility of muscle-training exercises concomitant to RT. Secondly, quality of life, fatigue, overall and bone survival, and local control will be assessed. Methods/Design: This study is a single-center, prospective, randomized, controlled, explorative intervention study with a parallel-group design to determine multidimensional effects of a course of exercises concomitant to RT on patients who have unstable metastases of the vertebral column, first under therapeutic instruction and subsequently performed by the patients themselves independently for strengthening the paravertebral muscles. On the days of radiation treatment the patients will be given four different types of exercises to ensure even isometric muscle training of all the spinal muscles. In the control group progressive muscle relaxation will be carried out parallel to RT. The patients will be randomized into two groups: differentiated muscle training or progressive muscle relaxation with 30 patients in each group. Discussion: Despite the clinical experience that RT is an effective treatment for bone metastases, there is insufficient evidence for a positive effect of the combination with muscle-training exercises in patients with unstable bone metastases. Our previous DISPO-1 trial showed that adding muscle-training exercises to RT is feasible, whereas this was not proven in patients with an unstable spinal column. Although associated with several methodological and practical challenges, this randomized controlled trial is needed. Trial registration: ClinicalTrials.gov, identifier: NCT02847754. Registered on 27 July 2016

POSITIVE study: physical exercise program in non-operable lung cancer patients undergoing palliative treatment

Background: Patients with advanced stage non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) often experience multidimensional impairments, affecting quality of life during their course of disease. In lung cancer patients with operable disease, several studies have shown that exercise has a positive impact on quality of life and physical functioning. There is limited evidence regarding efficacy for advanced lung cancer patients undergoing palliative treatment. Therefore, the POSITIVE study aims to evaluate the benefit of a 24-week exercise intervention during palliative treatment in a randomized controlled setting. Methods/design: The POSITIVE study is a randomized, controlled trial investigating the effects of a 24-week exercise intervention during palliative treatment on quality of life, physical performance and immune function in advanced, non-operable lung cancer patients. 250 patients will be recruited in the Clinic for Thoracic Diseases in Heidelberg, enrolment begun in November 2013. Main inclusion criterion is histologically confirmed NSCLC (stage IIIa, IIIb, IV) or SCLC (Limited Disease-SCLC, Extensive Disease-SCLC) not amenable to surgery. Patients are randomized into two groups. Both groups receive weekly care management phone calls (CMPCs) with the goal to assess symptoms and side effects. Additionally, one group receives a combined resistance and endurance training (3x/week). Primary endpoints are quality of life assessed by the Functional Assessment of Cancer Therapy for patients with lung cancer (FACT-L, subcategory Physical Well-Being) and General Fatigue measured by the Multidimensional Fatigue Inventory (MFI-20). Secondary endpoints are physical performance (maximal voluntary isometric contraction, 6-min walk distance), psychosocial (depression and anxiety) and immunological parameters and overall survival. Discussion: The aim of the POSITIVE trial is the evaluation of effects of a 24-week structured and guided exercise intervention during palliative treatment stages. Analysis of various outcomes (such as quality of life, physical performance, self-efficacy, psychosocial and immunological parameters) will contribute to a better understanding of the potential of exercise in advanced lung cancer patients. In contrast to other studies with advanced oncological patients the POSITIVE trial provides weekly phone calls to support patients both in the intervention and control group and to segregate the impact of physical activity on quality of life. Trial registration: ClinicalTrials.gov NCT02055508 (Date: December 12, 2013

Exercise for individuals with bone metastases: A systematic review

Background Exercise has the potential to improve physical function and quality of life in individuals with bone metastases but is often avoided due to safety concerns. This systematic review summarizes the safety, feasibility and efficacy of exercise in controlled trials that include individuals with bone metastases. Methods MEDLINE, Embase, Pubmed, CINAHL, PEDro and CENTRAL databases were searched up to July 16, 2020. Results A total of 17 trials were included incorporating aerobic exercise, resistance exercise or soccer interventions. Few (n=4, 0.5%) serious adverse events were attributed to exercise participation, with none related to bone metastases. Mixed efficacy results were found, with exercise eliciting positive changes or no change. The majority of trials included an element of supervised exercise instruction (n=16, 94%) and were delivered by qualified exercise professionals (n=13, 76%). Conclusions Exercise appears safe and feasible for individuals with bone metastases when it includes an element of supervised exercise instruction

Exercise recommendations for people with bone metastases: Expert consensus for healthcare providers and clinical exercise professionals

Purpose: Exercise has been underutilized in people with advanced or incurable cancer despite the potential to improve physical function and reduce psychosocial morbidity, especially for people with bone metastases because of concerns over skeletal complications. The International Bone Metastases Exercise Working Group (IBMEWG) was formed to develop best practice recommendations for exercise programming for people with bone metastases on the basis of published research, clinical experience, and expert opinion. Methods: The IBMEWG undertook sequential steps to inform the recommendations: (1) modified Delphi survey, (2) systematic review, (3) cross-sectional survey to physicians and nurse practitioners, (4) in-person meeting of IBMEWG to review evidence from steps 1-3 to develop draft recommendations, and (5) stakeholder engagement. Results: Recommendations emerged from the contributing evidence and IBMEWG discussion for pre-exercise screening, exercise testing, exercise prescription, and monitoring of exercise response. Identification of individuals who are potentially at higher risk of exercise-related skeletal complication is a complex interplay of these factors: (1) lesion-related, (2) cancer and cancer treatment–related, and (3) the person-related. Exercise assessment and prescription requires consideration of the location and presentation of bone lesion(s) and should be delivered by qualified exercise professionals with oncology education and exercise prescription experience. Emphasis on postural alignment, controlled movement, and proper technique is essential. Conclusion: Ultimately, the perceived risk of skeletal complications should be weighed against potential health benefits on the basis of consultation between the person, health care team, and exercise professionals. These recommendations provide an initial framework to improve the integration of exercise programming into clinical care for people with bone metastases