HEMATOPOIETIC STEM CELL TRANSPLANTATION

The Effect of a Multimodal Intervention on Physical Capacity and Functional Performance,Treatment-related Symptoms,and Quality of Life

Ph.D. DissertationMary Jarden

FACULTY OF HEALTH SCIENCESUNIVERSITY OF COPENHAGEN

Department of Hematology, The Finsen Center andThe University Hospitals Center for Nursing and Care ResearchCopenhagen University Hospital

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F A C U L T Y O F H E A L T H S C I E N C E S U N I V E R S I T Y O F C O P E N H A G E N

Ph.D. Dissertation Mary Jarden

Hematopoietic Stem Cell Transplantation

The Effect of a Multimodal Intervention on Physical Capacity and Functional Performance, Treatment-related Symptoms, and Quality of Life

Department of Hematology, The Finsen Center andThe University Hospitals Center for Nursing and Care Research Copenhagen University Hospital

2009

Ph.D. Dissertation:

Hematopoietic Stem Cell Transplantation.Th e Eff ect of a Multimodal Intervention on Physical Capacity and Functional Performance, Treatment-related Symptoms and Quality of Life

Mary Jarden

Th e dissertation will be defended on Monday, April 20, 2009 at 14.30 in the Henrik Dam Auditorium.

Offi cial opponents• Associate Professor Ole Weis Bjerrum MD, DMSc

Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark

• Head of Department Christoff er Johansen MD, Ph.D., DMScDepartment of Psychosocial Cancer Research, Th e Danish Cancer Society, Copenhagen, Denmark

• Professor Egil W. Martinsen MD, Ph.D.Clinic for Mental Health, Department of Research and Education, Aker University Hospital, Oslo, Norway

Scientifi c Advisors• Professor Lis Adamsen, Ph.D.

Th e University Hospitals Center for Nursing & Care Research Institute of Public Health & Faculty of Health Sciences Copenhagen University, Copenhagen, Denmark

• Doris Hovgaard, MD Department of Hematology, Bone Marrow Transplantation UnitCopenhagen University Hospital, Copenhagen, Denmark

• Ellen Boesen, Researcher, Psychologist, Ph.D.Danish Cancer Society, Th e Danish Cancer SocietyDepartment of Psychosocial Cancer Research,Copenhagen, Denmark

ISBN: 978-87-90769-07-9

Th e University Hospitals Center for Nursing andCare Research (UCSF), Copenhagen University HospitalDepartment 7331, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. ucsf@ucsf.dk

Print and Production: WERKs Grafi ske Hus a|s, Aarhus • www.werk.dkCover: Jacob Billesbølle

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ACKNOWLEDGEMENTS

Th is Ph.D. dissertation was developed and carried out through collaborative eff orts at the Department of Hematology and at the University Hospitals Center for Nursing and Care Research (UCSF), Copenhagen University Hospital. I gratefully ac-knowledge the support of this research by grants from Th e Lundbeck Foundation, Th e Novo Nordic Foundation, Th e Dan-ish Cancer Society, Th e Copenhagen Hospital Corporation and Th e Danish Nursing Society.

I wish to express my gratitude to my advisors; Professor Lis Adamsen Ph.D., Doris Hovgaard MD and Ellen Boesen Psycholo-gist, Ph.D. for their constructive guidance, discussions and invaluable support throughout the project period, in data anal-yses and manuscript preparation. I am grateful to Lis, who was my main advisor, for exceptional guidance and for being a constant source of inspiration in every aspect of the project. Lis’ advisory role has been invaluable, thank you!

Moreover, I would like to thank the Finsen Centers’ Director Kurt Stig Jensen and Center Nursing Director Jeanette Bech for their support in the realization of this project at Copenhagen University Hospital. Further, the study would not have been possible without support from Professor Niels Borregaard and Lene Landbo, Department of Hematology, Th ank you! I wish to express my appreciation to the department’s secretary, Rikke Ulrik for always being accommodating and helpful. I would like to thank the secretaries on the Bone Marrow Transplantation unit, Jytte Klitgaard and Marianne Tranberg who coordinated and scheduled the patient’s tests, the nurses and physicians for their daily fl exibility and support in assuring patient participation. And a special thank you to Alex Peter Hansen for assembling equipment and solving technical prob-lems along the way. Th ank you, to the BMT out-patient unit and BMT Secretariat where there was always an extra computer or desk avail-able and for never ending positive and enthusiastic support. A special thank you to the KMT coordinators; Jeanette Holder RN, Tina Lanther RN, Sine Rasmussen RN and Ann Mari Berthelsen RN in being helpful and involved in the patient inclusion discussions. Especially, thanks to Jeanette Holder for conducting interviews and for valuable contribution during the inter-view analyses phase and Hanne Bækgaard Laursen for assistance with the BMT database. Additionally, I want to thank my colleagues at UCSF; Ingrid Egerod Ph.D., Julie Midtgaard Ph.D., Vibeke Zoff mann Ph.D., Lone Friis Th ing Ph.D., Betina Lund Nielsen Ph.D graduate student, Tom Møller Ph.D graduate student and Hanne Bækgaard Laursen Ph.D graduate student. Th ey have all contributed with professional, inspiring and constructive discussions through-out the project. Furthermore, thanks to Ali Mohamad and Kjeld Stevns Jensen for computer and technical support. Most importantly, thank you to the patients who participated in this study, for their willingness to invest time and energy into this trial - they are a constant source of inspiration. Much appreciation to the project coordinators and investigators of ‘Body and Cancer’ and ‘PACT’; Morten Quist PT has shared his training/testing expertise, guided and supported me during the intervention process and thank you to Christina Andersen RN MPH, Jacob Uth PT, Kira Bloomquist PT and Professor Michael Rørth.

Further, I wish to express my gratitude to those who made valuable contributions to this project: Bente Kronborg and Ida Raun-Petersen for always willing, helpful and meticulous secretarial assistance and Anders Larsen for valuable librarian as-sistance throughout the entire study period. Database management, technical, and statistical support was provided by Knud Nelausen and Torben Gøth from the Department of Oncology, Copenhagen University Hospital and Marie Topp Baads-gaard, UCSF. Th ank you for conducting the statistical analyses, for statistical advice, discussion and important contribu-tions to the manuscripts. I wish to thank Kristine Jarden and Jacob Billesbølle for database keying and interview transcrip-tion and analyses assistance. My sincere gratitude goes to my American and Danish families and friends (from near and afar) for their love, support and patience over the last few years.

Finally, a heartfelt thanks to my husband, Jens Ole and our children Kristine, Hanna, Emily and Christopher, also to Jacob and Nicholas for having steadfast confi dence in me, for motivational support, and for always being there.

Mary Jarden, April 20, 2009

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ORIGINAL PAPERS

Th is dissertation is based on the following papers:

I. Jarden M, Hovgaard D, Boesen E, Quist M, Adamsen L. Pilot study of a multimodal intervention: mixed-type ex-ercise and psychoeducation in patients undergoing allogeneic stem cell transplantation. Bone Marrow Transplant. 2007;40:793-800

II. Jarden M, Nelausen K, Hovgaard D, Boesen E, Adamsen L. Th e Eff ect of a Multimodal Intervention on Treat-ment-Related Symptoms in Patients undergoing Hematopoietic Stem Cell Transplantation: A Randomized Con-trolled Trial. Pain and Symptom Manage, Advanced on line publication, April 2009, 1-17

III. Jarden M, Topp Baadsgaard M, Hovgaard D, Boesen E, Adamsen L. A Randomized Trial on the Eff ect of a Mul-timodal Intervention on Physical Capacity, Functional Performance and Quality of Life in Adult Patients under-going Allogeneic Stem Cell Transplantation. Bone Marrow Transplant, Advanced on line publication, 23 February 2009, 1-13

Th e articles are referred to in the text by their Roman Numerals.

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ABSTRACT

Th is study examines the eff ect of a physical activity and psychosocial intervention in patients with hematologic disease during allogeneic stem cell transplantation (allo-HSCT). Patients undergoing allo-HSCT are in a particularly stressful life situation, diagnosed with a life threatening disease while undergoing a treatment of total body radiation (TBI) and/or high dose chemotherapy under a 4-6 week hospitalization in an isolation room. Despite a survival of up to 70%, patients expe-rience short and long term physiological and psychological reactions as graft-versus-host disease, reduced cardiovascular and respiratory capacity, infections, mucositis, nausea and vomiting, loss of appetite, diarrhea, fatigue, depression, anxi-ety etc. Th ese reactions can contribute to physical, psychological and psychosocial stress before, during and after treat-ment, resulting in a delay into daily life activities. Th e purpose of this study was to alleviate the complexity of problems that the patients experience as a result of disease and treatment, and to prevent and compensate for physical weakness, for stressful physical and psychological symptoms and reactions.

Th e aim of the dissertation was to investigate the impact of a 4-6 week multimodal intervention, comprised of mixed-exer-cise, progressive relaxation and psychoeducation, in patients undergoing allogeneic stem cell transplantation. Th e dissertation is based on the assumption that the intervention would reduce loss of physical capacity and functional performance, and lessen treatment-related symptoms experienced, as well as better health-related quality of life and lei-sure time activity levels over time. In addition, the aim was to illuminate and explore the experience of patients in their adjustment to disease and treatment during hospitalization.

It was hypothesized that the multimodal intervention would be feasible and safe in patients undergoing allo-HSCT (article I) and that the intervention would; reduce the symptom burden (article II), reduce the loss of physical capacity (aerobic fi t-ness, muscle strength) and functional performance (stair climb test), and enhance health-related quality of life (question-naires) and have a benefi cial eff ect on clinical parameters (days with elevated temperature, length of hospitalization, etc.) (article III) and support the patient in handling their treatment situation while hospitalized (dissertation).

Design and population: Th e project is a randomized clinically controlled trial comparing an intervention and control group. In all, 42 adult patients admitted for allo-HSCT on the Hematology Unit at the University Hospital of Copenhagen par-ticipated.

Th e intervention is an individual and supervised, moderate intensity physical training, progressive relaxation and psycho-education program, 5 hours over 5 days/week. Th e physical training program comprises aerobic training on a stationary cycle, muscle strength training with free weights, and active and stretching exercises.

Methods: Data was collected at four time points; baseline, during and after intervention (post, 3 and 6 months) using quan-titative and qualitative methods: estimated VO2 max , muscle strength tests, functional test (stair climb), clinical parame-ters, psychometric questionnaires (EORTC QLQ-C30, HADS, FACT-An, Mini-MAC), individual semistructured interview, a monitoring logbook and a self-rated symptom assessment (SCT-SAS) questionnaire.

Ethics: Th e study was approved by the Scientifi c Committees of the Copenhagen and Frederiksberg municipalities (J.no. 01-173/04) and registered with the Danish Data Protection Agency (J.no. 2004-41-4266) and ClinicalTrials.gov (NCT00427115).

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Results: Th e multimodal intervention proved to be feasible and safe with no adverse events. Th e adherence rate to interven-tion was 90%. Signifi cant eff ect diff erences were found in pre-post scores for the physical capacity; VO2 max (p

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ABBREVIATIONS

Allo-HSCT Allogeneic Hematopoietic Stem Cell TransplantationAGvHD Acute Graft vs. Host DiseaseBMI Body Mass IndexBMT Bone Marrow TransplantationCITMAS Clinical International Trial Management System EORTC-QLQ-C30 European Organization of Research and Treatment of Cancer Quality of Life Questionnaire FACT-An Functional Assessment of Cancer Th erapy-Anemia scaleGEE General Estimate EquationsGvHD Graft vs. Host DiseaseHADS Hospital Anxiety and Depression ScaleHD-SCS High Dose chemotherapy with Autologous Stem Cell SupportHRQoL Health-Related Quality of LifeHSCT Hematopoietic Stem Cell TransplantationKPS Karnofsky Performance StatusMET Metabolic Equivalent Intensity levelMini-MAC Mental Adjustment to Cancer PCA Principal Component Analysis RAM Roy’s Adaptation ModelRM Repetition MaximumRPE Rate of Perceived ExertionSCT-SAS Stem Cell Transplantation Symptom Assessment ScaleVO2max Oxygen Consumption (uptake)JH Jeanette Holder KJ Kristine JardenLA Lis AdamsenMJ Mary Jarden

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TABLE OF CONTENTS

1 INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1 Hematopoietic Stem Cell Transplantation, Physical and Emotional Reactions . . . . . . . . . . . . . . . . . . . . . 2 2.2 Fatigue, Inactivity and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.3 Symptom Distress during and following Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . 2 2.4 Clinical Intervention Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.4.1 Exercise-based Interventions in Cancer Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.4.2 Exercise-based Interventions in Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . . 3 2.4.3 Progressive Relaxation and Psychoeducation in Cancer Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.4.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

3 HYPOTHESES AND AIMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

4 THEORETICAL FRAMEWORK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.1 Exercise Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4.2 Th e Roy Adaptation Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.3 Cognitive Behavioral Th eory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.4 Symptom Th eory Framework. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

5 MATERIAL AND METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.1 Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.2 Sample . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.3 Context . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.4 Multimodal Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.5 Control Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5.6 Data Collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5.6.1 Assessment Instruments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5.6.2 Physical Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 5.6.3 Functional Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 5.6.4 Leisure Time Physical Activity Level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 5.6.5 Questionnaires . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 5.6.6 Monitoring Logbook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 5.6.7 Stem Cell Transplantation Symptom Assessment Scale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 5.6.8 Semi-structured Individual Interviews. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

6 DATA ANALYSES AND INTERPRETATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 6.1 Quantitative Data Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 6.1.1 Pilot Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 6.1.2 Principal Component Analysis and General Estimates Equation . . . . . . . . . . . . . . . . . . . . . . . . . . 16 6.2 Qualitative Data Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

7 ETHICAL CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

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8 RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 8.1 Feasibility Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 8.1.1 Acceptance, Attrition, Adherence, Safety and Benefi ts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 8.2 Eff ect on Treatment-related Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 8.2.1 Symptom Profi le: Prevalence, Severity and Distress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 8.2.2 Symptom Clusters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 8.2.3 Longitudinal Intervention Eff ects on Symptom Clusters - A two group comparison . . . . . . . . . 19 8.3 Physiological and Psychological Eff ects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 8.3.1 Physical Capacity and Functional Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 8.4 Health-related Quality of Life, Fatigue and Psychological Wellbeing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 8.4.1 EORTC-QLQ-C30 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 8.4.2 FACT-An . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 8.4.3 HADS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 8.4.4 Associations among Physical Capacity Measures and Patient-rated Outcomes . . . . . . . . . . . . . . 21 8.4.5 Leisure Time Physical Activity Level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 8.5 Clinical Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 8.6 Intervention Adherence and Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 8.7 Coping Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 8.7.1 Mini-MAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 8.8 Th e Patients’ Experience in the Hematopoietic Stem Cell Transplantation Setting . . . . . . . . . . . . . . . . 22 8.8.1 Th e Patients’ Perspective on and Expectations of Hematopoietic Stem Cell Transplantation . . 22 8.8.2 Th e Patients’ Experience and Evaluation of the Multimodal Intervention . . . . . . . . . . . . . . . . . . 22 8.8.3 Th e Experience of Patients undergoing Hematopoietic Stem Cell Transplantation . . . . . . . . . . 23

9 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 9.1 Methodological Considerations and Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 9.1.1 Pilot Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 9.1.2 Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 9.1.3 Outcome Measurement Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 9.2 General Discussion of the Eff ects of the Multimodal Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 9.2.1 Multimodal Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 9.2.2 Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

10 CONCLUSION AND CLINICAL IMPLICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

11 FUTURE RESEARCH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

12 DANSK RESUMÉ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

13 REFERENCE LIST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

PAPER I-III

APPENDIX A Literature Review – Exercise-based studies and HSCT

APPENDIX B Questionnaires

1

Ph.D. Dissertation Mary JardenHematopoietic Stem Cell Transplantation

1 INTRODUCTION

A growing literature in allogeneic hematopoietic stem cell transplantation (allo-HSCT) has shown, that despite im-proved survival rates, patients experience substantial physiologic and psychologic symptoms and deterioration in health related quality of life (HRQoL) before, during and after transplantation. However, complementary interven-tion studies that aim to prevent or reduce these ‘stressors’ have to a lesser extent been in focus. A few studies in the HSCT setting have implemented exercise studies with var-ious outcome goals ranging from physiological, medical/clinical and psychosocial, but these studies were limited in number and type and often lacked randomized conditions. Th ere is a growing need for the development of interven-tions, implemented as complementary therapy in clinical practice that take into consideration the complex situation and multiple symptoms experienced by patients as a re-sult of disease and treatment. Recommendations for non-pharmacological adjuvant therapy i.e. exercise have not, as yet, been issued for patients undergoing allo-HSCT. Th e importance of studying and actively intervening with pa-tients with the goal of preventing or limiting these ‘stres-sors’ is a central issue. Complex treatments as HSCT may require multifacited interventions that consider the pa-tient’s symptom burden in the actual context (bedside/clinical research). Th is study was undertaken at Copenhagen University Hospital, the only hospital in Denmark to off er allo-HSCT. Th ough this study included a limited patient material (n=42), it has taken over two and a half years to recruit eli-gible patients. It was a fi rst time randomized study that of-fered a combined program of mixed-exercise: aerobic and resistance training, ROM, progressive relaxation and psy-choeducation during the patient’s entire hospitalization (4 – 6 wks) and measured multidimensional outcomes. Oth-er studies exercising patients undergoing HSCT began af-ter stem cell support or hematopoietic recovery, included a

single exercise element without a relaxation and psychoed-ucative intervention and the larger part of these studies included patients undergoing autologous stem cell trans-plantations, where patients are hospitalized for a shorter period (3 weeks) without the same transplantation sequel. Th e strict inclusion /exclusion criterion secured necessary safety measures, but was also partly responsible for ex-clusion of patients from an already small population. We wanted to evaluate if combining a mixed-exercise and re-laxation program with psychoeducation could motivate patients to remain safely and eff ectively physically active during their entire hospitalization and ultimately reduce loss of physical capacity, functional performance, health-related quality of life (HRQoL) and relieve the symptom burden experienced. Research considerations in designing clinically con-trolled randomized intervention trials, development of relevant assessment tools and combining outcome mea-surements that address and refl ect the complexity of the HSCT context will help in understanding the full impact of the patients’ experience during treatment. Th is may lead to best-practice treatment and care for patients in a complex situation. Th is research was inspired by theoreti-cal concepts from three disciplines; exercise physiology, a nursing adaptation model and cognitive behavioral theo-ry. We developed and tested the eff ect of an intervention and provided preliminary validation of a newly developed symptom assessment tool. Moreover, this study illuminat-ed the patients’ situation while undergoing allo-HSCT. Th e results showed that it may be a realistic goal to stabilize physical capacity and minimize loss of functional perfor-mance in patients undergoing allo-HSCT. Th ere were also HRQoL and clinical benefi ts such as a reduced symptom burden, which has the potential to give patients a more ad-vantageous starting point for recovery after hospital dis-charge.

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Ph.D. Dissertation Mary Jarden Hematopoietic Stem Cell Transplantation

2 BACKGROUND

Th is section presents an overview of the literature regard-ing treatment-related symptoms, complications as well as the complexity and the special challenges associated with allo-HSCT. Moreover, data are presented with special fo-cus on the benefi ts on physiologic and psychologic factors, as well as quality of life.

2.1 Hematopoietic Stem Cell Transplantation, Physical and Emotional Reactions

Allogeneic stem cell transplantation is an established treatment whereby more than 15,000 procedures are per-formed worldwide each year for a number of hematologi-cal malignancies such as acute myeloid and lymphoid leu-kemia, and bone marrow failure syndromes (Gratwohl et al., 2002; Frassoni, 2004). It is predicted that transplanta-tion rates for allo-HSCT will continue at the same or higher level in the immediate future (Gratwohl et al., 2002). De-spite clinical cure in 20-70% of all patients, depending on disease presentation, long term sequelae of immunosup-pression, chemotherapy toxicities and graft-versus-host disease (GvHD) debilitate a large number of patients.( Gratwohl et al., 2002; Carlson et al., 2006). Moderate to severe GvHD develops in 40-50% of patients undergoing allo-HSCT (Bearman et al., 1988; Weisdorf et al., 1990; Roy et al., 1992; Hings et al., 1994). Factors limiting the effi ca-cy of this treatment are death due to recurrence or treat-ment-related death due to infection or organ failure in the cytopenia and later immunosuppressed phase immediate-ly post-HSCT. Over the last decades, the cumulative eff ects of improvements in supportive care, drug dosing, stem cell technology and prophylaxis of GvHD have led to an in-creased number of complete remissions (Devergie, 2004). However, with the increasing number of transplants per-formed and the growing number of survivors, a shift in clinical focus from not only improving survival but also improving short and long-term quality of life has emerged (Andyrkowski et al., 1995). Patients in the recovery phase of HSCT commonly experience adverse physical and emo-tional reactions. Fatigue and muscle weakness can limit ability to accomplish activities of daily living. Additionally, depression, anxiety, fear, and frustration add to the diffi -culties of recovering from HSCT (Syrjala et al. 1993, An-

dyrkowski et al., 1995). Several studies confi rm that high levels of physical and psychological stress have been ob-served in patients prior to and at the start of HSCT and during follow-up periods (Baker et al., 1997, Mollasiotis & Morris, 1997, McQuellon et al.,1998, Fife et al., 2000). Th e mechanisms are not fully known, but it is assumed that several factors such as TBI, chemotherapy, GvHD, in-fections, long-term inactivity or bed rest and side-eff ects from medication can contribute to the physical and emo-tional weakening of the patient.

2.2 Fatigue, Inactivity and Cancer It is increasingly recognized as a problem that 30-75% of all cancer patients report fatigue continuing for months or years after completing active treatment (Patrick et al., 2002). A burgeoning literature regarding cancer-related fa-tigue (CRF) both during and after cancer treatments has grown substantially in recent years (Prue et al., 2006), though to a lesser extent in patients in the HSCT context. Fatigue is a multidimensional concept presented by phys-ical, cognitive and emotional symptoms, and is accom-panied by inactivity and lack of motivation (Smets et al., 1998). Th e term CRF is defi ned by the National Compre-hensive Cancer Network as ‘a persistent, subjective sense of tiredness related to cancer or cancer treatment that in-terferes with usual functioning’ (NCCN 2005). It often per-sists over time and can interfere with usual activities. Can-cer-related fatigue is more severe and distressing than the fatigue of everyday life, and rest does not relieve it. Rest is the most frequently recommended intervention; however unnecessary bed rest and a prolonged sedentary level can contribute to the development of weakness, which may re-sult in rapid and potentially irreversible functioning (Po-rock et al. 2000).

2.3 Symptom Distress during and following Hematopoietic Stem Cell Transplantation

Patients that have undergone HSCT experience treatment-related symptoms during and after treatment that can af-fect HRQoL. Patients experience multiple somatic, aff ective and cognitive symptoms during and after aggressive cancer treatment, where 11-13 simultaneously occurring symp-

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Ph.D. Dissertation Mary JardenHematopoietic Stem Cell Transplantation

toms have been reported.(Portenoy et al., 1994) During hospitalization for allo-HSCT, patients are typically on pro-longed bed rest, and experience complications from the my-eloablative treatment, ie. GvHD, side eff ects from medica-tions (immunosuppression & steroids), frequent infections and psychological reactions that can be debilitating. Th e most commonly reported symptoms are fatigue, diarrhea, insomnia, poor appetite, diminished concentration, mouth dryness, loss of hair and poor body image perception (Mo-lassitis et al.,1997; Larsen et al., 2007). Psychosocial wellbe-ing after transplant is infl uenced by mucositis toxicity, and other side eff ects, and psychological factors as anxiety, dis-tress and social support have a signifi cant impact on how severely patients experience mouth pain (Schulz-Kinder-mann et al., 2002) Fatigue is one of the most frequent side eff ects reported by patients who have undergone HSCT (So et al., 2003), physical activity decreased and this decline co-incided with diminished physical, emotional, role and cog-nitive functioning during the initial post transplantation period (Danaher et al., 2006) Fatigue was the main symp-tom interfering with daily life in 79% of patients (Molassi-otis & Morris, 1999). Loss of physical strength seem to be more pronounced in patients on corticosteroid treatment, and the causes of an impairment of physical performance are not fully understood, though low activity levels have been suggested to be a substantial contributor (Carlson et al., 2006). One study in patients undergoing HSCT showed a correlation between the number of symptoms experi-enced and poor functional status and general health (Lars-en et al.,2007) and in another study, changes in HRQoL could be explained entirely by changes in functional limi-tations and somatic symptoms (Broers et al., 2000). A Dan-ish study found patients prior to allo-HSCT to have lower VO2 max scores and elevated fatigue levels than the normal population, and these scores were unchanged six months post transplantation (Kalo et al., 2007). Reducing fatigue and treatment-related symptoms can be an important goal and there is a continued need for intervention strategies that address the specifi c impairments experienced by pa-tients undergoing allo-HSCT. To date, the general practice in Denmark regarding physical activity for patients under-going allo-HSCT is to inform patients prior to hospitaliza-tion about the importance of avoiding excessive bed rest during hospitalization and physical therapy is off ered af-ter stem cell replacement, 9-10 days after hospital admis-sion. In the home recovery period, patients are advised to remain physically active within own limitations.

2.4 Clinical Intervention Studies

2.4.1 Exercise-based Interventions in Cancer PatientsTh ere is a rapidly increasing literature on the eff ects of ex-ercise on cancer rehabilitation, especially for breast cancer patients, on whom the majority of research has been con-ducted (Courneya et al., 2007 & 1997; Conn et al., 2006). Despite that physical exercise showed positive eff ects on factors such as cardiorespiratory fi tness, treatment-relat-ed symptoms and physiological eff ects, the magnitude of these positive results still need to be established. A qualita-tive and quantitative review and meta-analysis found only small to moderate eff ect of physical activity interventions on these outcomes (Schmitz et al. 2005; Conn et al., 2006). Physical activity is reported as being well tolerated in can-cer survivors during and after treatment, however, conclu-sions about adverse eff ects are inconclusive (Schmitz et al. 2005).

2.4.2 Exercise-based Interventions in Hematopoietic Stem Cell Transplantation

Exercise has been proposed as a nonpharmacologic adju-vant therapy to combat the physiological and psychologi-cal symptoms of HSCT (Wiskemann & Huber, 2008). How-ever, little work exists in utilizing exercise interventions specifi cally in the HSCT setting. It is documented that there is a decline in exercise levels in cancer patients from prediagnosis to postdiagnosis (Courneya et al.,1997) and more specifi cally, a low level of “naturally-occurring” exer-cise amongst patients undergoing HSCT is reported, sug-gesting that a structured intervention may be necessary in order to promote exercise in this population (Courneya et al.,2000). To date, 15 intervention studies have been pub-lished that incorporated exercise regimes in various HSCT contexts. Benefi cial eff ects were found on aerobic capac-ity (Hayes et al., 2004; Dimeo et al., 2003; Dimeo et al., 1996; Carlson et al., 2006), muscle strength (Hayes et al., 2004; Mello et al., 2003), body composition (Coleman et al., 2003; Hayes et al., 2003), physical performance scores and perceived physical and emotional state (DeFor et al., 2007), immunological function (Kim & Kim 2006; Dimeo et al., 1997; Hayes et al., 2003), treatment related symp-toms i.e. fatigue (Carlson et al., 2006; Dimeo et al., 1999; Wilson et al., 2005) and HRQoL (Defor et al., 2007¸ Wilson et al., 2005; Hayes et al., 2004; (Table 3). Only four stud-ies, however, were initiated during the hospitalization pe-riod for patients undergoing specifi cally allo-HSCT (Mello

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Ph.D. Dissertation Mary Jarden Hematopoietic Stem Cell Transplantation

et al., 2003; Defor et al., 2007; Kim & Kim 2006; Cunning-ham et al., 1986). Most physical activity intervention stud-ies in the HSCT setting were exercise-only, unidimension-al (one-type exercise), limited to observational designs or nonrandomized prospective trials. Th e studies included patients undergoing high dose chemotherapy with autolo-gous stem cell support (HD-SCS), initiated after stem cell infusion and were either home-based or in the outpatient setting. Th ese fi ndings, despite the small sample sizes and lack of randomised design, indicate positive physiological and psychological benefi ts from exercise in patients after HD-SCS and allo-HSCT. However, due to lack of evidence, no recommendation can be issued for patients undergo-ing allo-HSCT.

2.4.3 Progressive Relaxation and Psychoeducation in Cancer Patients

In meta-analyses, the signifi cant benefi cial eff ects of psy-choeducational interventions were found for the out-comes of anxiety, depression, mood, nausea, vomiting, pain, and knowledge (Devine, 2003; Devine & Westlake, 1995). Clinically controlled trials using psychoeducation-al interventions based on cognitive-behavioral theory showed decreased emotional distress and enhanced cop-ing skills (Boesen et al., 2005; Greer et al., 1992; Golant et al., 2003), reduced pain and fatigue (Given et al., 2004) and

reduced symptoms and functional limitations (Doorenbos et al., 2005; Redd et al., 2001). Th e goal of relaxation train-ing is to teach patients how to establish a state of deep re-laxation, which has been shown to have a positive impact on cancer treatment related side eff ects, including pain and anxiety (Syrjala & Chapko, 1995; Arakawa et al., 1997; Molassiotis et al. 2002; Dimeo et al., 2004), and one exer-cise study with relaxation breathing decreased fatigue in patients undergoing allo-HSCT (Kim & Kim 2005). Sev-eral interventions were found to promote positive eff ects on psychosocial adjustment; attention to patients coping styles by the healthcare team, encouragement of aerobic exercise, attempts to lessen patients’ level of anxiety, and the presence of at least one staff member identifi ed by the patient as an important source of support over time, all may have positive infl uences on HRQoL (Wingard, 1998).

2.4.4 SummaryTh ese reports indicate that exercise, psychoeducational interventions and progressive relaxation can each posi-tively have an impact on physical and functional capacity and psychological indices in cancer patients. In this study, we chose to test a program integrating these elements, deemed a multimodal intervention, to support the pa-tient’s complex situation during allo-HSCT.

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Ph.D. Dissertation Mary JardenHematopoietic Stem Cell Transplantation

3 HYPOTHESES AND AIMS

Th e aim of this dissertation was to investigate the eff ect of a 4-6 week multimodal intervention, comprised of mixed-exercise, progressive relaxation and psychoeducation, in patients undergoing myeloablative allogeneic stem cell transplantation. Th e hypotheses were, that the intervention would: • Reduce the loss of physical capacity and functional per-

formance. • Reduce the intensity of treatment related physical and

psychological symptoms.• Improve health-related quality of life.• Improve clinical outcomes by reducing infections; in-

cidence of GvHD; shorten length of neutropenia and thrompocytopenia and length of hospitalization.

Th e main objectives of each research focus (Papers I – III), which constitutes this dissertation, are:• To investigate the feasibility, safety and preliminary

benefi ts of the multimodal intervention and evaluate the validity of the pilot study (Paper I).

• To identify symptom profi les and study the longitudinal eff ect of the multimodal intervention on symptom oc-currence, intensity and distress, during hospitalization and 3 and 6 months. Further to evaluate the validity of the symptom assessment tool (SCT-SAC) (Paper II).

• To investigate the eff ect of the multimodal intervention on physical and functional performance at post inter-vention, and to explore health related quality of life, fa-tigue, psychological wellbeing and clinical outcomes at post intervention, 3 and 6 months (Paper III).

• To explore the experience of patients undergoing allo-HSCT (summary presented in 8.8).

4 THEORETICAL FRAMEWORK

Th is study was based on the author’s previous clinical back-ground as an oncology and hematology nurse, including experience in care and treatment of patients in the HSCT setting. Th is knowledge and experience inspired the devel-opment of an intervention for this patient group, which was further built on theoretical concepts and empirical studies within the HSCT context. Th is was the initial basis for the development of the intervention. However, in the course of the study, through daily contact with patients over a 2½ year period, my professional role as research-er and collaborator was expanded to taking an active role in the patient’s symptom experience. Treatment-related symptoms were the patient’s greatest barrier to carrying out the intervention. Th is symptom burden, despite being well-known and observed in clinical practice and described in the literature, had an encompassing eff ect on the pa-

tient and was often the main obstacle in keeping active and carrying out everyday activities during hospitaliza-tion. Close patient contact within the context of the inter-vention provided a comprehensive insight in the enormity of the symptom burden experienced by patients that had activity as a goal during treatment. Because of this new in-sight, an additional theory-set was incorporated that of-fered support in understanding and examining this mul-ti-symptom experience (Paper II). Future interventions might not only include elements of the original multimo-dal intervention but consider incorporating a more sys-tematic focus on symptom management by highlighting the patient’s symptom burden through symptom cluster assessment and management, and prevention of symp-tom limitations. Th e theoretical research framework and process is illustrated in Figure 1.

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Ph.D. Dissertation Mary Jarden Hematopoietic Stem Cell Transplantation

In summary, this study was inspired by theoretical con-cepts from three disciplines (exercise physiology, adapta-tion model and cognitive behavioral theory), the research-ers own clinical experience and empirical sources. Th is multidiscipline framework, which is presented in the fol-lowing, has infl uenced the study’s design and composi-tion, intervention implementation, data collection, analy-ses and interpretation.

4.1 Exercise PhysiologyAn article from the British Medical journal in 1947, by R.A. J. Asher M.D. “Th e Dangers of Going to Bed” argued for the need to reassess medical orders of bed rest for pa-tients. Dr Asher asserted that bed rest is “anatomically, physiologically, and psychologically unsound” and in the ar-ticle equated bed rest to a bodily hazard, negatively aff ect-ing the respiratory system, blood vessels, skin, muscles and joints, bones, renal tract, alimentary tract, nervous system and mental changes (Asher, 1947). Th ese assump-tions have been tested over the past years revealing that prolonged bed rest produces profound changes. Saltin et al. study of fi ve healthy men, found after twenty days of bed rest, a pronounced decrease in maximal oxygen up-take, stroke volume and cardiac output (Saltin et al., 1968) and Convertino found similar results (Convertino, 1997). It then took fi ve weeks for the participants to return to

baseline levels (Saltin et al,. 1968). Bloomfi eld showed de-creases of 6 to 40% in muscle strength within 4-6 week of bed rest (Bloomfi eld, 1997) and LeBlanc found signifi -cant muscle atrophy after 5 and 17 weeks of bed rest (Le-Blanc, et al.,1997). Loss of bone mineral density is also documented after bed rest, though unlike the more rapid recovery of muscle mass and muscle strength, bone mass requires months to years of normal weight bearing activi-ties to recover (Bloomfi eld, 1997). Th e American College of Sports Medicine suggested that musculoskeletal atro-phy and changes in muscle properties contribute to de-clines in cardiovascular effi ciency (Graves et al., 2006). De-clines in cardiac effi ciency are refl ected in increased heart rate and blood pressure at rest and with submaximal exer-cise. Declines in pulmonary function that result from inac-tivity may include a poor ventilator response, diminished airfl ow and respiratory muscle function, and impairments in gas exchange and diff usion that predispose people to respiratory disease, i.e. pneumonia (Carlin & Salahudeen, 2006). Exercise is seen as an important intervention for cancer patients, though harms and risks must be assessed. Clinical concerns such as the potential immunosuppres-sive eff ects of high intensity exercise, pathological bone fractures in cancer patients with compromised bone den-sities, worsening of cardio-toxicity from chemotherapy and/or radiation, severe pain, nausea, and fatigue that

 Figure 1                                                                THEORETICAL RESEARCH FRAMEWORK AND PROCESS 

 

  

THEORY DEVELOPMENT  

Focus on Symptom Burden in allo‐HSCT 

Symptom Cluster Assessment + Management 

OUTCOME MEASURESBio/Psycho/Social   

Feasibility 

Attrition 

Safety 

VO2 max 

Muscle Strength 

Stair Climb 

Leisure Time Activity  

EORTC‐QLQ‐C30 

FACT‐An 

HADS 

Mini‐MAC 

Interviews 

SCT‐SAS 

 

 

 

 

 

 

 

 

 

SYMPTOM THEORY 

Lenz’s Theory of Unpleasant Symptoms 

Dodd’s Symptom Management Theory 

THEORETICAL FRAMEWORK  Clinical experience 

Exercise Physiology 

Cognitive Behavioral Theory 

Roy’s Adaptation Model 

Empirical Findings 

 

Clinical experience with Intervention:  

↑Symptom Burden 

MULTIMODAL INTERVENTION Bio/Psycho/Social 

Psychoeducation 

Cycle training 

Resistance training with free hand and ankle weights 

Active, core & stretching exercises 

Progressive Relaxation  

PERSPECTIVE 

FUTURE  INTERVENTION Bio/Psycho/Social  Multimodal Intervention during in‐hospital and at‐home recovery  

Symptom Cluster Assessment & Management   Prevention of Symptom Limitations 

 

 

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Ph.D. Dissertation Mary JardenHematopoietic Stem Cell Transplantation

may be intensifi ed by exercise, and the inability and/or un-willingness of cancer patients to tolerate exercise due to a compromised physical and emotional condition. In 2006, the fi rst international recommendations for exercise pre-scription for cancer patients were published requiring spe-cial attention to complications involving complete blood counts (hemoglobin level, absolute neutrophil and plate-let counts), infection and severe treatment-related symp-toms (Nieman & Courneya, 2006). Recently, the fi rst ten-tative physical exercise recommendations for patients in the HSCT setting have been published (Wiskemann & Hu-ber 2008), however, as mentioned earlier due to lack of ev-idence, no recommendations are available for patients un-dergoing allo-HSCT.

4.2 The Roy Adaptation Model Th e Roy Adaptation Model (RAM) was developed as a framework for theory, practice, and research in nursing (Roy & Roberts, 1981; Roy & Andrews, 1991). Th e RAM views the patient as being bio-psycho-social and behav-ioral in nature. Th e RAM is a general conceptual model which provides a frame of reference in the observation and interpretation of a phenomenon. Th is model has provided theoretical construction for several studies (Barone & Roy, 1996), and similar to our study, Mock constructed a study based on the bio/psycho/social person using the RAM in an exercise program for women with breast cancer (Mock et al., 1994). RAM assumes persons to be an adaptive sys-tem with coping processes acting to maintain adaptation in the following four modes: 1) Physiologic-physical: needs relating to oxygenation, nutrition, elimination, activity and rest, protection, 2) Self-concept: can be or exist with a sense of meaning and purposefulness, 3) Role function: need is social integrity; knowing who one is in relation to others so one can act; role taking process, 4) Interdepend-ence: need is to achieve relational integrity, i.e., the giv-ing and receiving of aff ection, respect, and value through eff ective relations and communication. Th e environment was defi ned as circumstances, and infl uences surrounding and aff ecting the development and behavior of persons with particular consideration of mutuality. In this study, isolation in an allo-HSCT unit was the environment. Th e goal was to promote adaptation through these four adap-tive modes, and thus contribute to health and quality of life by promoting strengths and competencies. Th is is done by assessing behavior and factors that infl uence adaptive abilities and by intervening to expand those abilities.

4.3 Cognitive Behavioral Theory Th e communicative element in the multimodal interven-tion was inspired and guided by principles from cognitive behavioral theory (Beck, 1995; Tingleff , 2006) and psycho-social interventions including patient education (i.e. treat-ment related, dealing with side-eff ects), behavioral (i.e. progressive muscle relaxation, exercise) and coping skills (i.e. active behavioral and active cognitive), stress man-agement and support (i.e. patient specifi c, goal oriented) (Fawzy, 1999). Cognitive therapy is based on identifi cation and then conceptualization of current thinking and behav-iors, evaluation and formulation of adaptive responses. In-terventions build on the cognitive model, which illustrates how thoughts, feelings, bodily sensations and behavior are mutually infl uenced by each other (Tingleff . 2006). Fun-damentally the cognitive behavioral approach is based on teamwork, requiring a solid alliance with the patient. Col-laboration and active participation are key factors because sessions are goal-oriented with emphasis on problem solv-ing. It is important to bring forth the patient’s own moti-vation and assure that the dialog and intervention are not forced. Psychoeducational (PE) care was found to benefi t adults with cancer in relation to anxiety, depression mood, nausea, vomiting, pain, and knowledge (Devine 1995). Barsevick found PE to reduce depressive symptoms in pa-tients with cancer and that behavioral therapy alone or in combination with cancer education was benefi cial (Barse-vick et al., 2002). PE is used to describe a behavioral ther-apeutic concept consisting of four elements; briefi ng the patients about their illness, problem solving, information acquisition, self care management of symptoms and emo-tional and social support for patients. PE is health edu-cation combined with behavioral counseling and dealing with emotions, perceptions, coping, relaxation and self-care (Given et al., 2002). PE has been shown to improve coping with pain, distress, and other unpleasant symp-toms and improve adherence to recommended regimens of care. (Fawzy, 1999) Cognitive behavioral therapy sup-ports approaching the patient as independent thinking individuals with resources, willpower and motivation to reach own goals, despite challenging situations.

4.4 Symptom Theory Framework Th e theory of unpleasant symptoms was developed in 1995, by Lenz (Lenz et al., 1995) and thereafter, revised and up-dated in 1997. Revisions resulted in a more accurate rep-resentation of the complexity and interactive nature of

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Ph.D. Dissertation Mary Jarden Hematopoietic Stem Cell Transplantation

the symptom experience. (Lenz et al.,1997). Th is theory is chosen because it emphasizes the complexity and interac-tion of symptoms and the interrelationships among symp-toms, infl uencing factors, and consequences of symptoms on performance. Th ese interrelationships make assess-ment more challenging than when symptoms are consid-ered individually. It is assumed that multiple factors aff ect performance, including functional and cognitive abilities and three categories of variables are identifi ed as aff ecting the occurrence, intensity, timing, distress level and quality of symptoms, 1) physiological factors, 2) psychological fac-tors, and 3) situational factors. Th ese factors overlap and aff ect the patient and family. Physiological impairments are refl ected in, and may be diagnosed by the presence of unpleasant symptoms. Th e aspects of physiologic factors may be related to body function, pathology, trauma. Physi-ological factors are measured and weighted by prognostica-tion models and are used to predict outcomes. Th e psycho-logical component of the model includes the individual’s mental state, reaction to illness, and degree of uncertainty and knowledge about the symptoms and their meanings. Th e importance of the caregiver and the social and envi-ronmental context, called situational factors in the theory, emerge as especially relevant in HSCT. When symptoms are examined in their entirety, and interventions take the interactive nature of symptoms, consequences or perform-ance outcomes into consideration, interventions become patient specifi c and, therefore, more eff ective.

Symptom Management Model is used to determine inter-vention strategies through an exploratory approach of how and when the intervention is delivered (Dodd, Jan-son et al., 2001; Dodd et al. 2001). Th is approach is taken to aff ect symptom experience and patient outcomes like functional status. In this model, person, environment and health state are interrelated. Within the symptom expe-rience, evaluation, perception and response are interre-lated. Th is model is helpful in the guidance of decisions made when approaching patients experiencing untoward symptoms. Th e assumptions about symptom manage-ment are that the patients’ perception is the gold stand-ard and symptom management is dynamic. Th e concepts of this theory are the 1) symptom experience, 2) the com-ponents of symptom management strategies, and 3) the outcomes of symptom management. In practice, symptom management is determined through a series of questions which enable assessment and defi ne the intervention. In research, symptom management can be evaluated by func-tional status, HRQoL, emotional status, morbidity and mortality, and health service (Dodd, Janson et al., 2001). In summary, the symptom theories have inspired in their own way in the analysis and interpretation of the complex symptom experience in the allo-HSCT setting. (Article II, Article III).

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Ph.D. Dissertation Mary JardenHematopoietic Stem Cell Transplantation

5 MATERIAL AND METHODS

5.1 DesignTh is study was a prospective, randomized controlled trial that compared an intervention group to a control group receiving usual care by four time points (baseline, post, 3 and 6 month follow-up). In Denmark, all allogeneic trans-plants are centrally coordinated and performed at Copen-hagen University Hospital. After patients signed a written informed consent, baseline measures were obtained and thereafter patients were randomized using the comput-erized Clinical International Trial Management System (CITMAS) (Th orhauge, 1999), stratifi ed by gender and age. Blinding the participants to allocation was not possible.

5.2 Sample From April 2005 to November 2007, patients were ap-proached during their pre-transplant hospitalization and presented with information about the study. Eligibility cri-teria included adult patients (18 – 65 years) of both gen-ders that were scheduled for a myeloablative allogeneic HSCT and were Danish speaking. Th e exclusion criteria were a prior HSCT transplantation, recent unstable cardi-ovascular or pulmonary disease, an abnormal electrocardi-ogram, psychiatric disorder and motor, musculoskeletal or neurological dysfunction requiring walking aids and bony metastasis. If prior to testing, the patients showed signs of infection (T>38oC), anemia (hemoglobin Hbg< 5 g/dl), neutropenia (absolute neutrophil count ANC

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Ph.D. Dissertation Mary Jarden Hematopoietic Stem Cell Transplantation

Figure 2 Patient Flow-Chart

PAPER 1

Data included up to post-testing

Pilot Study n= 19 (Intervention n=6, control n=8)

PAPER 2

Data included from post to both follow-up

Effect on Treatment-related Symptoms n=42 (Intervention n=17, control n=17)

PAPER 3

Data included from post to both follow-up

Physical Capacity, Functional Performance and QoL n=42 (Intervention n=17, control n=17)

DISSERTATION

Qualitative Interviews

Pre allo-HSCT: Expectations (n=42)

Post Intervention: Evaluation and Experience (Intervention = 15)

Post allo-HSCT: Patient Experience (Intervention n=15, control n=15)

82 PATIENTS SCHEDULED FOR

ALLO-HSCT EXCLUDED (n= 36)Health related n=16 Language barriers n=5 Various reasons, coordination, travel, hospitalization etc n=15

Approached n=46Declined participation (n=4)Health related n=1 Not interested n=3

RANDOMIZED n=42

Allocated to Intervention group

n=21

Allocated to Control group

n=21Loss to follow up (n=4)Drop out n=2 Sepsis n=1 Deceased (organ failure) n=1

Loss to follow up (n=4)Drop out n=1 TTP n=1 Deceased (organ failure) n=2 Assessment at

Post Interventionn=17

Assessment at Post Intervention

n=17

3 month Follow up n=17

3 month Follow upn=13

Loss to follow up (n=4)Deceased n=2 Complications n=2

6 month Follow up n=16

6 month Follow upn=13

Loss to follow up (n=1)Deceased n=1

Deceased n=2

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Ph.D. Dissertation Mary JardenHematopoietic Stem Cell Transplantation

ing 4-15 min, was individual and based on behavioral and cognitive therapy techniques (Tingleff , 2006). Th e aim was to foster a sense of emotional control and to increase mo-tivation for exercise. Th e patient’s medical, physical and emotional situation was reviewed and discussed with the aim of understanding and resolving symptoms, feelings, thoughts, issues of concern and reactions that relate to the patient’s present treatment phase. Th e length of this formal dialogue varied from day to day and was depend-ent upon the patient’s needs on that particular day. After daily goal-setting, the patient was activated to partake in the exercise element (mixed-type exercise) of the interven-tion which started with a 4 minute warm up. Stationary cycling was then initiated for a period of 15-30 min daily. Individual rest intervals were allowed and training did not exceed 75% of the maximal heart rate calculated by Kar-vonen’s equation (220-age-HR basal + 50/75%) (Karvonen et al., 1957). Th e subjective intensity of eff ort was evalu-ated by using the Borg Rate of Perceived Exertion scale (RPE), a visual analogue scale ranging from 6 (light eff ort) to 20 (very hard eff ort) (Borg, 1998). Intensity eff ort dur-ing training ranged between 10 and 13 (somewhat hard). Patient’s performance varied due to changes in clinical sta-tus and tolerance, therefore mean pedal frequency ranged between 30 and 70 cycles/min. and a mean work load of 50W (range 30-75 W) was readjusted daily to achieve the heart rate goal, and then kept constant during each ses-sion. Since patients cycled 5 days / week, the main goal of aerobic progression was to gradually increase exercise duration and intensity. Cycling alternated with the fol-lowing dynamic, stretching and resistance exercises: Daily dynamic exercises included neck movements, shoulder ro-tations, hip fl exion/extension, standing calf raise, ankle dorsi and plantar fl exion and performed in 1-2 sets of 12 repetitions and daily stretching exercises included chest ex-pansion, back expansion, hamstring stretch, quad stretch and double calf-stretch, holding positions between 15-30 s. Stretching exercises were performed after cycle train-ing. Resistance training was performed three times week-ly using free hand and ankle weights; bicep curl, shoulder press, triceps extension, chest press, fl yer, squat, hip fl ex-ion, knee extension and leg curl and extension. Daily core exercises for abdominal and back muscles were added. All exercises were performed in 1-2 sets of 10-12 repetitions. Weight was adjusted so the patient was able to perform 2 sets and up to 12 repetitions. Exercises were modifi ed so they could be performed lying, sitting or standing accord-

ing to the patient’s clinical status and tolerance level. Pro-gressive relaxation training was performed twice weekly for 20 min. Patients alternated between muscle tensing (5 s) and muscle relaxation (30 s) for each muscle group, while lying supine in bed and following audio recorded instruc-tions (Jacobsen, 1938).

5.5 Control GroupPatients assigned to the control group received usual care including the departments’ standard of care for physical activity, which was being off ered physiotherapy following allo-HSCT (day +1), from 15 min. -1 hr. weekly, varying from day to day and from patient to patient in mode, fre-quency, intensity and duration. Th e control group was not provided with a stationary cycle unless requested. Patients were asked to complete all outcome measures on the same time frame as the intervention group.

5.6 Data CollectionData collection incorporated both quantitative and qualita-tive methods. Th e purpose of collecting quantitative data was to study intervention eff ect through specifi c physi-ological measures, while questionnaires and clinical data provided for an examination of medical and treatment-re-lated symptoms and psychosocial eff ects. Furthermore, the methods were chosen as a point of reference in the comparison of similar international studies. Th e purpose of collecting the qualitative data was to provide a supple-mentary in-depth understanding and explanation of the patient’s experience in the allo-HSCT context, further-more, to obtain insight into the allo-HSCT context and evaluate the multimodal intervention from the patient’s perspective. Existing literature regarding exercise-based studies in the context of allo-HSCT have not evaluated their programs through qualitative methods.

5.6.1 Assessment Instruments Demographic data, behavioural profi les and andropomet-ric characteristics (body mass index (wt(kg)/ht(m2)) were obtained at baseline. Medical and transplant variables and Karnofsky Performance Scores (KPS) (Karnofsky & Burch-enal, 1949) were obtained through medical chart review. Th e KPS is primarily a patient functionality measure and takes into account disease status, the ability to carry on normal activity, as well as a patient’s general health Pa-tients’ performance status was evaluated at baseline us-ing the KPS. Th e KPS is rated on a scale of 1-100, in steps

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Ph.D. Dissertation Mary Jarden Hematopoietic Stem Cell Transplantation

of 10. Th e KPS was documented to have good predictive validity. Th e outcome measures were on physical capacity and functional performance at baseline during pre-trans-plantation admission (test 1) and repeated on the day of hospital discharge +1day (test 2). All tests were performed between 9:00 am and 12:00 noon by the principle investi-gator (MJ). Th e patients were instructed on proper tech-nique for all tests, and advised to stop if they experienced pain or extreme discomfort, nausea, or dizziness. Th e tests for physical capacity were measured by an estimated ox-ygen uptake (VO2max), one-repetition maximum (1RM) and maximal isometric voluntary strength (Newton) and for functional performance a 2 min. stair climb test. Ad-ditional outcome measures applied four questionnaires (EORTC-QLQ-C30, FACT-An, HADS and Mini-MAC) at four time points (test 1, test 2, 3 and 6 month followup) measuring cancer-specifi c quality of life, fatigue, psychoso-cial wellbeing and coping strategies. Self perceived symp-tom intensity and distress were measured at baseline, weekly during hospitalization and at three and six month follow-up (SCT-SAS). A logbook was utilized daily to doc-ument adherence to intervention and adverse events. In-dividual semistructured interview was carried out at two time points (baseline and hospital discharge). Paper V is in progress, however, the procedures and fi ndings are sum-marized in this dissertation (8.8).

Quantitative Data Collection

5.6.2 Physical Capacity (Paper I & III)Aerobic capacity. A single-stage 6 minute submaximal exer-cise test; the Aastrand-Rhyming cycle ergometer test was used to predict VO2 max values (Aastrand et al., 2003). Th e test is based on the linear relationship between VO2 and heart rate. Th e patients pulse was continuously monitored using a wireless heart rate transmitter. Resistance (Watt) was increased to elicit a steady-state heart rate between 125-170 b/min at a speed between 60-65 rpms. If after 6 minutes the HR was above 125b/min and stable, not fl uc-tuating more than 5 b/min, the test was terminated. VO2 max was determined using a nomogram with an age and body weight correction factor (Aastrand et al., 2003). VO2 max is stated in L/min. Isotonic muscular strength. Estimated 1RM tests were used to evaluate upper and lower body strength potential (Humphries et al., 2006). Th e two tests; chest press and leg extension, measured performance on technogym vari-

able resistance equipment and targeted the large muscle groups. 1 RM is stated in kilograms. Maximal isometric voluntary strength test. Th e right el-bow and knee fl exors were tested for maximal isometric strength (Humphries et al., 2006). Placed in a sitting posi-tion with fl exion of the right shoulder at 45 degrees and 90 degrees at the right elbow, the patient pulled a non-elas-tic strap placed in the right hand exerting the maximum strength sustained for 3 s. When measuring the right knee fl exors, the patient was placed in a sitting position with fl exion in the right hip and knee at 90 degrees. Th e patient kicked a non-elastic strap secured on the right ankle exert-ing the maximum strength sustained for 3 s. Th e measur-ing unit is stated in Newtons (N).

5.6.3 Functional Performance (Paper I & III)Th e two min. stair climb test was used to assess the pa-tient’s functional capacity and capability of performing everyday activities like stair climbing and walking in a con-trolled setting (Harding et al., 1994). Th e patient climbed and descended two fl ights of standardized stairs for two consecutive minutes with the goal of covering the maxi-mal number of steps.

5.6.4 Leisure Time Physical Activity Level (Paper I & III)Self-rated leisure time physical activity level was collected at baseline, 3 and 6 months. Form, intensity and duration of leisure-time activity were assessed in accordance with Saltin and Grimby’s defi nition (Saltin & Grimby, 1968). Patients were asked to classify themselves as being: a) sed-entary (completely inactive, e.g. primarily watching tele-vision, reading or performing other passive activities); b) walking, cycling for pleasure or performing other forms of low to moderate exercise (unstructured, unsupervised, irregular exercise; e.g. dog walking, gardening, golf); c) moderate to high intensity physical activity at least three hours/week (e.g. tennis, swimming); or as d) ‘athletic’ (high intensity exercise at least four hours/week; e.g. run-ning, high-impact aerobic).

5.6.5 Questionnaires (Paper III)Four questionnaires at four time points (baseline, post transplantation, three and six month follow-up) were ap-plied to measure cancer-specifi c quality of life, fatigue, psychological wellbeing and coping strategies. Th e ques-tionnaires were chosen according to empirical evidence of reliability, validity, and sensitivity to diff erences over time.

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Ph.D. Dissertation Mary JardenHematopoietic Stem Cell Transplantation

(1) Th e European Organization for Research and Treat-ment of Cancer Quality of Life Questionnaire C30 (EORCT QLQ-C30) comprising 30 items was admin-istered (Aaronson et al., 1993). Th e EORCT QLQ-C30 assesses health-related QOL in cancer patients and consists of six functional scales (physical, role, cog-nitive, emotional, and social functioning, and global QoL) and symptom scales (fatigue, nausea/vomiting, sleep disturbance, constipation, diarrhea, appetite loss, dyspnea) (Grønvold et al., 1997). Internal reli-ability coeffi cients range from 0.52 to 0.89 (Aaronson et al., 1993). Th e raw scores are transformed linear-ly into scores ranging from 0 to 100. A high score on the global health status represents a high QoL, a high score on the functional scale represents a high level of functioning, whereas a high score for a symptom scale indicates a high level of symptoms. QLQ-C30 focuses on the current period (5 items) and the last week (25 items).

(2) Fact-An (version 4) is a 47 item, cancer-specifi c ques-tionnaire consisting of a core 27-item questionnaire (FACT-General, or FACT G Total) measuring the four general domains of QoL, (physical, social/family, emo-tional and functional wellbeing), and an additional 20-item anemia questionnaire (FACT-An Anemia sub-scale) that measures 13 symptoms of fatigue (Fact-An Fatigue subscale) and seven non-fatigue related items (Yellen et al., 1997). Each of these measures is scaled with low scores indicating poor QoL and high scores indicating good QoL. Items that indicate higher fa-tigue levels are reversed scored and all items summed so that higher scores correspond with less fatigue. As originally constructed, the FACT-G total scores range from zero to 108, the FACT-An Anemia subscale scores range from zero to 80 and the FACT-An Fatigue subscale scores range from zero to 52. Internal consis-tency of FACT-An scores was expressed with the Cron-bach’s alpha coeffi cient. An alpha coeffi cient of 0.70 or higher was considered as suffi cient for the purpose of group comparisons.

(3) Th e Hospital Anxiety and Depression Scale (HADS) is a widely used instrument to assess symptoms of depression and anxiety. It is not a tool to diagnose mood disorders but it has proved to be reliable, val-id and responsive instrument to assess the severity of symptoms (depression and anxiety) of mood disor-ders. Th e self-administration comprises 14 items and

has a short completion time to make the HADS a us-able instrument for use in trials (Carroll et al., 1993; Johnston et al., 2000; Zigmond & Snaith, 1983). Th e HADS was designed to measure general anxiety and depression and was developed by Zigmond and Snaith (1983) for use in investigations in patients with physi-cal illness. Cronbach’s alpha values of 0.93 and 0.90, respectively, for the anxiety and depression scale are reported. HADS is used in this dissertation as an in-strument of assessment of psychological morbidity in the patients prior to allo-HSCT and to assess the eff ect of the multimodal intervention on psychological dis-tress between groups.

(4) Th e Mini-Mental Adjustment to Cancer Scale (Mini-MAC) (Watson et al., 1994) is a validated, 29 item short-form version of the Mental Adjustment to Can-cer Scale (Watson et al., 1988) that assesses patients’ adaptation to cancer across fi ve dimensions: Fighting spirit, Helplessness/Hopelessness, Anxious Preoccu-pation, Fatalism, and Denial (Cognitive Avoidance).

5.6.6 Monitoring Logbook (Paper I, II, III)A ‘monitoring logbook’ was used by the investigator (MJ) to document adherence to the intervention, adverse events and symptoms experienced. All components of the intervention performed were recorded daily including; ex-ercise mode, frequency, intensity, duration and progres-sion as well as subjective exercise response and heart rate. Components performed beyond that prescribed in the in-tervention program, i.e. weekends or evenings, were doc-umented by the patient. Th e control group received a mod-ifi ed logbook and was asked to register activity/exercise mode, frequency and duration during hospitalization. Th e logbook also included the structured symptom assess-ment questionnaire (SCT-SAS), which required patients to enter a numerical score for self-assessed treatment-related symptoms and report the symptom/symptoms that were most distressing (Appendix B).

5.6.7 Stem Cell Transplantation Symptom Assessment Scale (SCT-SAS) (Paper II)

Th e SCT-SAS is a self-developed questionnaire that as-sesses severity of a core set of symptoms experienced by patients undergoing allo-HSCT. We aimed at developing a symptom scale with good utility, minimum burden on the patient, though refl ective of the patient’s situation and experience. Patients were asked to give a total rating

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of the severity of the symptoms they experienced over the past week. Th e categorical scale (0=symptom not present, 1=mild, 2=moderate, 3=severe, 4=intolerable) was record-ed on a numerical scale from 0 – 4. Patients were then asked to report the symptom/s that most distressed them during the past week. Th e questionnaire was completed on the same day each week and the test points were the same for all patients: 1st evaluation: pre-screening (1½ -2 weeks prior to admission), 2nd evaluation: upon completion of conditioning regime, 3rd - 7th evaluations: 2 - 6 weeks after allo-HSCT, and the fi nal evaluations: 3 and 6 months after allo-HSCT. SCT-SAS is a 21-item questionnaire comprising physical, aff ective and cognitive symptoms, a 22nd (other men-tal health related symptom/s) symptom, 23rd (other pain symptoms) symptom and 24th (other physical / bodily symptom/s) symptom could be added to individualize the instrument. Th e symptoms included on the scale were nervousness, anxiety, stress, other emo-tional problems, fatigue, diminished concentration and memory problems, mouth pain, throat pain, headache, stomach pain, diarrhea, muscle aches, joint aches, other symptoms of pain, lacking appetite, diffi culty swallowing, nausea, vomiting, sleep diffi culties, constipation, loss of hair, skin disturbances, and other physical/bodily symp-toms. Th e SCT-SAS was modifi ed after the Cancer Th era-py Evaluation Program where Common Toxicity Criteria is used and measures the prevalence and severity of each symptom (CTC, 1999).

Qualitative Data Collection

5.6.8 Semi-structured Individual Interviews Qualitative data was generated using in-depth interviews with semistructured format, guided and developed from themes derived from this dissertation’s theoretical frame-work and existing literature. To assist in revealing and ac-centuating the patients’ unique experience (Patton, 1990; Kvale, 1996), a set of questions to guide the interview top-ics was used to allow fl exibility in the type of information the patient chose to share. Th is type of interview ensures that important information is obtained, while allowing the patient to freely express own views and it creates an opportunity for otherwise unanticipated information to emerge. Th e purpose of the interview was to evaluate the multimodal intervention through the patient’s experi-ence. Secondly, to describe issues that were important for the patient before, during and after allo-HSCT and lastly, to explore the ways in which patients adjusted to their sit-

uation. Th ese results can provide a foundation regarding the immediate eff ects of and responses to allo-HSCT, thus further practice and research can facilitate recovery after allo-HSCT and optimize reentry into daily living.

ProcedureTh e interviews were audio-taped and lasted 40 min.+ 15 minutes. Two semistructured interview guides were used at two test points; prior to hospitalization for HSCT (base-line) and at hospital discharge (post-intervention). Th e fi rst interview at baseline, included all patients (n=42) and the following pre-determined themes were addressed and collected: (1) personal and behavioral background, (2) his-tory of illness and treatment, (3) attitudes and experienc-es in dealing with illness and treatment, (4) expectations and preconceptions about the upcoming allo-HSCT, (5) attitudes and experiences regarding physical activity and (6) aspects of motivation and barriers to physical activity. Baseline data from this interview also contributed to the demographic, medical and behavioral characteristics in Pa-per III. Th e second interview guide covered questions for the intervention group (n=15) relating to experiences and evaluation of the intervention. Th e aim of this segment of the interview was to explore the experience of the patients participating in the intervention and their perspectives on the benefi ts and disadvantages of the intervention. Th e following pre-determined themes were addressed: 1) safe-ty, 2) own eff orts and achievements, 3) scope and limita-tions or restrictions, 4) motivation, 5) self assessment of physical and emotional wellbeing, 6) perspective on the in-tervention elements and an evaluation of the intervention, 7) evaluation of level of intervention intensity, time of day and length of time, 8) experiences with testing (physical tests and questionnaires), 9) impact of intervention and 10) suggestions for improvements. Th e remaining segment of the second interview was ap-plied to both the intervention group and control group. In all, 30 patients were interviewed at discharge (inter-vention n=15 and control n=15). Th e following were ad-dressed in this segment of the post interview: (1) patient’s appraisal of their situation, (2) experiences pertaining to the general impact of the treatment, (3) ‘themes’ of signif-icance to the patient that had an infl uence on the ability to cope and (4) strategies employed in handling the situation in the context of allo-HSCT. Patients were asked to share their personal experiences and eff orts to deal with the con-sequences of the treatment.

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Ph.D. Dissertation Mary JardenHematopoietic Stem Cell Transplantation

6 DATA ANALYSES AND INTERPRETATION

6.1 Quantitative Data Analyses (Paper III) In all, 42 patients (intervention n=21 and control n=21) were included in the study. It was calculated that with an inclusion of 20 patients in each group, the trial had 80% power to detect a diff erence in means of 0.55 points in the primary outcome VO2 max (diff erence between inter-vention group means of 2.82 and control group means of 2.27) assuming that the common standard deviation is 0.6 using a two group t-test with a 0.05 two-sided signifi cance level. Descriptive statistics (means and standard deviations, median) were used to characterize the demographic char-acteristics of the sample. Baseline comparisons of demo-graphic and physiological characteristics were performed using independent sample t-test of variance for continu-ous variables, i.e. age, BMI, KPS and Fisher’s Exact test for categorical variables. Th e primary analysis examined whether signifi cant diff erences existed between control and intervention groups in all outcome measures (physi-cal capacity, functional performance and questionnaires). Being normally distributed, independent samples t-tests were applied to calculate the eff ect diff erence between pre and test points (post intervention, 3 months and 6 months). A Pearsons correlation coeffi cient (R) was ap-plied to examine correlation between changes in the phys-ical capacity and functional performance and changes in the questionnaire scores. As a secondary analysis, we ap-plied a paired t-test to calculate the within group change in HRQoL outcome measures from pre to test-points (Ta-ble 2). For all analyses the intent-to-treat principle was applied. Available data for participants with missing data were included under the missing at random assumption. Participants classifi ed as loss to follow-up were compared to the study group for baseline demographic data using Fisher’s Exact test and independent t-test. Continuous variables not being normally distributed were geometri-cally transformed (sqrt(x)). Statistical analyses were car-ried out using SAS Enterprise for Windows (version 9.3.2) and a value of p 38oC), and reconstitution time measured in days from stem cell infusion (day 0) to bone marrow engraftment (ANC >0.5 x 109/l for two consecutive days). Benefi ts of the intervention were measured by pre- and post-testing for physical and functional capacity. To test for compara-bility of groups, the physical and functional capacity data was fi rst examined by conducting a Kolmogorov-Smirnov and Shapiro-Wilk test. Being normally distributed, inde-pendent samples tests were thereafter applied to compare the diff erence between the pre and posttests within each group and then between the two groups. Calculations for statistical analysis were performed using SPSS and a value of P

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Ph.D. Dissertation Mary Jarden Hematopoietic Stem Cell Transplantation

6.1.2 Principal Component Analysis and General Estimates Equation (Paper II)

An exploratory Principal Component Analysis (PCA) with varimax rotation was used to determine interrelation-ships between symptoms in each group, called “symptom clusters”. Th is study defi ned a symptom cluster as two or more symptoms that occur together, are stable, and are relatively independent of other clusters (Chen & Tseng, 2005). Symptom clusters were identifi ed with PCA as the extraction method, applied to data from the intervention and control groups separately. Th e PCA is a procedure that transforms a number of observed variables into a small-er number of variables; principal components. Th e fi rst principal component accounts for as much of the variabil-ity in the data as possible. Signifi cant principal compo-nents were selected with Eigenvalues higher than 1, and each component explained at least 10% of the variance for all time points. Th e highest factor loading score predicted the assignment of individual symptoms to an independent factor. Th e factor structure was revealed by this analysis and extraction was further simplifi ed and clarifi ed by Vari-max with Kaiser normalization. Th e Kaiser-Meyer-Olkin measure of sampling adequacy (> 0.5), the Bartlett’s test of sphericity (p 0.4) were included in the fac-tor analysis. Two methods were incorporated to justify the factors; Eigenvalues greater than 1 and Scree Plot exami-nation. Th en, we identifi ed the factor groups in the inter-vention and control groups that were loaded with the same symptoms of high inter-item correlation (> 0.4). Once the common factors were identifi ed, we were able to compare symptom cluster patterns of intensity over time between the two groups. For this, an analysis of General Estimate Equations (GEE), was conducted to compare symptom clus-ter patterns of intensity scores between the intervention and control groups. We used the Score Statistics for Type 3 GEE Analysis (Goodness of Fit, Tests of Model Eff ects and Parameter Estimates). Th e GEE method is a strategy for the analysis of repeated measurements, particularly cate-gorical repeated measurements. It provides a way to han-

dle continuous explanatory variables, a moderate number of explanatory categorical variables, and time-dependent explanatory variables. It also handles missing values, that is, the number of measurements in each cluster can vary from 1 to t. A value of P

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Ph.D. Dissertation Mary JardenHematopoietic Stem Cell Transplantation

7 ETHICAL CONSIDERATIONS

8 RESULTS

Th e results are summarized in Table 1

8.1 Feasibility Study (Paper I)Th e main objective of the pilot study was to examine the feasibility (acceptance and attrition), adherence, safety and benefi ts of the multimodal intervention.

8.1.1 Acceptance, Attrition, Adherence, Safety and Benefi tsAcceptance and attrition: During the inclusion period, 36 patients were registered, of which 22 were found eligi-ble, two declined participation. Th e study enrolled 20 pa-tients, an acceptance of 91%. One patient became ineligi-ble due to cancellation of allo-HSCT. Fourteen of nineteen patients (74%) completed all study requirements. In the intervention group, 6 of the 9 patients completed all study requirements, representing a 33% attrition rate. From the intervention group, one patient became ineligible shortly after the initiation of the intervention due to medical rea-sons. Two patients left the study, one after one week due to lack of interest in exercising, and one did not complete the post-tests due to travel and scheduling constraints. Two patients from the control group refused the post-tests due to complaints of tiredness. Of the 14 patients that com-pleted all study requirements, 6 patients were from the in-tervention group and 8 from the control group. Adherence: Patients in the intervention group trained mean 94% (89-100%) of the total expected training days. Th e training sessions included at least one of the physical

Th e project adhered to the regulations established by the Ethical Guidelines for Nursing Research in the Nordic Countries (SSN), all relevant laws and regulations in Den-mark, and the Declaration of Helsinki II. Th e study was ap-proved by the Scientifi c Committees of the Copenhagen

and Frederiksberg municipalities (J.no. 01-173/04) and the Danish Data Protection Agency (J.no. 2004-41-4266). Th e project is registered at ClinicalTrials.gov - identifi ca-tion nr. NCT00427115.

training components. Six of the nine days where patients did not train were due to constraints rela