HEMATOPOIETIC STEM CELL TRANSPLANTATION

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1 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. Dissertation Mary Jarden FACULTY OF HEALTH SCIENCES UNIVERSITY OF COPENHAGEN Department of Hematology, The Finsen Center and The University Hospitals Center for Nursing and Care Research Copenhagen University Hospital 2OO9

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3 FACULTY OF HEALTH SCIENCES UNIVERSITY OF COPENHAGEN 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 and The University Hospitals Center for Nursing and Care Research Copenhagen University Hospital 2009

4 Ph.D. Dissertation: Hematopoietic Stem Cell Transplantation. The Effect of a Multimodal Intervention on Physical Capacity and Functional Performance, Treatment-related Symptoms and Quality of Life Mary Jarden The dissertation will be defended on Monday, April 20, 2009 at in the Henrik Dam Auditorium. Official opponents Associate Professor Ole Weis Bjerrum MD, DMSc Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark Head of Department Christoffer Johansen MD, Ph.D., DMSc Department of Psychosocial Cancer Research, The 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 Scientific Advisors Professor Lis Adamsen, Ph.D. The 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 Unit Copenhagen University Hospital, Copenhagen, Denmark Ellen Boesen, Researcher, Psychologist, Ph.D. Danish Cancer Society, The Danish Cancer Society Department of Psychosocial Cancer Research, Copenhagen, Denmark ISBN: The University Hospitals Center for Nursing and Care Research (UCSF), Copenhagen University Hospital Department 7331, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. ucsf@ucsf.dk Print and Production: WERKs Grafiske Hus a s, Aarhus Cover: Jacob Billesbølle

5 ACKNOWLEDGEMENTS This Ph.D. dissertation was developed and carried out through collaborative efforts at the Department of Hematology and at the University Hospitals Center for Nursing and Care Research (UCSF), Copenhagen University Hospital. I gratefully acknowledge the support of this research by grants from The Lundbeck Foundation, The Novo Nordic Foundation, The Danish Cancer Society, The Copenhagen Hospital Corporation and The Danish Nursing Society. I wish to express my gratitude to my advisors; Professor Lis Adamsen Ph.D., Doris Hovgaard MD and Ellen Boesen Psychologist, Ph.D. for their constructive guidance, discussions and invaluable support throughout the project period, in data analyses 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, Thank 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 flexibility and support in assuring patient participation. And a special thank you to Alex Peter Hansen for assembling equipment and solving technical problems along the way. Thank you, to the BMT out-patient unit and BMT Secretariat where there was always an extra computer or desk available 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 interview 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 Zoffmann Ph.D., Lone Friis Thing Ph.D., Betina Lund Nielsen Ph.D graduate student, Tom Møller Ph.D graduate student and Hanne Bækgaard Laursen Ph.D graduate student. They have all contributed with professional, inspiring and constructive discussions throughout 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 assistance 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 Baadsgaard, UCSF. Thank you for conducting the statistical analyses, for statistical advice, discussion and important contributions to the manuscripts. I wish to thank Kristine Jarden and Jacob Billesbølle for database keying and interview transcription 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 confidence in me, for motivational support, and for always being there. Mary Jarden, April 20, 2009 i

6 ORIGINAL PAPERS This 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 exercise and psychoeducation in patients undergoing allogeneic stem cell transplantation. Bone Marrow Transplant. 2007;40: II. Jarden M, Nelausen K, Hovgaard D, Boesen E, Adamsen L. The Effect of a Multimodal Intervention on Treatment-Related Symptoms in Patients undergoing Hematopoietic Stem Cell Transplantation: A Randomized Controlled 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 Effect of a Multimodal Intervention on Physical Capacity, Functional Performance and Quality of Life in Adult Patients undergoing Allogeneic Stem Cell Transplantation. Bone Marrow Transplant, Advanced on line publication, 23 February 2009, 1-13 The articles are referred to in the text by their Roman Numerals. ii

7 ABSTRACT This study examines the effect 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 experience 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, anxiety etc. These reactions can contribute to physical, psychological and psychosocial stress before, during and after treatment, resulting in a delay into daily life activities. The 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. The aim of the dissertation was to investigate the impact of a 4-6 week multimodal intervention, comprised of mixed-exercise, progressive relaxation and psychoeducation, in patients undergoing allogeneic stem cell transplantation. The 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 leisure 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 fitness, muscle strength) and functional performance (stair climb test), and enhance health-related quality of life (questionnaires) and have a beneficial effect 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: The 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 participated. The intervention is an individual and supervised, moderate intensity physical training, progressive relaxation and psychoeducation program, 5 hours over 5 days/week. The 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 quantitative and qualitative methods: estimated VO 2 max, muscle strength tests, functional test (stair climb), clinical parameters, 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: The study was approved by the Scientific Committees of the Copenhagen and Frederiksberg municipalities (J.no /04) and registered with the Danish Data Protection Agency (J.no ) and ClinicalTrials.gov (NCT ). iii

8 Results: The multimodal intervention proved to be feasible and safe with no adverse events. The adherence rate to intervention was 90%. Significant effect differences were found in pre-post scores for the physical capacity; VO 2 max (p<0.0001), muscle strength tests: chest press (p<0.0001), leg extension (P=0.0003), isometric r. elbow (p=0.0009) and isometric r. knee (p<0.0001) and functional performance; stair climb (p=0.0008), favoring the intervention group. No significant effect differences were found in group comparison analyses on health-related quality of life (HRQoL), except for a significant reduction in diarrhea (EORTC QLQ-C30) (p=0,014) at post intervention, in favor of the intervention group. The intervention group showed no individual significant changes from pre-post, three or six month test points, however for the control group, significant decreases from pre-post occurred on physical functioning (p=0.004), and worsening in nausea and vomiting (p=0.04), appetite loss (p=0.004) and diarrhea (p=0.01) were found on the EORTC QLQ-C30. For the intervention group, significant improvements on emotional wellbeing at three months (p=0.04) was found. Likewise, there was increased emotional wellbeing at six months for intervention (p=0.01) and control groups (p=0.02). Significant deterioration was found among control patients at post testing for FACT-An (p=0.005), physical wellbeing (p=0.0003), functional wellbeing (p=0.003), and fatigue (<0.0001), though showed significant improvement on social wellbeing (p=0.006). There were no significant effect differences between groups on Mini-MAC or HADS, however there were significant improvements in anxiety scores for the intervention group from pre-3 months (p=0.02) and pre-6 months (p<0.0001). The Intervention group required fewer days of parenteral nutrition (p<0,01) and in favor of the intervention group, there were significant longitudinal effect differences (baseline, weekly during hospitalization, 3 and 6 months) in reduced symptom intensity on the following symptom cluster groups: gastrointestinal symptoms (nausea, vomiting, stomach pain, loss of appetite, diarrhea) (p=0,017), cognitive symptoms (concentration and memory problems and fatigue) (p=0;002), functional symptoms (muscle and joint pain) (p=0.009) and mucositis symptoms (mouth and throat pain, difficulty swallowing) (p=0,019). The two overarching themes that emerged at pre-transplantation were hope (survival) and fear (complications/treatment-related symptoms). Patients were interested in physical activity during hospitalization with the three most dominant reasons being, to improve rate of recovery, chances of survival and feelings of wellbeing. However, it was the feelings of wellbeing and a number of secondary motives that kept patients moving during hospitalization. At post interview, the most prominent theme was the multiple and concurrently occurring symptom experience throughout hospitalization. Conclusions and Implications: The multimodal intervention sustained physical capacity and minimized loss of functional capacity during hospitalization. No significant differences between groups on HRQoL were found, except for decreased diarrhea at hospital discharge. In pre/post comparisons, the intervention group showed stabilization of HRQoL up to 6 months after allo-hsct, though improved emotional wellbeing and decreased anxiety at both 3 and 6 months. The control group showed worsening of gastrointestinal symptoms, fatigue, physical and functional wellbeing, though improved social wellbeing at hospital discharge. A reduction in the symptom burden through-out hospitalization and in the follow-up period was found in the intervention group. Symptom cluster analyses methods proved to be applicable and have resulted in a new approach and new knowledge about the symptom burden experienced during and after allo-hsct. These findings stress the importance of a supervised, structured, individualized and multimodal exercise-based intervention that both considers and addresses the patients individual clinical needs. Further, the findings suggest the need for a post hospitalization follow-up program of this type to help sustain results and keep patients moving. iv

9 ABBREVIATIONS Allo-HSCT AGvHD BMI BMT CITMAS EORTC-QLQ-C30 FACT-An GEE GvHD HADS HD-SCS HRQoL HSCT KPS MET Mini-MAC PCA RAM RM RPE SCT-SAS VO 2 max JH KJ LA MJ Allogeneic Hematopoietic Stem Cell Transplantation Acute Graft vs. Host Disease Body Mass Index Bone Marrow Transplantation Clinical International Trial Management System European Organization of Research and Treatment of Cancer Quality of Life Questionnaire Functional Assessment of Cancer Therapy-Anemia scale General Estimate Equations Graft vs. Host Disease Hospital Anxiety and Depression Scale High Dose chemotherapy with Autologous Stem Cell Support Health-Related Quality of Life Hematopoietic Stem Cell Transplantation Karnofsky Performance Status Metabolic Equivalent Intensity level Mental Adjustment to Cancer Principal Component Analysis Roy s Adaptation Model Repetition Maximum Rate of Perceived Exertion Stem Cell Transplantation Symptom Assessment Scale Oxygen Consumption (uptake) Jeanette Holder Kristine Jarden Lis Adamsen Mary Jarden v

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11 TABLE OF CONTENTS 1 INTRODUCTION BACKGROUND Hematopoietic Stem Cell Transplantation, Physical and Emotional Reactions Fatigue, Inactivity and Cancer Symptom Distress during and following Hematopoietic Stem Cell Transplantation Clinical Intervention Studies Exercise-based Interventions in Cancer Patients Exercise-based Interventions in Hematopoietic Stem Cell Transplantation Progressive Relaxation and Psychoeducation in Cancer Patients Summary HYPOTHESES AND AIMS THEORETICAL FRAMEWORK Exercise Physiology The Roy Adaptation Model Cognitive Behavioral Theory Symptom Theory Framework MATERIAL AND METHODS Design Sample Context Multimodal Intervention Control Group Data Collection Assessment Instruments Physical Capacity Functional Performance Leisure Time Physical Activity Level Questionnaires Monitoring Logbook Stem Cell Transplantation Symptom Assessment Scale Semi-structured Individual Interviews DATA ANALYSES AND INTERPRETATION Quantitative Data Analyses Pilot Study Principal Component Analysis and General Estimates Equation Qualitative Data Analyses ETHICAL CONSIDERATIONS vii

12 8 RESULTS Feasibility Study Acceptance, Attrition, Adherence, Safety and Benefits Effect on Treatment-related Symptoms Symptom Profile: Prevalence, Severity and Distress Symptom Clusters Longitudinal Intervention Effects on Symptom Clusters - A two group comparison Physiological and Psychological Effects Physical Capacity and Functional Performance Health-related Quality of Life, Fatigue and Psychological Wellbeing EORTC-QLQ-C FACT-An HADS Associations among Physical Capacity Measures and Patient-rated Outcomes Leisure Time Physical Activity Level Clinical Outcomes Intervention Adherence and Safety Coping Strategies Mini-MAC The Patients Experience in the Hematopoietic Stem Cell Transplantation Setting The Patients Perspective on and Expectations of Hematopoietic Stem Cell Transplantation The Patients Experience and Evaluation of the Multimodal Intervention The Experience of Patients undergoing Hematopoietic Stem Cell Transplantation DISCUSSION Methodological Considerations and Limitations Pilot Study Validity Outcome Measurement Considerations General Discussion of the Effects of the Multimodal Intervention Multimodal Intervention Findings CONCLUSION AND CLINICAL IMPLICATIONS FUTURE RESEARCH DANSK RESUMÉ REFERENCE LIST PAPER I-III APPENDIX A Literature Review Exercise-based studies and HSCT APPENDIX B Questionnaires viii

13 Hematopoietic Stem Cell Transplantation Ph.D. Dissertation Mary Jarden 1 INTRODUCTION A growing literature in allogeneic hematopoietic stem cell transplantation (allo-hsct) has shown, that despite improved 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 intervention 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 various outcome goals ranging from physiological, medical/ clinical and psychosocial, but these studies were limited in number and type and often lacked randomized conditions. There is a growing need for the development of interventions, implemented as complementary therapy in clinical practice that take into consideration the complex situation and multiple symptoms experienced by patients as a result of disease and treatment. Recommendations for nonpharmacological adjuvant therapy i.e. exercise have not, as yet, been issued for patients undergoing allo-hsct. The importance of studying and actively intervening with patients with the goal of preventing or limiting these stressors is a central issue. Complex treatments as HSCT may require multifacited interventions that consider the patient s symptom burden in the actual context (bedside/ clinical research). This study was undertaken at Copenhagen University Hospital, the only hospital in Denmark to offer allo-hsct. Though this study included a limited patient material (n=42), it has taken over two and a half years to recruit eligible patients. It was a first time randomized study that offered a combined program of mixed-exercise: aerobic and resistance training, ROM, progressive relaxation and psychoeducation during the patient s entire hospitalization (4 6 wks) and measured multidimensional outcomes. Other studies exercising patients undergoing HSCT began after stem cell support or hematopoietic recovery, included a single exercise element without a relaxation and psychoeducative intervention and the larger part of these studies included patients undergoing autologous stem cell transplantations, where patients are hospitalized for a shorter period (3 weeks) without the same transplantation sequel. The strict inclusion /exclusion criterion secured necessary safety measures, but was also partly responsible for exclusion of patients from an already small population. We wanted to evaluate if combining a mixed-exercise and relaxation program with psychoeducation could motivate patients to remain safely and effectively physically active during their entire hospitalization and ultimately reduce loss of physical capacity, functional performance, healthrelated quality of life (HRQoL) and relieve the symptom burden experienced. Research considerations in designing clinically controlled randomized intervention trials, development of relevant assessment tools and combining outcome measurements that address and reflect the complexity of the HSCT context will help in understanding the full impact of the patients experience during treatment. This may lead to best-practice treatment and care for patients in a complex situation. This research was inspired by theoretical concepts from three disciplines; exercise physiology, a nursing adaptation model and cognitive behavioral theory. We developed and tested the effect of an intervention and provided preliminary validation of a newly developed symptom assessment tool. Moreover, this study illuminated the patients situation while undergoing allo-hsct. The results showed that it may be a realistic goal to stabilize physical capacity and minimize loss of functional performance in patients undergoing allo-hsct. There were also HRQoL and clinical benefits such as a reduced symptom burden, which has the potential to give patients a more advantageous starting point for recovery after hospital discharge. 1

14 Ph.D. Dissertation Mary Jarden Hematopoietic Stem Cell Transplantation 2 BACKGROUND This section presents an overview of the literature regarding treatment-related symptoms, complications as well as the complexity and the special challenges associated with allo-hsct. Moreover, data are presented with special focus on the benefits 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 performed worldwide each year for a number of hematological malignancies such as acute myeloid and lymphoid leukemia, and bone marrow failure syndromes (Gratwohl et al., 2002; Frassoni, 2004). It is predicted that transplantation rates for allo-hsct will continue at the same or higher level in the immediate future (Gratwohl et al., 2002). Despite clinical cure in 20-70% of all patients, depending on disease presentation, long term sequelae of immunosuppression, 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 efficacy of this treatment are death due to recurrence or treatment-related death due to infection or organ failure in the cytopenia and later immunosuppressed phase immediately post-hsct. Over the last decades, the cumulative effects of improvements in supportive care, drug dosing, stem cell technology and prophylaxis of GvHD have led to an increased number of complete remissions (Devergie, 2004). However, with the increasing number of transplants performed 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 emotional reactions. Fatigue and muscle weakness can limit ability to accomplish activities of daily living. Additionally, depression, anxiety, fear, and frustration add to the difficulties of recovering from HSCT (Syrjala et al. 1993, Andyrkowski et al., 1995). Several studies confirm that high levels of physical and psychological stress have been observed 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). The mechanisms are not fully known, but it is assumed that several factors such as TBI, chemotherapy, GvHD, infections, long-term inactivity or bed rest and side-effects from medication can contribute to the physical and emotional 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 fatigue (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 physical, cognitive and emotional symptoms, and is accompanied by inactivity and lack of motivation (Smets et al., 1998). The term CRF is defined by the National Comprehensive Cancer Network as a persistent, subjective sense of tiredness related to cancer or cancer treatment that interferes with usual functioning (NCCN 2005). It often persists over time and can interfere with usual activities. Cancer-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 result in rapid and potentially irreversible functioning (Porock et al. 2000). 2.3 Symptom Distress during and following Hematopoietic Stem Cell Transplantation Patients that have undergone HSCT experience treatmentrelated symptoms during and after treatment that can affect HRQoL. Patients experience multiple somatic, affective and cognitive symptoms during and after aggressive cancer treatment, where simultaneously occurring symp- 2

15 Hematopoietic Stem Cell Transplantation Ph.D. Dissertation Mary Jarden toms have been reported.(portenoy et al., 1994) During hospitalization for allo-hsct, patients are typically on prolonged bed rest, and experience complications from the myeloablative treatment, ie. GvHD, side effects from medications (immunosuppression & steroids), frequent infections and psychological reactions that can be debilitating. The most commonly reported symptoms are fatigue, diarrhea, insomnia, poor appetite, diminished concentration, mouth dryness, loss of hair and poor body image perception (Molassitis et al.,1997; Larsen et al., 2007). Psychosocial wellbeing after transplant is influenced by mucositis toxicity, and other side effects, and psychological factors as anxiety, distress and social support have a significant impact on how severely patients experience mouth pain (Schulz-Kindermann et al., 2002) Fatigue is one of the most frequent side effects reported by patients who have undergone HSCT (So et al., 2003), physical activity decreased and this decline coincided with diminished physical, emotional, role and cognitive functioning during the initial post transplantation period (Danaher et al., 2006) Fatigue was the main symptom interfering with daily life in 79% of patients (Molassiotis & 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 experienced and poor functional status and general health (Larsen et al.,2007) and in another study, changes in HRQoL could be explained entirely by changes in functional limitations and somatic symptoms (Broers et al., 2000). A Danish study found patients prior to allo-hsct to have lower VO 2 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 specific impairments experienced by patients undergoing allo-hsct. To date, the general practice in Denmark regarding physical activity for patients undergoing allo-hsct is to inform patients prior to hospitalization about the importance of avoiding excessive bed rest during hospitalization and physical therapy is offered after stem cell replacement, 9-10 days after hospital admission. In the home recovery period, patients are advised to remain physically active within own limitations. 2.4 Clinical Intervention Studies Exercise-based Interventions in Cancer Patients There is a rapidly increasing literature on the effects of exercise on cancer rehabilitation, especially for breast cancer patients, on whom the majority of research has been conducted (Courneya et al., 2007 & 1997; Conn et al., 2006). Despite that physical exercise showed positive effects on factors such as cardiorespiratory fitness, treatment-related symptoms and physiological effects, the magnitude of these positive results still need to be established. A qualitative and quantitative review and meta-analysis found only small to moderate effect of physical activity interventions on these outcomes (Schmitz et al. 2005; Conn et al., 2006). Physical activity is reported as being well tolerated in cancer survivors during and after treatment, however, conclusions about adverse effects are inconclusive (Schmitz et al. 2005) Exercise-based Interventions in Hematopoietic Stem Cell Transplantation Exercise has been proposed as a nonpharmacologic adjuvant therapy to combat the physiological and psychological symptoms of HSCT (Wiskemann & Huber, 2008). However, little work exists in utilizing exercise interventions specifically 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 specifically, a low level of naturally-occurring exercise amongst patients undergoing HSCT is reported, suggesting 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 published that incorporated exercise regimes in various HSCT contexts. Beneficial effects were found on aerobic capacity (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 symptoms 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 studies, however, were initiated during the hospitalization period for patients undergoing specifically allo-hsct (Mello 3

16 Ph.D. Dissertation Mary Jarden Hematopoietic Stem Cell Transplantation et al., 2003; Defor et al., 2007; Kim & Kim 2006; Cunningham et al., 1986). Most physical activity intervention studies in the HSCT setting were exercise-only, unidimensional (one-type exercise), limited to observational designs or nonrandomized prospective trials. The studies included patients undergoing high dose chemotherapy with autologous stem cell support (HD-SCS), initiated after stem cell infusion and were either home-based or in the outpatient setting. These findings, despite the small sample sizes and lack of randomised design, indicate positive physiological and psychological benefits from exercise in patients after HD-SCS and allo-hsct. However, due to lack of evidence, no recommendation can be issued for patients undergoing allo-hsct Progressive Relaxation and Psychoeducation in Cancer Patients In meta-analyses, the significant beneficial effects of psychoeducational interventions were found for the outcomes of anxiety, depression, mood, nausea, vomiting, pain, and knowledge (Devine, 2003; Devine & Westlake, 1995). Clinically controlled trials using psychoeducational interventions based on cognitive-behavioral theory showed decreased emotional distress and enhanced coping 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). The goal of relaxation training is to teach patients how to establish a state of deep relaxation, which has been shown to have a positive impact on cancer treatment related side effects, including pain and anxiety (Syrjala & Chapko, 1995; Arakawa et al., 1997; Molassiotis et al. 2002; Dimeo et al., 2004), and one exercise study with relaxation breathing decreased fatigue in patients undergoing allo-hsct (Kim & Kim 2005). Several interventions were found to promote positive effects 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 identified by the patient as an important source of support over time, all may have positive influences on HRQoL (Wingard, 1998) Summary These reports indicate that exercise, psychoeducational interventions and progressive relaxation can each positively 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 patient s complex situation during allo-hsct. 4

17 Hematopoietic Stem Cell Transplantation Ph.D. Dissertation Mary Jarden 3 HYPOTHESES AND AIMS The aim of this dissertation was to investigate the effect of a 4-6 week multimodal intervention, comprised of mixedexercise, progressive relaxation and psychoeducation, in patients undergoing myeloablative allogeneic stem cell transplantation. The hypotheses were, that the intervention would: Reduce the loss of physical capacity and functional performance. Reduce the intensity of treatment related physical and psychological symptoms. Improve health-related quality of life. Improve clinical outcomes by reducing infections; incidence of GvHD; shorten length of neutropenia and thrompocytopenia and length of hospitalization. The main objectives of each research focus (Papers I III), which constitutes this dissertation, are: To investigate the feasibility, safety and preliminary benefits of the multimodal intervention and evaluate the validity of the pilot study (Paper I). To identify symptom profiles and study the longitudinal effect of the multimodal intervention on symptom occurrence, 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 effect of the multimodal intervention on physical and functional performance at post intervention, and to explore health related quality of life, fatigue, 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 This study was based on the author s previous clinical background as an oncology and hematology nurse, including experience in care and treatment of patients in the HSCT setting. This knowledge and experience inspired the development of an intervention for this patient group, which was further built on theoretical concepts and empirical studies within the HSCT context. This 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 researcher 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. This symptom burden, despite being well-known and observed in clinical practice and described in the literature, had an encompassing effect on the patient and was often the main obstacle in keeping active and carrying out everyday activities during hospitalization. Close patient contact within the context of the intervention 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 insight, an additional theory-set was incorporated that offered support in understanding and examining this multi-symptom experience (Paper II). Future interventions might not only include elements of the original multimodal intervention but consider incorporating a more systematic focus on symptom management by highlighting the patient s symptom burden through symptom cluster assessment and management, and prevention of symptom limitations. The theoretical research framework and process is illustrated in Figure 1. 5

18 Ph.D. Dissertation Mary Jarden Hematopoietic Stem Cell Transplantation Figure 1 THEORETICAL RESEARCH FRAMEWORK AND PROCESS PERSPECTIVE THEORETICAL FRAMEWORK Clinical experience Exercise Physiology Cognitive Behavioral Theory Roy s Adaptation Model Empirical Findings MULTIMODAL INTERVENTION Bio/Psycho/Social Psychoeducation Cycle training Resistance training with free hand and ankle weights Active, core & stretching exercises Progressive Relaxation Clinical experience with Intervention: Symptom Burden SYMPTOM THEORY Lenz s Theory of Unpleasant Symptoms Dodd s Symptom Management Theory OUTCOME MEASURES Bio/Psycho/Social Feasibility Attrition Safety VO2 max Muscle Strength Stair Climb Leisure Time Activity EORTC QLQ C30 FACT An FUTURE INTERVENTION Bio/Psycho/Social Multimodal Intervention during in hospital and at home recovery Symptom Cluster Assessment & Management Prevention of Symptom Limitations HADS THEORY DEVELOPMENT Mini MAC Interviews Focus on Symptom Burden in allo HSCT SCT SAS Symptom Cluster Assessment + Management In summary, this study was inspired by theoretical concepts from three disciplines (exercise physiology, adaptation model and cognitive behavioral theory), the researchers own clinical experience and empirical sources. This multidiscipline framework, which is presented in the following, has influenced the study s design and composition, intervention implementation, data collection, analyses and interpretation. 4.1 Exercise Physiology An article from the British Medical journal in 1947, by R.A. J. Asher M.D. The Dangers of Going to Bed argued for the need to reassess medical orders of bed rest for patients. Dr Asher asserted that bed rest is anatomically, physiologically, and psychologically unsound and in the article equated bed rest to a bodily hazard, negatively affecting the respiratory system, blood vessels, skin, muscles and joints, bones, renal tract, alimentary tract, nervous system and mental changes (Asher, 1947). These assumptions have been tested over the past years revealing that prolonged bed rest produces profound changes. Saltin et al. study of five healthy men, found after twenty days of bed rest, a pronounced decrease in maximal oxygen uptake, stroke volume and cardiac output (Saltin et al., 1968) and Convertino found similar results (Convertino, 1997). It then took five weeks for the participants to return to baseline levels (Saltin et al,. 1968). Bloomfield showed decreases of 6 to 40% in muscle strength within 4-6 week of bed rest (Bloomfield, 1997) and LeBlanc found significant 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 activities to recover (Bloomfield, 1997). The American College of Sports Medicine suggested that musculoskeletal atrophy and changes in muscle properties contribute to declines in cardiovascular efficiency (Graves et al., 2006). Declines in cardiac efficiency are reflected in increased heart rate and blood pressure at rest and with submaximal exercise. Declines in pulmonary function that result from inactivity may include a poor ventilator response, diminished airflow and respiratory muscle function, and impairments in gas exchange and diffusion 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 immunosuppressive effects of high intensity exercise, pathological bone fractures in cancer patients with compromised bone densities, worsening of cardio-toxicity from chemotherapy and/or radiation, severe pain, nausea, and fatigue that 6

19 Hematopoietic Stem Cell Transplantation Ph.D. Dissertation Mary Jarden may be intensified by exercise, and the inability and/or unwillingness of cancer patients to tolerate exercise due to a compromised physical and emotional condition. In 2006, the first international recommendations for exercise prescription for cancer patients were published requiring special attention to complications involving complete blood counts (hemoglobin level, absolute neutrophil and platelet counts), infection and severe treatment-related symptoms (Nieman & Courneya, 2006). Recently, the first tentative physical exercise recommendations for patients in the HSCT setting have been published (Wiskemann & Huber 2008), however, as mentioned earlier due to lack of evidence, no recommendations are available for patients undergoing allo-hsct. 4.2 The Roy Adaptation Model The Roy Adaptation Model (RAM) was developed as a framework for theory, practice, and research in nursing (Roy & Roberts, 1981; Roy & Andrews, 1991). The RAM views the patient as being bio-psycho-social and behavioral in nature. The RAM is a general conceptual model which provides a frame of reference in the observation and interpretation of a phenomenon. This 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 system 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) Interdependence: need is to achieve relational integrity, i.e., the giving and receiving of affection, respect, and value through effective relations and communication. The environment was defined as circumstances, and influences surrounding and affecting the development and behavior of persons with particular consideration of mutuality. In this study, isolation in an allo-hsct unit was the environment. The goal was to promote adaptation through these four adaptive modes, and thus contribute to health and quality of life by promoting strengths and competencies. This is done by assessing behavior and factors that influence adaptive abilities and by intervening to expand those abilities. 4.3 Cognitive Behavioral Theory The communicative element in the multimodal intervention was inspired and guided by principles from cognitive behavioral theory (Beck, 1995; Tingleff, 2006) and psychosocial interventions including patient education (i.e. treatment related, dealing with side-effects), behavioral (i.e. progressive muscle relaxation, exercise) and coping skills (i.e. active behavioral and active cognitive), stress management and support (i.e. patient specific, goal oriented) (Fawzy, 1999). Cognitive therapy is based on identification and then conceptualization of current thinking and behaviors, evaluation and formulation of adaptive responses. Interventions build on the cognitive model, which illustrates how thoughts, feelings, bodily sensations and behavior are mutually influenced by each other (Tingleff. 2006). Fundamentally the cognitive behavioral approach is based on teamwork, requiring a solid alliance with the patient. Collaboration and active participation are key factors because sessions are goal-oriented with emphasis on problem solving. It is important to bring forth the patient s own motivation and assure that the dialog and intervention are not forced. Psychoeducational (PE) care was found to benefit adults with cancer in relation to anxiety, depression mood, nausea, vomiting, pain, and knowledge (Devine 1995). Barsevick found PE to reduce depressive symptoms in patients with cancer and that behavioral therapy alone or in combination with cancer education was beneficial (Barsevick et al., 2002). PE is used to describe a behavioral therapeutic concept consisting of four elements; briefing the patients about their illness, problem solving, information acquisition, self care management of symptoms and emotional and social support for patients. PE is health education combined with behavioral counseling and dealing with emotions, perceptions, coping, relaxation and selfcare (Given et al., 2002). PE has been shown to improve coping with pain, distress, and other unpleasant symptoms and improve adherence to recommended regimens of care. (Fawzy, 1999) Cognitive behavioral therapy supports approaching the patient as independent thinking individuals with resources, willpower and motivation to reach own goals, despite challenging situations. 4.4 Symptom Theory Framework The theory of unpleasant symptoms was developed in 1995, by Lenz (Lenz et al., 1995) and thereafter, revised and updated in Revisions resulted in a more accurate representation of the complexity and interactive nature of 7

20 Ph.D. Dissertation Mary Jarden Hematopoietic Stem Cell Transplantation the symptom experience. (Lenz et al.,1997). This theory is chosen because it emphasizes the complexity and interaction of symptoms and the interrelationships among symptoms, influencing factors, and consequences of symptoms on performance. These interrelationships make assessment more challenging than when symptoms are considered individually. It is assumed that multiple factors affect performance, including functional and cognitive abilities and three categories of variables are identified as affecting the occurrence, intensity, timing, distress level and quality of symptoms, 1) physiological factors, 2) psychological factors, and 3) situational factors. These factors overlap and affect the patient and family. Physiological impairments are reflected in, and may be diagnosed by the presence of unpleasant symptoms. The aspects of physiologic factors may be related to body function, pathology, trauma. Physiological factors are measured and weighted by prognostication models and are used to predict outcomes. The psychological 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. The importance of the caregiver and the social and environmental 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 performance outcomes into consideration, interventions become patient specific and, therefore, more effective. Symptom Management Model is used to determine intervention strategies through an exploratory approach of how and when the intervention is delivered (Dodd, Janson et al., 2001; Dodd et al. 2001). This approach is taken to affect symptom experience and patient outcomes like functional status. In this model, person, environment and health state are interrelated. Within the symptom experience, evaluation, perception and response are interrelated. This model is helpful in the guidance of decisions made when approaching patients experiencing untoward symptoms. The assumptions about symptom management are that the patients perception is the gold standard and symptom management is dynamic. The concepts of this theory are the 1) symptom experience, 2) the components 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 define the intervention. In research, symptom management can be evaluated by functional 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). 8