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The recovery patterns and effects of exercise rehabilitation on the physiological and psychological health… Niesen-Vertommen, Sherri 1998

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THE R E C O V E R Y PATTERNS A N D EFFECTS OF EXERCISE REHABILITATION ON THE PHYSIOLOGICAL A J N D PSYCHOLOGICAL H E A L T H OF CHILDREN WHO H A V E SURVIVED TREATMENT FOR A M A L I G N A N C Y by SHERRINDH S E N - V E R T O M M E N B.Sc , Physical Therapy, University of Montana 1983 M.P.E., University of British Columbia, 1989 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSPHY in THE F A C U L T Y OF G R A D U A T E STUDIES Interdisciplinary Studies We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH C O L U M B I A July, 1998 © Sherri Niesen-Vertommen In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of \JnC&A JUs-i^ Lo^_yu xdtu M ) The University of British Columbia Vancouver, Canada Date 3 5 , DE-6 (2/88) 11 ABSTRACT Two studies were conducted. A longitudinal study (12 months) was designed to describe the physiological and psychological recovery patterns in a group of pediatric patients who were recently treated for a malignancy. An intervention program (12 week rehabilitation exercise program), was used to separate the effects of deconditioning from the disease and/or its treatment in children who had been out of treatment for a malignancy for at least one year. In the twelve month study, 10 pediatric patients recently out of treatment and 10 healthy controls were tested at 0, 6, 12 weeks and 6 and 12 months. In the twelve week study, 18 patients and 52 healthy controls were assigned to an exercise or no exercise group and were tested at 0, 6 and 12 weeks. At each test session, all subjects were tested for measures of height, weight, sum of skin folds, blood pressure, and pulmonary function. Each subject completed a 30s Wingate test on a cycle ergometer, for measures of anaerobic capacity, and a maximal oxygen consumption test (15 or 20 W/min, ramp protocol) to volitional fatigue for measures of aerobic fitness. A measurement of self-esteem and self-confidence were tested using the Harter scale Self-Perception Profile for Children and Adolescents. All subjects were also evaluated at 0 and 12 weeks (again at 6 and 12 months in the 12 month study) using Doppler and M-mode echocardiography to note cardiovascular changes during semi-supine exercise. Results of both studies show no significant differences between the patients and the healthy controls in any of the physiology, psychology, or cardiology measures. The patients did demonstrate a similar response to exercise in many measures but their values were reduced in magnitude. The patients consistently performed below both the healthy controls in all physiological and cardiology measures but these trends were not statistically significant. It would appear that the majority of children and adolescent patients who were followed in this study are functioning remarkably well both physically and psychologically compared to their healthy controls. T A B L E OF CONTENTS Abstract 11 Table of Contents iii List of Tables V List of Figures vi List of Abbreviations viii Acknowledgments xii Dedication xiii Introduction 1 Purpose 7 Research Hypotheses 7 Limitations 9 Methods and Procedures 10 Results Twelve Month Descriptive Study 25 Twelve Week Training Study 49 Discussion Physiology Measures 74 Psychological Profile 87 Cardiology Measures 89 Conclusion 95 Recommendations 97 iv Appendix One: Review of the Literature Late Effects of Treatment 99 Cancer Studies 111 Healthy Training Studies 120 Cardiac Rehabilitation Program Studies 124 Psychological Research with Chronically 111 Populations 128 Echocardiography/Doppler Measures 132 References 134 Appendix Two: Self-Perception Profile for Children (SPPC) 150 Appendix Three: Self-Perception Profile for Adolescents (SPPA) 154 Appendix Four: Cardiology Results for Cancer Subjects in 12 Month Study 159 Appendix Five: Cardiology Results for Healthy Subjects in 12 Month Study 162 Appendix Six: Cardiology Results for Cancer Controls 165 in 12 Week Training Study Appendix Seven: Cardiology Results for Cancer Exercisers 167 in 12 Week Training Study Appendix Eight: Cardiology Results for Healthy Controls 169 in 12 Week Training Study Appendix Nine: Cardiology Results for Healthy Exercisers 171 in 12 Week Training Study V LIST OF TABLES Twelve Month Descriptive Study 1. Demographic Characteristics of Cancer and Healthy Subjects 26 2. Patient Treatment Profile 27 3. Pulmonary Function Tests of Cancer and Healthy Subjects 30 4. Anaerobic Capacity Measures of Cancer and Healthy Subjects 32 5. Cardiorespiratory Fitness Measures of Cancer and Healthy Subjects 34 6. Comparison of Observed Study Values and Reported Literature Norms (a-b) 36 7. Psychological Results of Cancer and Healthy Subjects 37 Twelve Week Training Study: 8. Demographic Characteristics of Cancer and Healthy Subjects 51 9. Patient Treatment Profile 52 10. Chemotherapeutic Therapies 53 11. Pulmonary Function Tests of Cancer and Healthy Subjects 56 12. Anaerobic Capacity Measures of Cancer and Healthy Subjects 58 13. Cardiorespiratory Fitness Measures of Cancer and Healthy Subjects 60 14. Comparison of Observed Study Values and Reported Literature Norms 62 15. Psychological Results of Cancer and Healthy Subjects 65 16. Late Effects of Chemotherapeutic Therapies 110 17. Training Studies in Children with Congenital Heart Disease 125 18. Training Studies in Children with Congenital Heart Disease 126 vi LIST OF FIGURES Twelve Month Descriptive Study: 1. Forced Vital Capacity (FVC) 31 2. Forced Expiratory Volume in One Second ( F E V i ) 31 3. Anaerobic Capacity - Absolute Peak Power (Watts) 33 4. Anaerobic Capacity - Relative Peak Power (Watts/kg) 33 5. Anaerobic Capacity - Total Work (kJ) 33 6. Cardiorespiratory Fitness - Absolute Peak Oxygen Uptake (l/min) 35 7. Cardiorespiratory Fitness - Relative Peak Oxygen Uptake (ml/kg/min) 35 8. Psychology Measures - Scholastic Competence 38 9. Psychology Measures - Athletic Competence 39 10. Cardiology Measures - Heart Rate (a-d) 43 11. Cardiology Measures - Doppler Cardiac Output Index (a-d) 45 12. Cardiology Measures - Shortening Fraction (a-d) 47 Twelve Week Training Study: 13. Forced Vital Capacity (FVC) 57 14. Forced Expiratory Volume in One Second ( F E V i ) 57 15. Anaerobic Capacity - Absolute Peak Power (Watts) 59 16. Anaerobic Capacity - Relative Peak Power (Watts/kg) 59 17. Anaerobic Capacity - Total Work (kj) 59 18. Cardiorespiratory Fitness - Absolute Peak Oxygen Uptake (l/min) 61 19. Cardiorespiratory Fitness - Relative Peak Oxygen Uptake (ml/kg/min) 61 20. Psychology Measures - Scholastic Competence 66 21. Psychology Measures 22. Cardiology Measures 23. Cardiology Measures 24. Cardiology Measures Athletic Competence Heart Rate (a-b) Doppler Cardiac Output Index (a-b) Shortening Fraction (a-b) LIST OF ABBREVIATIONS A C S M American College of Sports Medicine A L L Acute Lymphoblastic Leukemia A M L Acute Myeloblasts Leukemia AS Aortic Stenosis ASD Atrial Septal Defect ATS American Thoracic Society A V C Atrioventricular Canal a-vo2 Arteriovenous Oxygen B.C. British Columbia B M T Bone Marrow Transplant BPd Blood Pressure in Diastole bpm Beats per minute BPs Blood Pressure in Systole B S A Body Surface Area Ca(C) Cancer Control Ca(Ex) Cancer Exerciser CHF Congestive Heart Failure CI Cardiac Index CNS Central Nervous System CO Cardiac Output CoA Coarctation of the Aorta c s Contrast Statistics DLCO Diffusion capacity of the lung for carbon monoxide EF Ejection Fraction ET Ejection Time FEV1 Forced Expiratory Volume in One Second FON Fontan FS Fractional Shortening F V C Forced Vital Capacity Gy Gray: One unit of absorbed dose of inonizing radiation He(C) Healthy Control He(Ex) Healthy Exerciser Hg Mercury H R Heart Rate IVSd Interventricular Septum in Diastole IVSs Interventricular Septum in Systole L V Left Ventricle L V E D Left Ventricular in End-Diastole Dimension L V E D I Left Ventricular in End-Diastole Index L V E S Left Ventricular in End-Sytole Dimension LVESI Left Ventricular in End-Sytole Index M A F V Mean Aortic Flow Velocity M H R Maximal Heart Rate M I Mitral Insufficiency MVCFc Mean Velocity of Circumferential Fibre Shortening, rate corrected heart rate M W Maximal Voluntary Ventilation NBO Neuroblastoma PB Barometric Pressure PHV Peak Height Velocity PP Peak Power PD Pulsed Doppler PS Pulmonary Stenosis Q Cardiac Output RER Respiratory Exchange Ratio RIHD Radiation-Induced Heart Disease R M Repeated Measures (Statistical Analysis) RMS Rhabdomyosarcoma RPE Rating of Percieved Exertion rpm Revolutions per minute RT Radiation Therapy RV Residual Volume Sa02 Arterial Oxyhemoglobin Saturation SD Standard Deviation SE Standard Error SI Stroke Index SPPA Self-Perception Profile for Adolescents SPPC Self-Perception Profile for Children SPSS Statistical Package for the Social Sciences sv Stroke Volume TF Tetralogy of Fallot T G A Transposition of the Great Arteries TLC Total Lung Capacity V C Vital Capacity V E Expired Ventilation per Minute Vmax Peak Aortic Velocity V0 2 Rate of oxygen uptake VC>2max Maximal rate of oxygen uptake VSD Ventricular Septal Defect VTI Velocity Time Integral WAnT Wingate Anaerobic Test xii ACKNOWLEDGEMENTS I would like to extend my sincere appreciation to Dr. Don McKenzie, who has been my supervisor throughout the course of my Ph.D. program. I am very grateful to him for his advice, his knowledge in so many different areas of medicine, and his gift of freedom in letting me muddle through the waters of academia and fundraising for this research. I am also very grateful to my committee members - Dr. Ken Coutts, Dr. George Sandor, and Dr. Peter Hochachka. They each provided me with their time, ideas, expertise and support. I would also like to thank Kim Keays, my research assistant, who was invaluable in helping me run the training programs with the children, collect the data and support me over the two years we worked together. Also my sincere appreciation goes to all of the volunteers who gave of their time to help train the children and collect the data; Deanne Henry, Dana Reid, Joey Synder, David Smith, Shanna Lumm and John Wang. I am so very grateful to Diana Jespersen who has helped me endless times during my career as a student, be it on the computer, in the running trails, or on the water dragon boating; to Nancy McLaren whose lunch time runs and Mocha Valencias were my peace of mind; to Clyde Smith whose hugs and a listening ear were such a gift; and to all of the staff at the Allan McGavin Sports Medicine who made my time there so enjoyable and full of laughter. I am grateful to Chris Badjik and Tim Boothman for their statistical consultation of my data and to Terry and Jim Potts for their cardiology technical expertise. I am so very thankful to the many children who have survived cancer and their families who gave generously of their time and who really made the study worthwhile. And also to the children who volunteered to be the healthy controls in this study, thank you for your dedication and support of this research. I am indebted to The Lotte and John Hecht Memorial Foundation for their financial support of this research and to all of the many private donors who gave so that this research could be accomplished. DEDICATION This thesis is dedicated to -my Mother, who has always given me the freedom and the wings to choose what I really want in my life, and to encourage those choices; my sister and brother, who have always been there for me; Livio who brought me back from Kenya to pursue relationships, academia and self lessons; Deanne, my dear friend, confidant and often lifeline over the last five years; my friends and colleagues, whose support, guidance, and love contributed to the completion of this thesis. My thanks to all of you. 1 INTRODUCTION Cancer is the leading cause of disease-related death among children, second only to trauma as the leading cause of death in children between the ages of 1 and 15 years (1). For the children who survive cancer the quality of survival is as important as survival itself. Cancer treatments that are currently being used result in a greater than 70 - 80% overall survival rate for these children (2). Some researchers have calculated that by the year 2000, one out of every 1000 persons in North America who has reached 20 years of age wil l be a cured cancer patient. (3) Thus, each year there will be an increasing number o f children entering the group o f childhood cancer survivors. The number of newly diagnosed children with cancer in this country is small relative to the overall cancer experience. In Canada, it is projected that in 1997 approximately 1330 children and teenagers will be diagnosed with cancer and approximately 240 will die from their disease (4). In British Columbia approximately 137 children are diagnosed with cancer every year (5). Leukemia (Acute Lymphoblastic Leukemia A L L ) accounts for greater than 32% of new cancers and remains the most common of the childhood cancers. Cancers of the brain (astrocytoma) and spinal cord (neuroblastoma) are the second most common group of childhood cancer, which constitute approximately 21% of new cases, while lymphomas (Hodgkin's and Non-Hodgkin's) account for almost 12% of new cases (6). Cancer therapy often results in long-term complications referred to as late effects. The impact of late effects can be both physical and psychological. Late effects may be caused by either the cancer itself, by its treatment, or prolonged physical inactivity imposed by the disease and/or its treatments. Treatment may include surgery, radiotherapy, chemotherapy, or combinations of the three. The nature, timing and frequency of the development of late effects are dependent upon: 1) the location and extent of the primary disease; 2) the type and intensity of the initial treatment; and 3) the age, physiologic, and developmental status of the child at the time of diagnosis and treatment (3). Late effects may be associated with damage to vital organ systems, that may 2 be present immediately or not be evident until many years after the initial diagnosis of cancer and may adversely affect long-term survival and/or quality of life of former patients. Common late effects include: damage to the central nervous system, impaired growth and development, gonadal development and reproduction aberrations, genetic aberrations, oncogenesis, disruption of function in the heart, kidney, liver, lungs, bladder, gastrointestinal tract, skeleton, and abnormal findings in the psychosocial and intellectual realms (2,3,7). Very few survivors of childhood malignancy will be free of long-term problems related to their initial treatment. Some researchers suggest that approximately half of all children with cancer may face certain long-term adjustment problems (7). More attention is now being focused both on the short-term complications and late effects of treatment in these children. The consequences of treatment of cancer in children are obviously far different from the results of similar treatment in adults. Childhood is a time of physical growth and emotional development. These two features add entirely new dimensions to the usual side effects of cancer and its treatment that are not experienced in adults. It is important for the health professional to realize that these effects can be lasting and persist long after childhood cancer has been cured. The anthracycline antibiotics contains some of the most valuable antitumor agents, and one of them, Adriamycin (Doxorubicin™) has the broadest spectrum of activity of any available cancer chemotherapeutic agent. While it is one of the most powerful antitumor agents it also has significant side effects. Adriamycin cardiotoxicity affects 2 to 27% of patients receiving this drug and therefore presents formidable clinical problem (8). Endoymocardial biopsy has been used to identify the characteristic myocardial lesion as a result of anthracycline therapy. It has been shown that there is a direct relationship between the amount of drug given and the amount of morphologic damage (9). The degree of morphological damage and the resulting myocardial dysfunction are also related, but in a more complex, parabolic, nonlinear fashion. This means that there is a "threshold" for the amount of damage that must occur before clinical heart failure is observed (9). There appears to be a large range of variability among different subjects in the severity of morphologic damage per amount of drug administration. Due to the variability, some 3 patients can safely receive more than the usual empirical limit of 450 to 550 mg/m2, but others may have to be limited to lower doses (10). The clinical effects of these drugs can be divided into acute, subacute, and chronic. The chronic effects of anthracyclines are more significant clinically and have been more thoroughly evaluated (8, 11, 12,13). The clinical presentation is that of congestive cardiomyopathy, with elevated filling pressures and decreased cardiac output. Clinical symptoms are often delayed several months after the last dose of the agent, because of the time necessary for the full exposure of the cytotoxic effects of the drug (14). The mechanism of action is not exactly known, but there are effects on the myocardial sarcolemma, mitochondrial function, nucleus, sarcoplasmic reticulum, and also the myofibrils (15). Anthracyclines may induce biochemical changes capable of producing significant cellular damage. These changes may be due to: 1) conversion of doxorubicin to a toxic metabolite; 2) interaction with cell membranes; 3) release of vasoactive substances; 4) changes in contractile protein; 5) generation of reactive oxygen radicals; and 6) immunological alterations (15). Exercise intolerance results from abnormal cardiac, respiratory, or musculoskeletal function as well as deconditioning or a combination of these factors. Exercise tolerance may be limited in children treated for a malignant disease. First the disease process itself may involve specific pathological factors that limit exercise-related function (16). Secondly, the treatment protocols are complex and intensive and may take several years to complete. It soon became evident, as new classes of drugs were synthesized or discovered, that each had its own spectrum of toxicity's. Most shared myelosuppression, but pronounced organ-specific associated complications that are relatively drug-specific (17). Thirdly, there may be a significant change in the level of physical activity during the course of the disease and/or treatment and subsequently muscle disuse, atrophy and deconditioning is a common feature of the child with chronic disease (16). Finally, the psychological impact of chronic disease is significant, and may influence the ability of the child to participate in recreational, leisure or school exercise programs. A disease such as cancer can drastically change a child's normal lifestyle. The child may no longer have the energy, or feel well enough to play as he or she used to. Exclusion 4 from regular activities at school or with playmates may result in a decreased self-esteem and mental outlook on life, two attributes that are important in the recovery of any disease. Exercise programs provide children with an enjoyable social atmosphere as well as an improved physical well-being. Looking at the late effects of treatment is also very important since most will have received treatment (e.g. radiation or anthracycline) now known to be associated with late, and perhaps progressive cardiotoxicity. Survivors of childhood malignancies represent one of the largest new groups at risk for premature cardiovascular disease. A survey by the Pediatric Cardiomyopathy Registry of more than 100 pediatric cardiology centres in North America showed that more than 15% of all patients with cardiomyopathy had previously been treated for malignancy during childhood or adolescence (18). Research (cross-sectional and longitudinal) clearly illustrates the relationship between aerobic fitness or physical activity and mortality and morbidity in adults. The assumption is that aerobic fitness is related to functional health in individuals. In adults this relationship has a strong association, but is not well established in children and adolescents. Since physical inactivity is a risk factor for cardiovascular disease in adults and since physical activity behaviors may track from adolescence into adulthood, there is cause for concern for the oncology patient with a compromised cardiovascular system who may be especially vulnerable to acquired heart disease. Exercise testing and training have now become an important tool in the evaluation and treatment of disease in children and adolescents. It can yield information on the functional severity and natural history of a disease and it can help assess the effects of such therapeutic interventions such as a rehabilitation program. Bar-Or (16) states that children with a chronic illness often display a subnormal exercise capacity. This is a result of two main causes: 1) hypoactivity which leads to detraining and, 2) specific pathophysiological factors that limit one or more exercise-related functions. Disease or illness can directly induce hypoactivity. It is important to realize that a hypoactive, unfit child, often enters a vicious circle of further hypoactivity and detraining. For a healthy child, physical activity is part of their daily routine since most children have a natural tendency to be active and 5 energetic. When the integrity of play is compromised by a disease such as cancer, the risks and benefits of exercise must be assessed. Past studies from this laboratory support these findings. McKenzie et al., (20) studied 29 children, ages 8 to 18 who had been successfully treated for solid tumors. The time since their last treatment varied from 6 months to 15 years with an average of 3.4 years out of treatment. They found patients who had been treated for malignancy had a profound reduction in cardiorespiratory fitness and anaerobic power relative to their healthy peers. Twenty of these children from the original study were then given home rehabilitation programs as a treatment intervention and retested 8-12 months later. The repeat evaluation demonstrated no significant changes, neither positive nor negative, in these patients (21). The authors conclude that these patients had an unexplained, sustained reduction in aerobic and anaerobic capacities. Anecdotally, the authors also reported that the parents observed a change in attitude towards school, sports, and generally most activities after being tested. The most frequent comment centered on the improvement in self-esteem and confidence that the testing itself seemed to have instilled in them. These initial descriptive studies demonstrate that there is a significant difference between children who have survived treatment for solid tumors and their healthy controls and that these differences do not improve with time. Recent publications also support these results. Shaw et al., (22) studied adults and children who were survivors of childhood A L L and found that 65% had one or more abnormalities for respiratory function. Kadota et al., (23) studied children who had been treated for Hodgkin's lymphoma and their results showed abnormal pulmonary function tests, reduced exercise times and maximal oxygen uptake in 9 of 12 long-term surviving patients. Jenney et al., (24) studied 70 survivors of A L L and found that survivors of childhood leukemia have impaired lung function, a diminished exercise capacity and reduced ejection fraction and fractional shortening indices. Pihkala et al., (25) also studied exercise tolerance in 30 patients treated for pediatric malignancies and found the patients differed from normal controls in the maximum workload achieved in a graded exercise test and in values of maximal aerobic capacity. In all of the above mentioned studies the cancer patients were 6 anywhere from 2 to 13 years out of treatment. No studies have looked at children who are recently off treatment and how they compare to matched controls over time. In healthy individuals, maximal exercise tolerance is limited primarily by cardiovascular and musculoskeletal function. Aerobic exercise training results in changes in skeletal muscles specific to the muscles involved in training and in the cardiovascular response to exercise (26). These changes include muscle capillary proliferation, increase in myoglobin levels to augment oxygen transport, and increased oxidative metabolic activity in muscle cells. Cardiovascular changes include an increase in stroke volume at rest and during exercise, increase in maximum cardiac output, and higher arteriovenous oxygen extraction with exercise. Physiologic adaptations to training include an increase in maximal oxygen consumption (V0 2max) and a higher anaerobic threshold (work level before the onset of anaerobic metabolism and lactic acidosis). The primary role of exercise for the cancer patient is to help prevent the loss of functional capacity. This objective is achieved through adaptations in the cardiovascular and respiratory systems as well as in the working muscle. In addition, exercise may play a role in diminishing the side effects associated with treatment, including psychological burdens. It has been suggested (27) that exercise training may improve an individual's quality of life by increasing life satisfaction through the enhancement of arousal, self esteem and body image. Brown et al., (28) suggested that training may also assist in the treatment of anxiety, stress and reactive depression. These and other factors suggest that exercise training may contribute to heightened sense of well-being of the patient following training. A number of studies on other chronically ill populations have used exercise training as an intervention technique. Exercise has been shown to improve the functional capacity of patients with cardiovascular disease (29, 30, 31), diabetes mellitus (32, 33), chronic obstructive pulmonary disease (34), cerebral palsy (35), cystic fibrosis (36) and peripheral vascular disease (37, 38). In addition, epidemiological studies by Frisch et al., (39) and Paffenbarger et al., (40) suggested that regular physical exercise aids in increasing the individual's resistance to disease. It seems logical to consider an exercise training program as an adjunct therapy in cancer treatment. 7 Exercise seems to be one of the easiest, least expensive and most applicable tools that we can use. Moderate exercise shows promise as a way to delay or reverse a patient's decline in functional ability. However, no guidelines exist for objective evaluation of functional capacity or for restorative exercise programs designed specifically for cancer patients. There is no information on the normal rate of recovery of the cardiovascular, respiratory, and musculoskeletal systems and psychological health of a child recovering from cancer treatment, or if an intervention program of rehabilitative exercise can influence this pattern of recovery. Purpose After reviewing the literature two separate studies were designed: 1. A longitudinal study (12 months) - the purpose was to describe the physiological and psychological recovery patterns in a group of pediatric patients who were recently treated for a malignancy. 2. An intervention program (12 weeks) - the purpose was to separate the effects of deconditioning from the disease and/or its treatment in children who had been out of treatment for a malignancy for at least one year, by providing an exercise rehabilitation program and monitoring the change in functional capacity and psychological health. Research Hypotheses 1. Exercise tolerance (aerobic and anaerobic capacity), cardiac function, and psychological health will be reduced in children recently treated for a malignancy and will remain significantly lower than the healthy control group over the twelve month testing period. 2. A twelve week program of rehabilitation exercise will significantly improve the exercise tolerance and psychological health in children who have been out of treatment for a malignancy for at least one year. However, the survivors of childhood cancer will not attain the same training effects as the healthy control groups and will therefore demonstrate a reduced functional capacity (both aerobic and anaerobic), and measure self-esteem, and self-confidence over the testing period. 3. Children who participate in the exercise rehabilitation program will demonstrate significant improvements in cardiac function. This will include increases in maximum cardiac output index (CI), and stroke volume index (SI), when compared to healthy control patients. The survivors of childhood cancer will however, not attain the same training effect as the healthy control group and will therefore demonstrate reduced increases in cardiac indices with exercise. 9 LIMITATIONS The results of the study were limited by: 1. Recruitment was based on participation by volunteers and entering the exercise or non-exercise groups was not randomized but based upon availability to participate in the exercise program. Thus the self-selected sample may influence the results. 2. The patient population in the study was heterogeneous in regards to disease type, treatments received, age at diagnosis, and time since completion of therapies. 3. Subject recruitment proved to be difficult in the patient groups and hence a small n (sample size) resulted. 4. Subjects ranged in age from 7 to 17 years old, resulting in pre- and postpubertal children being compared for similar training effects. Thus age was used as a covariate in the statistical analysis. 5. There was a difference in the number of males and females in each group. Thus gender was used as a covariate in the statistical analysis. 6. Previous training levels for the healthy control groups were not controlled for and hence there were various initial levels of fitness in this group. 7. Investigators were not blinded to the exercise or control group each subject participated in due to they were the same ones administering the exercise program. 8. Due to limitation of patient availability, it was not possible to have the subjects come into the laboratory for a familiarization sessions with the equipment and test procedures before the initial test session. 9. It was not possible to perform both an exercise echocardiogram and aV02max test during the same test session. The exercise echocardiogram required the subjects to be in a semi-supine position, with their head tilted backward when recording data due to angle of the Doppler probe needed to record flow velocities. Therefore, the V0 2 max test was performed in an upright position and the exercise echocardiogram is performed in a semi-supine position. This limits direct comparisons between the two tests. 10 METHODS AND PROCEDURES This was a collaborative project with the Department of Pediatrics, the Oncology and Cardiology Departments at B.C. Children's Hospital and the Sports Medicine Division at the University of British Columbia. SUBJECTS Twelve Month Descriptive Study Oncology patients: 10 subjects (4 males, 6 females) who had completed treatment for a malignancy were enrolled in the study from the Long-term Follow-up Clinic at B.C. Children's Hospital. These children and their parents were provided with the information on the study and informed consent was obtained prior to enrolling in the project. Al l volunteer subjects were enrolled in the study within one year of completing treatment. Prior to testing, all subjects were cleared medically to participate in the study by the oncology team at B.C. Children's Hospital. Control group: 10 subjects (4 male, 6 female) free of disease or injury were studied on the same schedule. This group was necessary to identify the changes that occur due to growth and maturation during the length of the study period. All children and their parents were provided with the information on the study and informed consents were obtained prior to enrolling in the project. The control group was composed of subjects matched for age, gender and activity level who were siblings or friends of the oncology patients. The advantage of this is was that they were relatively easy to obtain as control subjects and were similarly matched for socioeconomic status and psychological background. Al l subjects were tested at the Allan McGavin Sports Medicine Centre at the University of British Columbia and in the Division of Cardiology, at B.C. Children's Hospital. 11 Twelve Week Training Study Oncology Patients: 18 subjects (7 males, 11 females) who had completed treatment for malignancy were enrolled in the study. Patient selection was not randomized. Seventy information letters detailing the study were mailed to the parents of all children who met the inclusion criteria from the registry at the Long-term Follow-up Clinic at B.C. Children's Hospital. Thirty-eight parents responded to the letters for more information. Of those who responded, twenty were unable to enter the study due to the location of the exercise program, time constraints on the part of the parents and/or children, or inadequate transportation to the designated facility. Eighteen children did enter the study which was 26% of the available data population. The children and their parents were provided with the information on the study and informed consent was obtained prior to enrolling in the project. Al l volunteer subjects were enrolled in the study anywhere from one to ten years after completing treatment for their cancer. Prior to testing, all subjects were cleared medically to participate in the study by the oncology team at B.C. Hospital. All subjects were then assigned to the exercise or control groups based on their availability to enter into the rehabilitation program. Control group: 52 subjects (31 males, 21 females), were recruited from Lord Byng Secondary School and McRoberts Secondary School, along with siblings or friends of the children who had cancer and who were participating in the research. Al l subjects were free of disease or injury and were studied on the same schedule as the oncology group. This group was necessary to identify the changes that occur due to growth and maturation during the length of the study period. Al l subjects were then assigned to the exercise or control groups based on their availability to enter into the rehabilitation program. Al l subjects were tested at the Allan McGavin Sports Medicine Centre at the University of British Columbia and in the Division of Cardiology, at B.C. Children's Hospital. 12 Inclusion criteria: 1. Ages 7-18 years, residents of the lower mainland area of British Columbia 2. Clinically free of residual disease 3. Cleared for clinical exercise testing by the B C Children's Hospital Oncology team 4. Required intensive therapy to include anthracycline dosage below 300 mg/m2 or >300 mg/m2 if the shortening fraction (FS) is >20% Exclusion Criteria: 1. Anthracycline dosage >300 mg/m2 i f FS<20% 2. Mediastinal radiation 3. Lower limb amputees 4. Neurological dysfunction 5. Patients who have not received any chemotherapy The oncology patients were a heterogeneous group in terms of age, gender, primary disease, extent of disease, and the multitudes of treatments received. Therefore, the inclusion/exclusion criteria were based on some commonalties in the treatments received so as to establish baseline treatment requirements. Participants were restricted to those patients who had received intensive chemotherapy which had required hospitalization, as the hypothesis was that the general physical debilitation associated with chemotherapy, radiation, and a sedentary lifestyle may account for the observed physiological changes. The exercise program would therefore be of major interest to these children and their parents. Mechanical and neurological causes for poor exercise performance, and similarly, patients who had received agents with known side-effects of major organ dysfunction were excluded. Of these agents, Bleomycin is known to cause specific disorders of pulmonary function in larger dosages. Therefore, only patients with low dose Bleomycin were admitted to the study. The side-effects of anthracyclines on cardiac function is well known and therefore exclusion of those patients who have evidence of significant cardiac dysfunction associated with anthracycline dosages was 13 necessary. Patients who had radiation therapy to the chest, due to the potential thoracic damage that has been identified with radiation therapy to this areas, were also excluded. Patients had to be able to perform all of the tests both cognitively and biomechanically and so the established age criteria was 7 years of age and over. To quantify the activity level of each subject the parents were asked to complete a questionnaire described by Bar-Or (41). For the purpose of this study the following four questions were used: a) whether the child's exercise ability was average, above average, or below average; b) whether the child was as active, more active, or less active than his/her friends; c) whether the child was as active, more active, or less active than his/her siblings; and d) whether the child trained regularly or was involved in any recreational activity that required physical effort. This information was used in the matching of activity levels of patients and control subjects. In order to determine the influence of activity or the absence of it, all subjects were asked to keep a daily activity log for the initial three month duration of the study. The journals asked the children to detail their recreational activities that day, the length of time they participated in the activity, and to give each activity a rating of perceived exertion (RPE) score on a scale of 6-20. 14 STUDY DESIGN/STATISTICAL ANALYSES The 12 month study compared healthy and recovering children at 5 time points: 0 weeks, 6 weeks, 3 months, 6 months and 1 year. This is a 2 group design (experimental/control) with repeated measures on the 5 testing sessions. Age and sex were used as covariates in all analyses. The 12 week study compared the exercise program and non-exercise program in healthy children and children treated for cancer at 3 time points: 0 weeks, 6 weeks and 12 weeks. This is a 2 (experimental/control) x 2 (exercise/no exercise) factorial design with repeated measures on the 3 testing sessions. Age and sex were used as covariates in all analyses. Analyses were performed for 21 physiology variables, 6-9 psychology scores, and differences in 7 cardiology variables measured at the exercise-75% stage minus the rest/upright stage. All variables were fitted to a repeated measures A N O V A model to test for differences between healthy children and children treated for cancer, and between the exercise group and the non-exercise group, and changes in group differences over time. When significant results appeared in the repeated measures analyses, separate contrast analyses were then conducted at each time point to find where differences were the greatest. These latter tests are considered post hoc tests. All analyses included age (at week 0) and gender as covariates. All tests were conducted using an alpha level of p=0.05. The Statistical Package for the Social Sciences (SPSS) was used in all analyses. 15 The following three contrast analyses were examined at specific time points: (i) children treated for cancer in the non-exercise program versus children treated for cancer in the exercise program, Ca(C) versus Ca(Ex); (ii) children treated for cancer in the non-exercise program versus healthy children in the non-exercise program, Ca(C) versus He(C); (iii) children treated for cancer in the exercise program versus healthy children in the exercise program, Ca(Ex) versus He(Ex). The He(Ex) versus Ca(C) was not used as a contrast comparison as it provided the least important group comparison of the available three of four possible comparisons. Sample Size Calculation The statistical power analysis program of Borenstein and Cohen was used to determine the sample size for each subgroup. With the power established at 0.8 and alpha level at (a = 0.05) we calculated that 8 subjects were required in each subgroup. The sample size was doubled to include both males and females and allowed for a 20% attrition rate, leading to a target sample size of 20 subjects per group. Al l hypotheses were tested simultaneously. The subjects from each group were assigned to the exercise or non-exercise group depending on availability to enter the exercise program. Training was provided according to the guidelines detailed later in this section and lasted for 12 weeks. This period of time was chosen as an adaptation to a training stimulus, which would be achieved by this time, if it were going to occur. This period of time also represents a significant commitment by the subjects and their parents and any longer duration of training might affect subject compliance in this study. Al l subjects were tested at 0, 6 and 12 weeks, for both the twelve week and twelve month 16 studies, and again at 6 and 12 months, for the twelve month study, following the completion of their oncology treatments. These testing times were chosen as: 1. The rate of recovery should be most rapid in the months immediately following treatment completion. Following children for twelve months should be adequate time to note the initial recovery patterns of the various physiological systems. 2. The supervised rehabilitative exercise program lasted 12 weeks and the subjects were tested at 0, 6 and 12 weeks. This provided adequate data points to establish a pattern of training adaptations in the different physiological systems if they occurred. 3. This testing pattern represented a reasonable demand of the subject's time. More frequent testing may have resulted in less compliance from the subjects or their parents. TESTING PROCEDURES The methods for both the 12 month and 12 week study were identical except for the testing times were extended in the longitudinal study to 6 and 12 months. The clinical records from B.C. Children's Hospital, on these patients were available to the research team. This included age at time of diagnosis, investigations performed, diagnosis, details of treatments received, date therapy was completed and other relevant patient data. A. The Applied Physiology Laboratory at the Allan McGavin Sports Medicine Centre: Anthropometric Tests Basic measurements were performed for height, weight (Detecto industrial scale) and sum of five skinfold (mm) sites. The skinfold were measured in triplicate using Harpenden calipers (John Bull, British Indicators Ltd) at the triceps, biceps, subscapular, iliac crest, and medial calf. The averages at each site were summed to create a skinfold score (SOS) for each subject. Resting diastolic and systolic blood pressure (mmHg) (Baumanometer ®, Copiague, N Y ) as well as resting heart rate were recorded at this time. 17 Pulmonary Function Tests Pulmonary function tests were performed using the spirometry software package that exists for the Medical Graphics Metabolic Cart (St Paul, Minnesota) CPX/D system. The system was calibrated prior to each testing session by withdrawing and injecting a known volume (5 x 3.00 Litres) through the pneumotach (MGC, disposable) at various flow rates with dead space constant at 40 ml. Environmental conditions such as temperature, humidity and barometric pressure (PB) were entered into the system. Tests were all performed at rest and in standing to determine forced vital capacity (FVC), forced expired volume in 1 second (FEVi), F E V i / F V C ratio and the Maximal Voluntary Ventilation in 12 seconds (MVV-12). Measures of the best of three trials were selected according to the criteria of the American Thoracic Society. Data obtained was recorded in absolute values and was also compared to normative values generated by the CPX/D software and described as percentages of predicted values, based on individual weight, height, and body surface area. Anaerobic Capacity A Monark cycle ergometer model 814E was used to perform a 30 second Wingate Anaerobic Test (WAnT) as described by Bar-Or (42). Prior to the test the ergometer was adjusted for an optimal seat height and subjects then warmed-up for 3 minutes at low intensity. Resistance was applied based on body mass (75 g/kg). The WAnT commenced from a rolling start and when a constant pedal rate of over 80 rpm was achieved a countdown of "3-2-1-go" was given, and the test resistance was applied and the computer activated. Pedal revolutions were recorded using a magnetically triggered counting device. Subjects were verbally encouraged throughout the test. The peak power in any 5 second interval (Watts) and (Watts/kg), the total work (kJ) done over the 30 seconds and the percentage decrease in power over the 30 seconds was determined. This test has been found to be reliable (test-retest reliability of r=.95 to .97) and validity estimates using a variety of criterion variables have been reported. Using a 300 m run as the criterion, Bar-18 Or and Inbar (43) found a validity coefficient of -.83, with 25 m swimming times as the criterion r = -.87 and -.90 (44, 45). Cardiorespiratory Fitness The Medical Graphics CPX-D Exercise Testing System was used for the direct measurement of the functional capacity of the heart and lungs at rest and during exercise to maximum. Exercise was completed on an electronically braked cycle ergometer (Lode B V Excalibur V2.0, Groningen, The Netherlands) using a ramp protocol while the load was increased by 15 or 20 watts (depending on size of the subject) per minute to volitional fatigue. After a 3 minute warm-up period, subjects exercised continuously maintaining a pedal rate of 70-80 rev/min through out the test. Expired gases were collected and analyzed on a breath by breath basis. Electrocardiographic (ECG) monitoring (Lifepack 6, Physio Control, Againcourt, Ontario) was done in conjunction with the test to determine the cardiac response to progressive exercise during the assessment of maximal oxygen consumption. Percent arterial oxygen saturation (%Sa02) was measured with an ear oximeter (OhmedaBiox 3740, Louisville, CO) and averaged every fifteen seconds. The accuracy of pulse oximetry is ± 3% (46), and has been validated (r = 0.96) as a measure of arterial hemoglobin oxygen saturation in critically ill patients (47). Peak oxygen uptake is defined as the maximal value of VO2 obtained over 4 highest consecutive 15 second periods. The test was terminated based on subject volitional fatigue such that they could not maintain their pedalling rate or their position on the bike. Maximal oxygen uptake (VOimax) in children has been shown to have a reliability and reproducibility similar to that observed in adults, despite failure to always achieve a plateau in oxygen uptake. Baggley and Cumming (48) reported a reliability coefficient of r = .92 in 14 to 17 year olds. This is similar to the reliability coefficient of r = .95 reported by Boileau (49). A lower reliability coefficient r = .81 was reported by Cummingham (50) for 10 year old boys using a cycle ergometer test. To determine the subjective strain that the child undergoes during exercise, we used a Rating of Perceived Exertion (RPE) 6-20 point scale, as devised by Borg (51). The scale was explained to the child before the start of the exercise test and then once the 19 test was complete the child was asked how hard they had exercised with 6 being the lightest possible effort and 20 being the hardest possible effort. Psychological Profiles The Self-Perception Profile for Children (SPPC) - 8 to 13 years The SPPC (52, 53) (Appendix 2) is a 36 item instrument designed to assess a child's perceptions of competence across the cognitive, social and physical domains. Six subscales tap the areas of scholastic competence, social acceptance, athletic competence, physical appearance, behavioural conduct, and global self-worth. The separate measures of an individual's perceived competence in different domains, as well as an independent assessment of global self-worth provides a richer and more differentiated perspective than instruments which only provide a single self-concept score. Item responses are scored on a 4-point scale where 4 represents the most adequate self-judgment and 1 represents the least adequate self-judgment. A total of six subscale means define a child's profile. Internal consistency for all six subscales (across four samples) has been found to be very satisfactory. Cronbach alpha reliabilities ranged from .71 to .86. Construct validity of the SPPC was supported through factor analysis. Across three different sample, each of the five domain-specific subscales define their own factor. The factor loadings for each subscale are substantial, and no cross-loading greater than .18 are evident. The global self-worth judgment is qualitatively different from the self-descriptions in each of the specific domains and is therefore not included in the factoring process (53). The Self-Perception Profile for Adolescents (SPPA) - 13 to 18 years As the SPPC does not provide an adequate profile of the adolescent self-concept, the 45-item SPPA (52, 54) (Appendix 3) was used for older subjects. The SPPA alters the wording of some items in the existing instrument (SPPC) and assesses three additional domain-specific subscales (i.e., job competence, close friendship, and romantic appeal). Item responses are scored on a 4-point scale where 4 represents the most adequate self-judgment and 1 represents the least adequate self-judgment. A total of nine subscale means define an adolescent profile. Internal consistency for all nine subscales has been 20 found to be very satisfactory. Cronbach alpha reliabilities ranged from .74 to .92. Construct validity of the SPPA was supported through factor analysis. Across four different samples, each of the eight domain-specific subscales define their own factor. The factor loadings for each subscale are substantial, and no cross-loading greater than .30 are evident. The global self-worth judgment is qualitatively different from the self-descriptions in each of the specific domains and is therefore not included in the factoring process (54). B. Division of Cardiology at B.C. Children's Hospital: All subjects had a limited M-mode, two-dimensional (2D) echocardiogram , and pulsed Doppler (PD) studies performed using a Vingmed C F M 800 Ultrasound System (Horten, Norway) with an annular phased array transducer. A range of transducers were used (5.0. 3.5, and 2.35 MHz) with duplex imaging to maximize the image in terms of resolution and penetration for each patient. Continuous, single-lead electrocardiographic monitoring was obtained throughout the study. All data were collected by the same pediatric echocardiographer to reduce inter-observer variability. All data was recorded on video tape and optical disk. With the patient lying in the left lateral position, a baseline study was performed. STEP 1: The aortic annulus was imaged in the 2D parasternal long-axis view and the internal systolic aortic diameter (d) was measured three to five times. These results were then averaged. STEP 2: A 2D short-axis view was then obtained of the left ventricle (LV) just distal to the tips of the mitral valve leaflets. By placing a cursor in the mid-portion of this image, an L V M-mode study was obtained. Blood pressure (BP) was taken simultaneously with the M-mode recording (STANDBY/MODEL Baumanometer). STEP 3: The patient was then placed supine with a pillow positioned under the shoulders, in order to extend the neck, and expose the suprasternal notch area. The transducer was placed in the suprasternal notch and a suprasternal long-axis view of the aorta was obtained. The sample volume was positioned with duplex imaging in the ascending aorta, as close to the aortic valve as possible and a PD recording was obtained, ensuring that the cleanest signals were obtained. The maximum frequency shift with the narrowest spectral 21 width were used localized using both the audio signal and the spectral display of the Doppler shift frequency from fast Fourier transform spectral analysis on a monitor. Hard copy records were made of three consecutive wave-forms using a strip-chart recorder at 100 mm/s. The subjects were then placed in a semi-supine position (approximate angle of the trunk was 45 degrees from vertical) leaving the body flexed at the trunk, the legs extended horizontally, and their feet strapped into the electronically-braked semi-supine cycle ergometer (Collins Pedalmate, Collins Total Work Integrator). Handgrips located near the upper portion of the thighs aided in stabilizing the subjects. They remained at rest, in this position for 5 minutes before another HR and BP were taken. Heart rate was measured electrocardiographically. Systolic and diastolic cuff blood pressures were obtained in the right arm by auscultation. An exercise test was then performed consisting of three, two minute stages. The wattage at each stage was individualized and set at 25%, 50%, and 75% of a previously determined maximal oxygen consumption test. All subjects were instructed to cycle for two minutes at each stage, while maintaining a pedal rate of 60 to 80 revolutions per minute. Steps 2, and 3 were repeated with the subject in the semi-supine position during the last minute of each exercise stage, immediately post exercise, and three minutes post exercise. Cardiac Measurements Body surface area (BSA) (m2) was automatically calculated by the Vingmed 800 software from the height and weight taken when all subjects came for testing. L V dimensions in end-diastole (LVED) were measured as the greatest distance from the posterior edge of the ventricular septum to the left ventricular endocardial surface and in end-systole (LVES) as the shortest distance from the ventricular septum to the endocardial wall in systole. From the spectral doppler tracing, the following measurements 22 were made utilizing the software provided by the C F M 800 System: 1) dv/dt, 2) peak aortic flow velocity, 3) mean aortic flow velocity, 4) velocity time integral. (VTI), 5) stroke volume, 6) R-R interval, and 7) aortic ejection time (ET). Al l measurements were made on three different cardiac cycles and the results were averaged. The outer edge was used as the defining border rather than the modal velocity because it is easily recognized and not as dependent on subjective estimate and the angle of insonation. The mean velocity of flow multiplied by the aortic cross sectional area of the vessel (e.g. aorta which can be measured by M-mode echocardiography) has been shown to correlate well with cardiac output. Doppler echocardiography may be performed at the same time as standard echocardiography and measurement of aortic flow is performed from the suprasternal notch approach. The use of mean aortic velocity may be as accurate an indexed value as calculating cardiac output as has been shown by Seear et al., (55). 23 Calculations: From the above measurements, the following calculations were determined: 1) Fractional Shortening (FS) (%) = L V E D - L V E S / L V E D x 100 L V E D = left ventricular end-diastolic dimension (cm), L V E S = left ventricular end-systolic dimension (cm). 2) Ejection Fraction (EF) (%) = ( L V E D 3 - L V E S 3 / L V E D 3 ) x 100 3) Rate corrected mean velocity of circumferential fiber shortening (MVCFc) (circ/sec) M V C F c = L V E D - L V E S / L V E D x ET /VR-R ET/VR-R = rate corrected ejection time (seconds). 4) Stroke Volume (SV)= VTI x AoCSA VTI = velocity time integral, AoCSA = aortic cross-sectional area, AoCSA = 7id2/4, where (d) = aortic root diameter (an assumption is made that the aorta is a round tube of constant diameter). 5) Stroke Index (SI) (ml/m2) = SV/BSA B S A = body square area 6) Doppler Cardiac Output (CO) (l/min) CO = SV (VTI x AoCSA) x HR CO = cardiac output, HR = heart rate 7) Cardiac Index (CI) (L/min/m2)= CO/BSA 8) Body Surface Area (BSA) = 0.007184 x height (cm) 0 7 2 5 x weight (kg) 0 4 2 5 24 Rehabilitative Exercise Program Volunteers for the 3 month supervised exercise rehabilitative program were assigned to either the exercise (cancer, healthy) or non-exercise (cancer, healthy) group depending on their availability for the exercise program. The exercise programs were held at Lord Byng Secondary School, McRoberts Secondary School, and Trout Lake Community Centre. Training consisted of both a 10 minute warm-up and cool down period, and a gradual increase in duration each week of cardiovascular exercise from 25 -30 minute sessions working up to 45 - 50 minute exercise sessions within the child's training heart rate zone. The exercise sessions were held 3 days/week for approximately 1 hour sessions. On the basis of the maximal heart rate response obtained during the pre-program exercise test, the training heart rate range of 50 - 80% of maximal heart rate (MHR) for the exercise sessions was calculated for each child. The optimal training intensity window was set at 60 - 80% MHR, which fullfills the recommendations of the American College of Sports Medicine (ACSM) (56). Children wore small, portable heart rate monitors (Polar Vantage X L ) or were taught to take their own pulse at the carotid artery to record heart rate during each exercise session. Heart rates were recorded every 10-15 minutes to ensure the children were exercising in their appropriate training zone. The training sessions had an emphasis on aerobic activities but anaerobic exercises were also included in each session. Activities included aerobic team sports such soccer, ultimate frisbee, dodge ball, hand ball, indoor floor hockey, and basketball. Anaerobic activities included interval running, obstacle courses, and circuit training with weights and sprint activities interspersed. Al l sessions were supervised by 2 - 4 volunteer instructors. Family members were also invited to observe and/or participate in all exercise sessions. 25 RESULTS Statistical reporting: Repeated measures (RM) results indicate an overall difference between the groups using observations from all testing sessions simultaneously. Contrast statistics (CS) results address differences at individual testing sessions. All statistical analyses included age and gender as covariates and hence all p-values are adjusted for these two factors. However, figures show unadjusted data, so as to provide an absolute look at all groups tested. Error bars shown in the figures represent ± 1 standard error. These bars should not be confused with 95% confidence intervals which represent approximately ± 2 standard errors. Significance testing was conducted with an alpha level of 0.05. Twelve Month Descriptive Study Twenty-two children volunteered for the study initially, two subjects (one cancer patient and a healthy control sibling) had to drop out of the study after two test sessions due to family re-location to another city. This resulted in ten pediatric cancer patients (Ca) 4 male, 6 female, mean age 13.0 years [range 9.7 to 15.6]) and ten healthy controls (He) 4 male, 6 female, mean age 12.6 years [range 9.6 to 16.1]). Demographics and anthropometric data are summarized in Table 1. Both height and weight (RM p=0.001) changed significantly over the testing period for both groups but there were no significant differences between the patient and healthy subjects in height, weight, or sum of skinfolds (SOS). Over the one year period, the patients grew on average, 3.0 cm but increased their SOS by 3 mm and the healthy children grew on average, 3.3 cm and decreased their SOS by 7.9 mm. Treatments varied depending on the type of the tumor, anatomical location and specific treatment protocols used in the clinical trials. The time from the last treatment to enrollment in the study was 7 months (range 2 to 11 months). Of the children who received radiation, 3 had cranial radiation, and 1 had radiation to the femur. When we excluded the one subject with extremely high levels of radiation, the mean was decreased to 19 Gy from 28.2 Gy. Patient treatment profiles are summarized in Table 2. 26 o CD 1 Q ZJ CO ro cu X T 3 C ro (D o c ro O LU • ! +" cu c ro ro O =3 CD C O O E ^ 0) E 0) ro C O II 1 k o . c o CO CO c\i ai E C N E C O C N =5 C O C D E CN E ^ C O O , L O £ • C N co cri C O LU CO, c CO CO N CU co E Q. ' 0*0) CU C D c CO a) 0 c co cn E CD < < h-co co °H L O C O in co T T « LO CO C O C O « m co co co <N m in cn m T T L O C O ™ L O T J " co C N <N m T T cvi n . L O cn in M-c CO CU LU E co D ) j?> E X o C N in L O co L O cn m co co m C N in co L O cn in L O C N L O C N L O cn cri c ro cu UJ E co O) cu 21 O CO CD T -C D L O C D ^ C O v -O C N N - T -L O C D O C N cn co r-- C N c n C D co S 0 0 C O C D C D 00 o T i -ed ci C D T -cn io ci C O T -c CO CU UJ E CO oo _ O E co E CD co CD < CD CO CD i CD > CD W o CO 3 CO I CO o CO 1= CO o 'c O) 'co • c o c CD s 03 CO CD C C CD ° i t CL 2 a) 27 Table 2. Patient Treatment Profile Sex Age Diagnosis Time/Last Dose (MKT) Surgery RT Chemo (yrs) Rx (mos) (mg/m2/Gy) (Gy) therapy 2 14 A L L 5 414A+ 18 Gy no 18 yes 1 9 A L L 4 75A no yes 1 15 A L L 2 285 A + 18 Gy yes 18 yes 2 15 Hodgkin's 11 175 A + 21 Gy yes 21 yes 2 14 Hodgkin's 11 300 A yes yes 2 9 Ewings Sarcoma 11 375 A +55.8 Gy yes 55.8 yes 2 13 Undiff. Sarcoma of Liver 8 300 A no yes 2 11 Osteonogenic Sarcoma 11 300 A yes yes 1 10 Plasma Cell Granuloma 8 yes yes 1 14 Burkitt's Lymphoma 7 75 A yes yes Mean 12.4 7.1 255 A 28.2 SD 2.41 3.3 122 18.5 1 = male, 2 = female, Dose (A/RT) = dosage of anthracyclines + radiation therapy, RT = radiation therapy, Gy = Grays, ALL = acute lymphoblastic leukemia 28 PHYSIOLOGICAL D A T A Pulmonary function There were no significant differences between the Ca and He subjects in spirometry measures over the one year test period. All measures demonstrate a steady increase over the year corresponding to an increase in age and size. The results are presented in Table 3 and Figures 1 and 2. Anaerobic Capacity There was a significant difference (RM p=0.009) in relative peak power (PP) (Watts/kg) over time between the two groups. However, the individual contrast (CS p=0.02) demonstrate a difference at time zero with the He attaining higher PP measures, but no significant differences were observed at subsequent time points. Total work changed significantly (RM p=0.012) over the test period for both groups, corresponding to the increase in height and weight over the year. The results are presented in Table 4 and Figures 3 through 5. Cardiorespiratory Fitness There were no significant differences over the one year time period in any of the maximal aerobic measures between the Ca and He subjects. There was a trend for the Ca to demonstrate lower observed values in all of the aerobic capacity measures initially but no significant differences were observed in the following time points. All children did satisfy criteria for maximal effort during all test sessions and there were no significant differences between groups in maximal heart rate or RER over all test sessions. Sa02 values were not significantly different in both groups. The patient group did demonstrate a small but steady increase in peak VO2 (a gain of 1.8 mr1-kg"1-min"1 over the one year test period) and workload (15.2 watts), whereas the He remained essentially the same in peak VO2 measures and increased their workload measures by only 6.2 watts over the one year. The results are presented in Table 5 and Figures 6 and 7. 29 Activity Journal All children were asked to keep a daily activity log noting how often, for how long, and how hard (Rating of Perceived Exertion - RPE), they exercised during the initial 3 month test period only. Six of the ten patients and seven of the ten control subjects completed the journal entries. This data was treated as descriptive information since not all children completed the journal information and some submitted incomplete data. However, the available data reveals the He group exercised more often and for much longer time periods but both groups had similar RPE scores. Also, the He subjects daily activity levels did not change over the course of the study but there was a trend for the Ca to increase their daily activity levels as the study continued. 30 o CD ro 0) •a c: ro i_ CD o £Z ro O o w 00 Q) h-tz o L U C O +" c ro CD E 1 * LL. -3 ro £ I I £ 5 -C O J D ro (D IX IO E CNJ E CD o <£ CD £ CN CD E C M E CD o £ cd CD LU CO co a) a. E 1,4; D) .E O < l -CN CN CO ci T - CN CO ci O C O C O o O C M cd d CO d 1 - CO CO ci O C O C O o cn co C N O CD co c\i o co co C N C D c ro CD LU E co > £ Ll_ ~ C O C N CD CN i n C N un C N i n C N C N C\i UO CN CO CN UO C N LU £ LL ^ un '. CD CO C O CN C N C N 3" C N <NcN CD C O CN ^ CO C N o> CD cri oo oo CD co C O c ca CD L U E co O > UL COLLI DL. 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E o J) c 1- CO . 5 O < h-1 L O oo • $ 5 CO CO T t oo CO CD CO CO C D L O C N L O ^ O L O T t Ti-en cri co L O oo co oo c CO CO UJ E CO CO o 0 _ CO CO a cn oo CO ci T - CD 00 ci T t L O 00 o O L O cd ci C D 00 CO ci T t L O C O O C N L O 00 ci T t L O CO d r- L O h~ ci T t CD ci c CO CO UJ E co 1 a) I coi L O T t cri T -o co cri cn T t cb T • T - C N co 00 C N T t C N cri i -00 CN CO T - 1 OO C N 00 v -T t CO CN 00 c CO CO UJ E co 1 o o j*c cu cu CD < cu co co l_ cu > CO &_ cu o 0-CO CU 0_ ^c CU cu @ CO O > cu I o o V CL co to - o Figure 3. Anaerobic Capacity - Absolute Peak Power Watts (mean +/- SE) 600.00 500.00 400.00 (0 C 300.00 (8 200.00 100.00 0.00 0 weeks •Ca •He 6 weeks 12 weeks 6 months 1 12 months Figure 4. Anaerobic Capacity - Relative Peak Power Watts/kg (mean +/- SE) 10.00 8.00 °» 6.00 w % 4.00 2.00 0.00 0 weeks 6 weeks 12 weeks 6 months 12 months Figure 5. Anaerobic Capacity • Total Work kJ (mean +/- SE) 12.00 i •Ca •He 0 weeks 6 weeks 12 weeks 6 months 12 months cn o cu CD IX E CM E CD o S 5 ^ CD ™ CM •5 CD I s- CM O I S - CM d CD CM O I s- CNJ d oo "sr d co co ID CM oo CM CO 1 X 1 L O CM I S - CM q L O GO T — CO CD <9 £ C D CD CD L O CD CD CD CO ^ CD CM CM cd ^ C D CM CM C D C O L O CO CM C D C O C O C O C D C O C D d CD 00 oS d o d CD d I S - C O I CD ' CO I O E CM E CD o CO CM CD C O C O d 00 CM d I s- CM d CD CM d CD CM d C O CD I s- q CM cd 00 CO I s- T — CO CM CO C D d CO CM d CO o d I s-C D L O Is-C N * cn co Lri M . C D C O CD CM L O 00 C D d I s-d L O CM CD CO LO 00 T J " L O d 00 C D -rj- CM| CD LU CO |co OJ o o < I-c ro CD LU E co CD ro CM o ro 0. c ro CD LU E co ro 4-* CL „ p % CO ff c 'E I51 c ro CD LU E co ro c CD > c ro CD LU E CO CD •4-* ro 1 l j c ro CD U J I E CO CD E 2 'c 35 Figure 7. Cardiorespiratory Fitness - Relative Peak Oxygen Uptake ml/kg/min (mean +/- SE) 45.00 40.00 , 35.00 30.00 g 25.00 £ a 1 a 20.00 15.00 10.00 5.00 0.00 0 weeks 6 weeks 12 weeks 6 months 12 months 36 LITERATURE NORMS COMPARISONS A comparison of the (He) subjects based on aerobic measures by Krahenbuhl et al (57) and anaerobic measures by Blimkie et al (58) were also made to the age and combined sex values at the initial test time, for peak oxygen consumption (VO2) (L/min) and (ml" ^ g"1-min"1) peak anaerobic power (PP) (Watts/kg). The mean values for the He subjects in this study are not similar to published norms for VO2 (ml"1-kg"1-min"1) or (L/min) due to the large variation in this population. Peak power mean values for the He subjects were similar compared to published norms. Although not statistically significant, the He subjects are substantially different from normative values in the literature. When comparing the Ca subjects mean values to the above reported literature norms, a significant difference was seen in both aerobic measures but not in anaerobic power. The results are presented in Table 6a and b. Table 6a. Comparison of Observed Study Values for Healthy Children (at week 0) and Reported Literature Norms V0 2(L/min) V0 2 (ml kg"1 min"1) PP(Watts/kg) Observed+ 1.8(0.4) 34.4(5.7) Expected++ 2.31 45.25 p-value 0.23 0.09 8.6 (0.8) 8.90 .72 + Mean and standard error, ++ Mean value Table 6b. Comparison of Observed Study Values for Cancer Subjects (at week 0) and Reported Literature Norms V0 2(L/min) V0 2 (ml kg"1 min"1) PP(Watts/kg) Observed+ 1.6(0.42) 30.2(4.0) Expected++ 2.31 45.25 p-value 0.006 0.004 8.2(1.1) 8.90 .54 + Mean and standard error, ++ Mean value PSYCHOLOGICAL D A T A There were no significant differences between the (Ca) and (He) subjects in regards to all 9 domains in the psychological profile. However, not all children chose to answer each question so the number of subjects who completed all questions in that 37 CO O (U Ic? 13 CO ro cu X T 3 C CO 8 U J c CO CO , O ^ o £ & 8 3 E CO s —' CD i Ct _ T J CO ^ ~ L co _ —^< o c JZ o £^ CO CNJ Q_ T-_CD CO H E CM CO CM CM c i T— d o E CM CM T— CM 0) CD CM d CM d 0 Q E O CM T- CO o o CN T— CM d CM d o <J CO CM CM CM JZI -»—» < CO CM d CM d $ CM CM CM CM o CM d CM d E Is- CD CO CM T— d T— d ai E CD CO CO nc CD d d ro Q 0 o UO CM CJ) CO o CM d d < ro o o CO T- CO CO CO CD d T _ d Is- CM CD CM O d x— d E Is- CO CO CM T— d T— d 0 u c CD E CO CD CM ' CD T— d T— d Q /Om Lf) o CM d CM d o w ro o CD CD CM . c CD T— d T— d o CO Is- CM CO CM O d CM d c c ro ro 0 UJ 0 UJ ^ to ^ CO a(c; e(C] o X E CM CD O E CM 0 O c 0 -4—' 0 Ql E a n o CD O E CM o ^ CM CM O U O CO CM d CM d CM d CD CM T - d CO CM d CD CM d CO O CM CM d t - CM CM d CM CO CM d r - CM CM d CO CM CM d c ro 0 UJ ^ CO o ro o Is- CO r - 1 d CM CO CM d CO uo CM d un CM CO CM t - d CM CO CM d CD CO CM d Is- CM CM d Is- Is-CM d CM v -CN d CM CM CM d CO CM CM d CO CM CM d CM CM d c ro 0 UJ 2 CO o 0 E CM E CD CM CD o E CM o E CM E CD CM 5 CD o CO CM 1- d CD CO T-' d CO d un co i - d CD CD CM T - d CJ) CM d CM O CJ) CM T - d CD T-T - d c ro 0 LU ^ CO o ro o CO CM T - d O CM CM d Is- CM d CD CM ^" d un co d Is- CM ^' d O CO CM d CJ) Is-T-' d CD O d CD CM d CO CO d O CM CM d v - CM CM d O CM CM d c ro 0 LU ^ CO o 0 cz co o 'cz "to I cz o cz CD l_ CO CO CD o c .CO XJ Q . ZJ o O ) Figure 8. Psychology Measures - Scholastic Competence (mean +/- SE) 12 Month Study Time - 0 Weeks 4.0 -I jS 3.0 • Ca BHe 12 Month Study Time -12 Weeks 4.0 , 12 Month Study Time -12 Months 4.0 | 3.0 • Ca B He Figure 9. Psychology Measures - Athletic Competence (mean +/- SE) 12 Month Study Time - 0 Weeks 4.0 !S 3.0 • Ca lU He 12 Month Study Time -12 Weeks 4.0 § 3.0 o u w • Ca D He 40 particular domain are provided in the figures. Although repeated measures analysis demonstrates no significant differences between the two groups, contrast statistics do demonstrate a significant difference in scholastic competence at week 0 (CS p=0.03) and 12 (CS p=0.02) with the (He) subjects scoring higher, but are similar to the patient values at week 6, and 6 and 12 month test sessions. Athletic competence was not statistically different at any test point throughout the study. The results are presented in Table 7 and Figures 8 and 9. CARDIOLOGY D A T A Four of the children participating in the physiology testing were not involved in the cardiology testing due to entering the study one year prior to the other subjects. At this time cardiology measures had not been introduced into the testing protocol. This resulted in 7 patients and 9 controls for whom there is complete data. All repeated measures analyses were measured at the exercise 75% stage minus the rest/semisupine stage. Incomplete data at various stages occurred due to respiratory interference, pectoralis muscle hypertrophy, and/or small cardiac abnormalities such as mitral valve prolapse or aortic valve insufficiency. It proved very difficult to obtain consistent measures of posterior wall thickness during exercise, especially at the higher workloads due to increased body movement and respiratory artifact. The resting and exercise hemodynamic data are summarized in Appendix 4 and 5. Each subject exercised to a workload of 75% of their predetermined V02max and no subject experienced symptoms of chest pain, dizziness or significant arrhythmia in any of the test sessions. In the repeated measures analyses, no significant differences were observed in any of the cardiac measures between the Ca and He subjects at any test period throughout the study. While the magnitude of response may be reduced in the patients versus the healthy controls, the patterns of response to exercise are similar in all indices. There is a visible 41 trend observed in all of the measures with the He subjects consistently performing better than the Ca subjects. Resting supine versus resting semi-supine data. Doppler Cardiac index (CI), stroke index (SI), ejection fraction (EF), shortening fraction (FS), and mean aortic flow velocity (MAFV) all decreased, although not significantly, when the subject assumed a resting semi-supine posture from the resting supine position and heart rate (HR), blood pressure (BP) and ejection time (ET) all increased in both groups. Resting semi-supine, exercise and recovery data. At semi-supine rest, there were no significant differences in blood pressure or heart rate (Figure 10 a-d) between the He and Ca. Diastolic blood pressure did not change significantly with the increase in exercise workload in either group. The rise in (BP) and (HR) during exercise, although not significant, was higher in the He than the Ca subjects. Echocardiography Doppler changes during exercise In the patient group the left ventricular end-diastolic and end-systole dimensions indexed (LVEDI, LVESI) were not significantly different compared to the He subjects at rest and at the 75% exercise workload. The L V E D I was greater in the patients at all workloads and changed only minimally during exercise with a slight decrease noted at the 75% workload. The LVESI decreased considerably during exercise in both groups with values consistently being smaller in the healthy subjects. Doppler (CI) and fractional shortening, and are all initially reduced in magnitude in the Ca compared to the He subjects, with both groups demonstrating similar patterns of response to exercise, and all measures progressively increasing as the exercise workload increases (Figures 11 a-d and 12 a-d). Although not statistically significant there is a visible trend demonstrating that the Ca subjects perform consistently below the He subjects at all exercise workloads. However, by the one year test session, similar values are observed in all four of the above measures for the patient and control groups. Doppler mean aortic flow velocity and average ejection time were similar in both groups at rest and at the 75% exercise workload. Mean aortic flow velocity increased by 2 fold and average ejection time fell by 33% as exercise progressed. Stroke index (SI), demonstrated a large 42 increase during the initial 25% increase in workload, a leveling off by the 50% workload and a slight decline in SI by the 75% workload in both groups. The measurement of SI at the highest workloads proved to be a technically difficult measure to obtain due to respiratory interference. 43 Figure 10. Changes in Heart Rate during Rest, Excercise & Recovery in Cancer and Healthy Subjects (mean +/- SE) n=7 Ca, n=9 He 180.0 I 120.0 100.0 80.0 60.0 Heart Rate -12 Month Study Time = 0 Weeks / A >—Ca I — H e Rest, Rest, Ex -supine upright 25% Ex - Ex - Post - 1 Post - 3 50% 75% Min Min 44 Figure 10. Changes in Heart Rate during Rest, Excercise & Recovery in Cancer and Healthy Subjects (mean +/- SE) n=7 Ca, n=9 He Heart Rate -12 Month Study Time = 6 Months 180.0 -r 60.0 -I 1 1 • 1 1 1 1 Rest, Rest, Ex - Ex - Ex - Post - 1 Post - 3 supine upright 25% 50% 75% Min Min 45 Figure 11. Changes in Doppler Cardiac Index during Rest, Excercise & Recovery in Cancer and Healthy Subjects (mean +/- SE) n=7 Ca, n=9 He 0.00 Cardiac Index -12 Month Study Time = 0 Weeks Ca " — H e Rest, Rest, Ex- Ex- Ex-supine upright 25% 50% 75% Post - 1 Post - 3 Min Min 46 Figure 11. Changes in Doppler Cardiac Index during Rest, Excercise & Recovery in Cancer and Healthy Subjects (mean +/- SE) n=7 Ca, n=9 He Cardiac Index -12 Month Study Time = 6 Months 8.00 | 7.00 4 1.00 0.00 -\ 1 1 \ 1 1 1 Rest, Rest, Ex - Ex - Ex - Post - 1 Post - 3 supine upright 25% 50% 75% Min Min 47 Figure 12. Changes in Shortening Fraction during Rest, Excercise & Recovery in Cancer and Healthy Subjects, (mean +/- SE) n=7 Ca, n=9 He Shortening Fraction -12 Month Study Time = 0 Weeks 50.0 45.0 40.0 35.0 30.0 25.0 A 1 1 1 1 1 1 ' — C a l — H e Rest, Rest, Ex - Ex - Ex - Post - 1 Post - 3 supine upright 25% 50% 75% Min Min 48 Figure 12. Changes in Shortening Fraction during Rest, Excercise & Recovery in Cancer and Healthy Subjects, (mean +/- SE) n=7 Ca, n=9 He Shortening Fraction -12 Month Study Time = 6 Months 50.0 -, 45.0 4 25.0 -I 1 1 1 1 1 1 Rest, Rest, Ex - Ex - Ex - Post -1 Post - 3 supine upright 25% 50% 75% Min Min 49 Twelve Week Training Study Statistical reporting: Repeated measures (RM) results indicate an overall difference between the groups using observations from all testing sessions simultaneously. Contrast statistics (CS) results address differences at individual testing sessions. All statistical analyses included age and gender as covariates and hence all p-values are adjusted for these two factors. However, figures show unadjusted data, so as to provide an absolute look at all groups tested. Error bars shown in the figures represent ± 1 standard error. These bars should not be confused with 95% confidence intervals which represent approximately ± 2 standard errors. Significance testing was conducted with an alpha level of 0.05. Seventy-four children volunteered for the study, one subject had to withdraw due to time constraints; a second withdrew after tearing two knee ligaments in a school soccer game; and two of the patients who started in the exercise program (1.5 weeks) had to switch to the control group when their parents were unable to provide transportation to the fitness facility. This resulted in 18 pediatric patients and 52 healthy controls. The subjects were not randomized but were divided into four groups based on their availability to enter into the exercise rehabilitation program. The four groups and the mean age (years) of each group are: Cancer Controls (Ca(C) n=8; 10.6 yrs); Cancer Exercisers (Ca(Ex) n=10; 11.8 yrs), Healthy Controls (He(C) n=14; 14.0 yrs); and Healthy Exercisers (He(Ex) n=38; 14.6 yrs). All anthropometric measures of height, weight, and SOS ( R M p=0.001) changed significantly over the testing period for all groups. There were significant differences (RM p=0.01) between the Ca(Ex) and He(Ex) subjects in height. Weight was not significant with R M analyses but CS demonstrate all three test times to be significantly different for the He(Ex) versus the Ca(Ex). Sum of skinfolds (SOS) were not significantly different for either R M or CS comparisons. When looking at the data it is obvious that the patients are younger, smaller and lighter than the healthy controls. In the statistical analyses, the 50 difference in groups was accounted for by using age and gender as covariates. The results are summarized in Table 8. Treatments varied depending on the type of the tumor, anatomical location and specific treatment protocols used in the clinical trials. The mean age at diagnosis was 6.4 years (range 2.5 to 8.3) and the time since completion of their treatments was 5.3 years (range 1 to 10 years). Of those who received radiation, 4 had cranial, 2 abdominal, and 2 bowel and ovaries. When looking at the two cancer groups separately, the Ca(C) had 2 subjects who had radiation (1 at 10.8 Gy and 1 at 48.6 Gy both to the ovaries and bowel), mean of 29.7 Gy, and 4 were treated with anthracyclines with a mean of 135 mg/m2, the Ca(Ex) had 6 subjects treated with radiation with a mean of 17.2 Gy and 5 were treated with anthracyclines with a mean of 263 mg/m2. Cancer treatment regimens and chemotherapeutic therapies are summarized in Tables 9 and 10. 51 00 O CU Jz? ZJ CO >» ro cu x TJ C ro cu o £Z ro O <*— ° Cu § co I + ro g ro £ O o TJ ZJ Q_ CO ro ^ E ^ 3s 00 ro X I 0 0 co |o .of o d c o C M CO C D C D CO CD • CJ CD C M CD L O CD~ O ) - d cd L O C M C D C O IS-1^  L L . CO~ C M ^ d C M C M C D C D ' d d [co -CM C D LU CO c 0) CO N 0 co E cu CD c CO C L ' • 3 +- +-O CD 0 , i - CD cn o< < CO 0 0 * £ CM * C D C M § CM-C D C M C D L O T - CM C D L O T— C D d ™ C O L O CM ' . L O C O L O C O d T L O -sr o C M CM d * •^r CM d ^ C O C M c CO 0 LU E CO C D j» E X o C O * IS- IS-C D C M L O L O L O C O C O L O L O C O CO C O cd C D C O C O C O C O CM C O C O CJ) C M CM C O C O C O c CO 0 LU E co D ) 0 C O C D C O L O co C O L O CJ) L O C D C D C O C D C D C D C D L O uri L O . o L O C D C D CJ) C O C O c CO 0 LU E co CO _ o I co E CD CD CD CD O) < CD O) CD > CO to XJ O cz C O ZJ CO CO o CO CM co 2XL CD CD o o-LU LO CO ~Jo O O to > CD I CZ CD CD 5 LO o d v C L to > X X LU LU CD X cz CD CD 5 CD fl3 .2> o) CD 'CD LO o d v C L or O 52 Table 9. Patient Treatment Profile Sex Age (yrs) Diagnosis Time/Last Dose (A/RT) Surgery RT Chemo at Study Rx (mos) (mg/m2/Gy) (Gy) 2 11 A L L 84 100 A no yes 2 14 A L L 120 no yes 1 7 A L L 24 150 A no 18 yes 2 12 A L L 36 B M T yes 1 13 A M L 108 240 A+18 Gy B M T 18 yes 1 9 Wilm's 12 yes yes 2 13 Wilm's 60 yes yes 2 11 Hodgkin's 36 175 A yes yes 1 11 NBO 108 10.5 Gy yes 10.5 yes 1 12.5 RMS 72 28 Gy yes 28 yes 2 11 A L L 72 390 A + 18 no 18 yes Gy 2 10 A L L 60 100 A no yes 1 12 A L L 72 75 A no yes 2 11 A L L 48 no yes 2 9 Wilm's 84 360 A + 10.8 yes 10.8 yes Gy 1 10 Wilm's 72 265 A + 10.8 yes 10.8 yes 2 9 Wilm's 42 yes yes 2 9.5 RMS 48 48.6 Gy yes 48.6 yes Mean 10.8 64.2 206.1 20.3 SD 1.8 29.9 115.1 14.5 1 = male,;2 = female; A L L = acute lymphoblastic leukemia; A M L = acute myeloblasts leukemia; NBO = neuroblastoma; RMS = rhabdomyosarcoma; Dose (A/RT) = dosage of anthracyclines + radiation therapy; Gy = Grays; B M T = bone marrow transplant. Table 10. Chemotherapeutic Therapies Profile for both the Twelve Month and Twelve Week Study Treatments Received Males Females (n=ll) (n=17) Actinomycin 2 3 Mean dose (mg/m2) 175 210 Adriamycin 3 9 Mean dose (mg/m2) 175 265 Daunomycin 3 4 Mean dose (mg/m2) 251 212 Bleomycin 3 Mean dose (mg/m2) 310 Cisplatinum 1 1 Cyclophosphamide 8 8 Procarbazine 3 Vinblastine 3 Vincristine 11 15 VP 16 3 3 Prednisone 2 8 L-Asparingase 5 7 Methotrexate 6 8 6MP 3 5 A R A - C 7 4 6TG 3 3 Dexamethosone 1 Carboplatinum 1 1 C-ASP 1 5 A Z A 1 D-ASP 1 54 PHYSIOLOGICAL D A T A Pulmonary Function There was a significant difference (RM p=0.031) for FVC between the Ca(Ex) and He(Ex) over all 3 test sessions, with the He(Ex) have consistently higher values. F E V i and M W did not demonstrate a R M significance but CS do reveal differences between the Ca(Ex) and He(Ex) group comparison at specific but inconsistent time points. F E V i was different at the initial test point but not week 6 and 12. M W was different at all three test times and F E V i / F V C was different at week 6 and 12 but not initially. There were no R M significance for F E V i / F V C for the Ca(C) and He(C) change over time but CS demonstrate a significant difference at week 6 and 12. These differences correspond to the differences in size between the He(Ex) versus the Ca(Ex) and the He(C) versus the Ca(C) subjects. All other spirometry measure demonstrated nonsignificant differences between the patient and healthy control subjects. Although the figures look significantly different, after adjusting for age and sex the repeated measures group comparisons demonstrate no significant differences. These results suggest that all groups demonstrated the same pattern of change over the twelve weeks (except for FVC) and that the training program itself had no effect on pulmonary measures. The results are presented in Table 11 and Figures 13 and 14. Anaerobic Capacity There was a significant difference (RM p=0.03) in total work and peak power (watts) (RM p=0.02) between the Ca(Ex) and He(Ex) groups, with the He(Ex) having greater values at all 3 time points. These absolute differences correspond to the differences in size between the He(Ex) versus the Ca(Ex). Peak power (Watts/kg) did demonstrate a R M significance (RM p=004) with CS demonstrating a difference at week 12 only. The pattern observed by week twelve in both of the cancer groups was a decrease in relative PP from week six, whereas both of the healthy groups increased slightly. The results are presented in Table 12 and Figures 15 through 17. 55 Cardiorespiratory Fitness There was a significant difference in workload (Watts) (RM p=0.04) and absolute peak V 0 2 (L/min) (RM p=0.05) between the Ca(Ex) and He(Ex), with the He(Ex) having greater values at all 3 time points but not for any other group comparison. Again these absolute differences correspond to the differences in size between the He(Ex) versus the Ca(Ex). Both the Ca(Ex) and the He(Ex) demonstrated a small increase in relative peak VO2 (mr,kg"1-min"1) (Ca(Ex) = 3.1 and He(Ex) =1.3 mr 'kg'min"' increase) measures over the 3 month period, although it was not significant. The Ca(C) and He(C) remained unchanged over the same 3 month period. All groups demonstrated a small but steady increase in ventilation, heart rate, total time and workload over the test sessions. There were no differences in maximal heart rate, RER or Sa0 2 values between the groups in any test sessions. The results are presented in Table 13 and Figures 18 and 19. Subset of Healthy Control Data Due to the differences in age and sex between the two patient groups and the two healthy control groups, a subset of the data, from the two healthy control groups, was rank ordered and matched by age and sex to the patient data. There again, were no significant differences found for any of the physiological measures in this subset of data. Due to this finding, the original group data will be used to demonstrate all further results in this study Activity Journal All children were asked to keep a daily activity log noting how often, for how long, and how hard (Rating of Perceived Exertion) (RPE) they exercised during the 3 month test period. Six Ca(C), 3 Ca(Ex), 6 Ffe(C), and 26 He(Ex) completed the journal entries. Since the data is incomplete with the Ca(Ex) only averaging complete data for 5 of the 12 weeks, the Ca(C) averaging complete data for 8 weeks and the He(C) and He(Ex) completing data entry for 11 of the weeks, the results are inconclusive. 56 CD l o l x CO IO IO IO oo CO CD T f CN CD CN CO O T f *— CD O T f CN CD O 2. CO CO CN CO d co CD CD d LU a) CD C N CO CO <D a. 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C L o V o o V V o > LL LU O "ro aT O X tf) CO > > i n o d V CD ro C L O O o o C L C L C L X UJ aT X tfl > UJ 'ro' o g CO CO w Qi O O O 57 Figure 13. Forced Vital Capacity - FVC (mean +/- SE) 4.50 4.00 3.50 f 3.00 CO 2.50 9 s 2.oo r 1.50 1.00 f 0.50 0.00 - - A 4 0 weeks 6 weeks Ca(C) * - Ca(Ex) -He(C) He(Ex) 12 weeks Figure 14. Forced Expiratory Volume in One Second FEV, (mean +/- SE) (0 2.00 0.50 0.00 Spflpg* m mttnam - . - - - - - - - - A T A 1 1 • • — Ca(C) * - Ca(Ex) « — H e ( C ) He(Ex) 0 weeks 6 weeks 12 weeks CD I X l o CD I X CO I O IO CO IO CO <~-C O to C M co C M CO d ^" * ' CD o CM C D d , CO CD C M C O d C O ^ C D CD d CD N Ito CO 0 ^ 0 UJ £ CO c CO 0 E CO CO C M CO CO C D C M ai d L O L O CJ) L O d d C O d CM L O co d O CD co d C D -tf d CM C M cd d C O L O i< d c CO 0 LU E CO I f l CL ^ 8 | CL * O 00 d * O 00 d L O C M C O C M C M C O C O CJ) C D d CM CJ) d o o L O L O d L O d o Is-L O d c CO 0 LU E co o ro o CD CD CO CD O ) LO LO < O O CD ° ° O ) V V CO O 59 Figure 15. Anaerobic Capacity - Absolute Peak Power Watts (mean +/- SE) 700.00 600.00 500.00 J2 400.00 I 300.00 200.00 100.00 0.00 0 weeks 6 weeks 1 wt 12 weeks Figure 16. Anaerobic Capacity - Relative Peak Power Watts/kg (mean +/- SE) OB "55 to 5 12.00 10.00 8.00 6.00 4.00 2.00 0.00 0 weeks jjjjjjj: + 6 weeks 12 weeks Figure 17. Anaerobic Capacity - Total Work kJ (mean +/- SE) 0 weeks 6 weeks 12 weeks IX oo C O co CM C O LO CM •Ic L O CM * N " CM C D C O C O C D C O 00 CO C M C M L O CM ° T - L O CM O LO ° ° . 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E |CP < I-c ro 0 LU E co ro 4—' C L 13 pi ro 0 0-c ro 0 LU E CO . c L* ro C L _ D c 5"S ro ^ ff £ c ro 0 LU E co c o ro = c c ro 0 LU E co 0 -»-» ro a: tr ro 0 E D J C ro 0 LU E CO 0 E I-£ E c ro 0 LU E co T J ro o - . 5 -S2 ro 5 61 Figure 18. Cardiorespiratory Fitness - Absolute Peak Oxygen Uptake l/min (mean+/-SE) 3.00 T m i 0.00 0 weeks 6 weeks 12 weeks Figure 19. Cardiorespiratory Fitness - Relative Peak Oxygen Uptake ml/kg/min (mean +/- SE) 45.00 1 40.00 35.00 i 30.00 f — -c E 25.00 4 O) =S 20.00 E 15.00 4 10.00 5.00 J 0.00 0 weeks 6 weeks 12 weeks 62 LITERATURE NORMS COMPARISONS A comparison of the healthy control subjects based on aerobic measures by Krahenbuhl et al (57) and anaerobic measures by Blimkie et al (58) were also made to the age and combined sex values at the initial test time, for peak oxygen consumption (VO2) (L/min) and (mr1-kg"1-min"1) peak anaerobic power (PP) (Watts/kg). The mean values, for all three above measures, for the He(Ex) in this study at age 14.6 years are significantly different from the published literature values and are significantly different for VO2 (ml" '•kg^-min"1) at age 14 years but not for the other 2 measures. Peak power values in the 14 year olds are not significantly different due to a large variance in the healthy control population. When the patient groups are compared to the literature norms for healthy children, there is a significant difference for both of the V 0 2 measures but not for anaerobic power. The results are presented in Table 14. Table 14. Comparison of Observed Study Values for Cancer Patients and Healthy Subjects (at week 0) versus Reported Literature Norms. Ca(C) Ca(Ex) He(C) He(Ex) n 8 10 14 38 age (years) 10.6 11_8 14J) 14.6 V02(L/min) Observed+ Expected-H-p-value 1.1 (0.2) 1.75 0.01* 1.2 (0.2) 2.06 0.02* 2.2 (0.2) 2.57 0.09 2.4 (0.1) 2.66 0.01* V0 2(ml kg"1 min1) Observed* Expected-H-p-value 31.7 (2.7) 46.5 0.001* 28.0 (3.2) 45.6 0.001* 40.0 (2.0) 44.7 0.04* 38.4(1.2) 44.4 0.001* PP(Watts/kg) Observed+ Expected-H-p-value 7.3 (0.5) 8.32 0.08 8.0 (0.6) 8.72 0.26 9.9 (0.5) 9.45 0.38 9.6 (0.2) 10.0 0.05* + Mean and standard error, Mean value-H-, * (p<0.05) 63 TRAINING P R O G R A M The American College of Sports Medicine (ACSM) training guidelines (56) were followed throughout the program with the aerobic exercise programs running 3x/week for 12 weeks. The attrition rate for this study was extremely low with only 2 children having to leave the study due to time constraints or injury at school. Along with this, there was an 88% compliancy rate (attended 32 of 36 sessions) for the He(Ex) and 78% for the Ca(Ex) (attended 28 of 36 sessions) for attending the exercise sessions. Heart rates were monitored every 15 minutes either manually at the carotid artery by the children themselves or staff personnel or by use of a polar heart rate monitor to ensure adequate training intensity. The target zone was between 70% to 85% of the maximum exercise heart rate for all healthy children and started at 60% for the first 3 weeks for the cancer patients before moving up into the 70% to 85% range. Cancer patients are often deconditioned and can benefit from lower intensities (20% to 60% of maximum heart rate) which may not be as threatening or fatiguing (169). Other clinical populations, such as cardiac rehabilitation, programs begin the first 2-3 weeks at intensities of 60% before progressing to 70-80% of maximal heart rate (30). Measured exercise heart rates averaged 162 ± 6 bpm (78% of Max HR) in the He(Ex) group (mean age 14.6 yrs) for the entire 12 week study period. The Ca(Ex) average HR was 140 + 8 bpm (67% Max HR) in the Ca(Ex) group for the first 3 weeks of the study and then increased to 160 + 7 bpm (76% of Max HR) for the last 9 weeks of the study. It did prove difficult to motivate the children, especially those under 10 years old, to maintain the desired heart rate intensity throughout the intended duration of the program on any particular day (i.e. 30-45 minutes of continuous exercise). The older children were able to maintain the desired heart rate throughout the day's program using circuit training, treadmills, bicycles, stairmasters and weight training machines. 64 P S Y C H O L O G Y D A T A Only 6 psychological domains were used in this study due to the younger children, the Ca(C) and Ca(Ex), were too young to answer the adolescent questionnaire which included questions on job competence, romantic appeal and close friendship. Not all children chose to answer each question and so the number completing all questions in that particular domain are provided in the figures. All 6 psychological variables demonstrated a significant change over the 3 month testing period (RM p=0.001 to 0.021) (Table 15) but there were no overall consistent patterns of observation in all domains. There was a significant difference (RM p=0.03) in the mean scholastic competency scores between the Ca(C) and the He(C) groups and the Ca(Ex) and He(Ex) groups with CS demonstrating differences at 0 and 6 weeks but not by 12 weeks in either group, with the two patient groups scoring consistently higher than the two healthy groups throughout all test sessions (Figure 20). Self-worth demonstrated a significant difference (RM p=0.001) between the Ca(C) and He(C) group with CS demonstrating differences only initially at time zero but not at weeks 6 and 12 with the Ca(C) scoring higher. Social acceptance demonstrated a significant difference (RM p=0.049) between the Ca(C) and the Ca(Ex) group with CS demonstrating differences initially, with the Ca(C) scoring higher, but there were no significant differences by week 6 or 12. Athletic competence demonstrated a significant difference (RM p=0.002) between the Ca(C) and the He(C) group with CS demonstrating differences at week 6 and 12 and was almost significant at time zero (CS p=0.058). The Ca(Ex) and He(Ex) group demonstrated a significant difference at 0 and 6 weeks but not by 12 weeks (Figure 21). The two patient groups scored consistently higher on athletic competence than the healthy controls at all 3 time points. Both groups are within normative ranges (albeit often the low end of the average range) developed by Harter (52). 65 LO <D J Q CO I— cu o c £ I1 o O o "•4—' 0) 5 CU CM T — o c ro Q ce o CD < ro o o co o cu o c cu Q E o O o -4—' CO ro CD CM x ° ci O CM CM d T - CM CM d CD CM CM d CO T -CM d CO CM T - d T - CM CM d CM CM CM d c ro CU UJ 2 CO o ro O O CM CM O CM d co CM d CD CM x • d CO h- CM T - d CD CM T - d CM CM O CO CM CM d c ro 0 LU ^ CO LU ro O CO CM x • d Is- CM x • d CD CM d CD CM x • d co LO CD CO c ro 0 LU S CO O 0 X LO CD T - d CO CO CO CD T - d c ro 0 LU ^ co X LU 0 X CM O 0, > ml > "d" CM T - d CM LO CM T - d LO CM d CD CO T - d O CM CM d I— CO CO c ro 0 LU 2 CO O ro O ^ d CD co T - d CD CO T - d O CO CM d O T -CM d CO CM CM d CM CM d c ro 0 LU ^ CO X LU ro O •^ r CM T - d L O CM d CM CM CM O CM T -CM O O CM CM O 00 CO q CM CM d c ro 0 LU ^ CO O 0 X CD CO CD T -d O T -CM d O T -CM d CM O CM O c ro 0 LU ^ CO X LU 0 X co C D CD CD C O C O CD CD © "x" LU aT X io > "x1 UJ aT O T J cz CD C M co o ^ ^ CD CD CD <1> > © LU "QT X co > LU CD o T J C CD So CD J£ 25 o @ S o CD CD © LU 03 TO" - 1 -o £ co _ > O o o £ o 3 <= E J O CD O -«=> O CD CO CO cz CD CD 03 J 3 CD O cz CD 8 5 " o < o 2 03 o ^ o S= CO < CD J D CD O CZ CD ^» CD C L O O O O M— w m m m oooo oooo V V V V C L C L C L C L C0 CO CO CO o o o o 66 Figure 20. Psychology Measures - Scholastic Competence (mean +/- SE) 4.0 S 3.0 o o co ra 12 Week Study Time-0 Weeks 2.0 -1.0 J "1 n = 8 rt = 9 Ca(Ex) vs Ca(C) p= ns Ca(C)vsHe(C) p= 0.018 Ca(Ex) vs He(Ex) p= 0.002 n = 14 n = 33 ICa(C) ICa(Ex) IHe(C) IHe(Ex) 4.0 a 3.0 0 o to c ra 1 2.0 1.0 12 Week Study Time-6 Weeks n = 8 ICa(C) n = 8 • Ca(Ex) Ca(Ex) vs Ca(C) p= ns Ca(C) vs He(C) p= 0.005 Ca(Ex) vs He(Ex) p= 0.012 n = 14 IHe(C) n = 34 • He(Ex) 12 Week Study Time -12 Weeks Ca(Ex) vs Ca(C) p= ns Ca(C) vs He(C) p= ns Ca(Ex) vs He(Ex) p= ns | 3.0 -• Ca(C) BCa(Ex) BHe(C) • He(Ex) 6 7 Figure 21. Psychology Measures - Athletic Competence (mean +/- SE) 12 Week Study Time - 0 Weeks 4.0 , Ca(Ex) vs Ca(C) p= ns Ca(C)vsHe(C) p= 0.058 Ca(Ex) vs He(Ex) p= 0.010 3.0 CO • Ca(C) BCa(Ex) BHe(C) BHe(Ex) 12 Week Study Time - 6 Weeks Ca(Ex) vs Ca(C) p= ns Ca(C) vs He(C) p= 0.014 Ca(Ex) vs He(Ex) p= 0.029 jS 3.0 BCa(C) BCa(Ex) BHe(C) BHe(Ex) 12 Week Study Time -12 Weeks 4.0 <8 3.0 c | 2.0 1.0 Ca(Ex) vs Ca(C) p= ns Ca(C) vs He(C) p= 0.037 Ca(Ex) vs He(Ex) p= 0.073 i i n = 7 ICa(C) n = 8 • C a ( E x ) n = 11 BHe(C) n = 36 IHe(Ex) 68 CARDIOLOGY D A T A All repeated measures analysis was measured at the (exercise 75%) stage minus the (rest/semi-supine) stage. Incomplete data at various stages occurred due to respiratory interference, pectoralis muscle hypertrophy, and/or small cardiac abnormalities such as mitral valve prolapse or aortic valve insufficiency. The resting and exercise hemodynamic data are summarized in Appendix 6-9. Each subject exercised to a workload of 75% of their predetermined V 0 2 m a x and no subject experienced symptoms of chest pain, dizziness or significant arrhythmia in any of the test sessions. It proved very difficult to obtain consistent measures of posterior wall thickness during exercise, especially at the higher workloads due to increased body movement and respiratory artifact. No significant differences (RM p<0.05) were observed in any of the cardiac measures between the patient and healthy groups at any test period throughout the study. While the magnitude of response may be reduced in the patients versus the healthy controls, the patterns of response to exercise are similar in all indices except for differences observed in stroke index. There is a visible trend observed in all of the measures with the (He) subjects consistently performing better than the (Ca) subjects. Resting supine versus resting semi-supine data. Doppler Cardiac index (CI), stroke index (SI), ejection fraction (EF), and mean aortic flow velocity (MAFV) all decreased substantially when the subject assumed a resting semi-supine posture from the resting supine position in all four groups. There was an inconsistent pattern with shortening fraction (FS) which either remained the same or increased slightly in both the Ca(C) and He(C) groups but decreased in the Ca(Ex) and He(Ex). Heart rate (HR), blood pressure (BP) and ejection time (ET) all increased in all four groups. 69 Resting semi-supine, exercise and recovery data. During semi-supine rest, there were no significant differences in blood pressure or heart rate between any of the four groups. The rise in systolic blood pressure (BP) and heart rate (HR) (Figure 22 a-b) during exercise, although not significant, was higher in the He(C) and He(Ex) groups than the Ca(C) and Ca(Ex) groups. Diastolic blood pressure did not change significantly with the increase in exercise workload in any of the four groups. Similar patterns of decline back to baseline values were observed for all groups. Echocardiography Doppler changes during exercise In the patient groups the left ventricular end-diastolic and end-systole dimensions indexed (LVEDI, LVESI) were not significantly different compared to the He(C) and He(Ex) at rest and at the 75% exercise workload. The L V E D I was greater in the patients at all workloads and changed only minimally during exercise with a slight decrease observed at the 75% exercise workload. The LVESI decreased considerably during exercise in all groups with values consistently being smaller in the healthy controls. Doppler Cardiac Index (CI) is similar at rest in all four groups (mean of 2.8 1/min/m2) but is reduced in magnitude in the two patient groups at the 75% workload (Ca(C) - 5.3; Ca(Ex) - 5.7 1/min/m2) compared to the healthy control groups (He(C) - 6.3; He(Ex) - 6.7 1/min/m2). All groups demonstrate similar patterns of response to exercise, with CI progressively increasing with the increase in workload. (Figure 23 a-b). Fractional shortening is similar at rest (mean 33 ± 2%) and at the 75% workload (mean 40 ± 2%) in all four groups and demonstrates a progressive increase with the increase in workload in both the He(C) and He(Ex) groups. The Ca(C) and Ca(Ex) start out with a variable pattern of response to exercise at week 0 but by week 12 they follow a similar pattern of response at all stages of exercise except for an unexplained anomaly of a sharp increase at the 50% workload observed in the Ca(C) (Figure 24 a-b). Doppler mean aortic flow velocity and average ejection time were similar in both groups at rest and at the 75% exercise workload. Mean aortic flow velocity increased by 2 fold and average ejection time fell by 33% as exercise progressed. Stroke index (SI), although not significant, 70 demonstrated inconsistent patterns at various stages of exercise amongst the healthy and patient groups. The measurement of SI at the highest workloads proved to be a technically difficult measure to obtain due to respiratory interference and the differences between the groups could be due to measurement error. Figure 22. Change in Heart Rate during Rest, Exercise & Recovery in Cancer and Healthy Subjects -12 Week Study (mean +/- SE) Heart Rate -12 Week Study Time • 0 Weeks 180.0 T Rest, Rest, Ex- Ex- Ex- Post- Post-supine upright 25% 50% 75% 1min 3min Heart Rate -12 Week Study Time = 12 Weeks 180.0 T Rest, Rest, Ex- Ex- Ex- Post- Post-supine upright 25% 50% 75% 1min 3min Figure 23. Change in Doppler Cardiac Index during Rest, Exercise & Recovery in Cancer and Healthy Subjects -12 Week Study (mean +/- SE) Figure 24. Change in Shortening Fraction during Rest, Exercise & Recovery in Cancer and Healthy Subjects -12 Week Study (mean +/- SE) 74 DISCUSSION The initial descriptive studies from this laboratory found that children treated for cancer had significant deficiencies in their aerobic and anaerobic capacities. These children were studied on average 3.4 years after completion of their therapies. The purpose of the twelve month study was to describe the physiological and psychological recovery patterns in children recently treated for cancer and the aim of the twelve week study was to introduce a supervised rehabilitative exercise program as a form of intervention. In both the twelve month and the twelve week studies the results show no significant differences between the cancer patients and the healthy controls in the physiology, psychology, or cardiology measures. Although it was non-significant, the patients in the twelve month study tended to start at lower values in all measures but within six weeks demonstrated similar values to their healthy controls. In the twelve week training study there were initial differences between all four groups which remained throughout the study in all physiological measures. The He(Ex) and Ca(Ex) self-selected into the exercise groups and as these two groups already tended to exercise, their rate of change when adding an exercise rehabilitation program remained unchanged over the twelve weeks. In this study, there were visible trends demonstrating that the two cancer groups consistently performed below both the healthy groups in all physiological measures. Absolute measures of F V C , anaerobic PP (Watts) and workload and aerobic peak VO2 (l/min) and workload were significantly different at all three test points for the Ca(Ex) and He(Ex) group comparison only. These absolute differences correspond to the differences observed in height and weight between the two groups. The results of both studies are in contrast to the following five studies that do evaluate the respiratory status and exercise capacity of children surviving childhood cancer. Miller et al., (59) studied 29 survivors of acute lymphoblastic leukemia (ALL) and/or solid tumors, the age at diagnosis was 3.7 years, with the mean interval since completion of therapy being 2.9 years. Twenty of the patients had received radiation therapy with 5 of those receiving thoracic radiation ranging from 15 to 60 Gy. They found 75 48% of the subjects had some abnormality of pulmonary function testing, indicative of a restrictive pattern (1). They noted two trends in their study, namely that those patients diagnosed at younger than 3 years of age and those patients who received thoracic radiation demonstrated the highest incidence of PFT abnormalities. Shaw et al., (22) looked at 26 adult and children survivors of A L L who had completed treatment on average of 6.8 years prior to entering the study and whose mean age at diagnosis was 5.9 years. The mean chemotherapeutic and radiation dosages were not given, although the authors note that in the treatment of A L L , most notably methotrexate (which has well-recorded pulmonary toxicity) is used frequently for treatment in these patients. When assessing the patients respiratory status they found that 65% had one or more abnormalities for vital capacity (VC), total lung capacity (TLC), and residual volume (RV). In the twelve month study there were no significant differences between the healthy subjects and patients who had recently finished treatment for a malignancy for all pulmonary measures. In the twelve week training study the pulmonary measures demonstrate inconsistent patterns of differences between groups for contrast comparisons. The repeated measures significance was observed only for FVC and not for any other pulmonary measure. The intervention of the exercise program in this study seemed to have little effect on pulmonary function measures. Kadota et al., (23) studied twelve patients who had been treated for Ffodgkin's lymphoma, in which all children were treated with thoracic (mantle) irradiation, mean dose of 35 Gy with or without chemotherapy. The patients ranged in age from 6-16 years at the time of diagnosis, were tested 9.8 years after their last treatment. Results of their study showed a pattern of restrictive lung disease in 5 of the 12 patients, reduced exercise times and decreased maximal oxygen uptake in 9 of 12 long-term surviving patients. In a study by Jenny et al., (24) 70 survivors of A L L and 146 age and sex matched control subjects, ages (6-30 years) were tested for spirometry and exercise capacity. The median age at diagnosis was 5.8 years and the time since completion of chemotherapy was 4.2 years. They found a significant reduction in F E V i , F V C , TLC and transfer for carbon monoxide (DLCO) again identifying a restrictive impairment of lung function. There was a mild but significant reduction of both maximal and submaximal indices of exercise capacity. The 76 authors concluded the observed changes were due to the treatment for the disease, specifically the irradiation and chemotherapeutic agents that are used to treat patients with A L L . Pihkala et al., (25) studied 30 patients aged 8 to 25 years treated for pediatric malignancy who had received chest irradiation (RT) ± chemotherapy. The mean interval since RT was 7 years. The median RT dose for mediastinum and/or lungs was 25 Gy (range 10 to 51 Gy). The median cumulative dose of anthracyclines was 250 mg/m2 (range 0 to 480 mg/m2). Both the mean maximum workload and maximum oxygen consumption were < 80% of predicted values in 11 of 30 patients. The lack of significance between survivors of childhood cancer and healthy controls, for physiological parameters in both studies, may be due to a number of factors. The above mentioned studies tested children who were very young at the age of diagnosis; the age ranges were different from those in this study - most combined adult with child or adolescent data; the population of survivors differed with most studies focusing on A L L or Hodgkin's lymphoma patients who received intensive treatments for their cancer; the time since diagnosis was many years prior to their study taking place; and there was a lack of control groups in which to compare data. In the twelve month study, the mean age at diagnosis was 11.8 years (range 9.1 to 15.5) and the time since completion of therapy was only 7 months. In the twelve week study the mean age at diagnosis was 6.4 years (range 2.5 to 8.3) and the time since completion of their treatments was 5.3 years (range 1 to 10 years). Many of the other studies examined children who were younger than 5 years old at the time of diagnosis. Miller et al. (59) suggests that it is possible that in the younger children, the insult from various forms of therapy may have caused more damage to the rapidly growing lungs of the younger patients. Also, the time since completion of therapy may be a significant factor as pointed out by Lipshultz et al (13). The longer the time from the completion of therapy, the increased potential for greater damage to appear. The mean dosage of anthracycline (255 mg/m2 -12 mos study; 206 mg/m2 -12 week study) and radiation therapy ( 28.2 Gy - 12 mos study; 20.3 Gy - 12 week study) are not considered to be in the toxic range, however, two patients did receive abdominal radiation in the twelve week study, no one received thoracic radiation. Documented cardiotoxic levels occur with anthracycline dosages at or above 450 mg/m2 and pulmonary toxicity occurs 77 with radiation dosages at or above 30 Gy (60). The last significant difference between studies is the fact that only 1 of the 5 previously mentioned studies used a control group with which to make comparisons. Both healthy and patient controls have been included for valid comparisons in this study. The results may have been affected by recruiting controls who were unusually unfit. Comparison of the healthy control values for aerobic and anaerobic capacity to those expected based on the age and sex specific values reported by Krahenbuhl et al (57) and Blimkie et al (58) reveal that in the twelve month study the measures of VO2 (l/min), V 0 2 (ml'-kg'-min"1) and Peak Power (watts/kg) were all not significantly different from the literature values. However, when examining the mean values for each measure it is obvious that there is a substantial difference in both the absolute and relative aerobic measures, with the healthy control data in this study, having values much lower than the reported literature norms. The reason for not attaining a significant difference was due to the large variability in the control data. The control subjects were recruited by asking the cancer patient to bring along a friend or sibling with them to all test sessions. It is possible that the friends or siblings of the patient, shared their exercise habits, and so both groups were not as physically active as other children of the same age and sex. When comparing this data to earlier studies done in this lab (61) in which a significant difference was found between the patient and controls in both aerobic an anaerobic capacity, the present patient data is very similar in mean age at the time of the study and in aerobic and anaerobic measures. However, the healthy control data is significantly lower than previous laboratory findings in both aerobic and anaerobic capacity. When comparing the patient aerobic measures to the literature norms there is a statistically significant difference between the two means for both absolute and relative oxygen uptake. It is clear that the healthy control data in the present studies is not representative of literature norms. In another related study in this lab (62), children who had juvenile rheumatoid arthritis were studied for fitness measures in which the same control recruitment protocol was utilized. They found that their control population had significantly lower aerobic (VO2) (ml"1-kg'1min'1) measures compared to the same literature norms by Krahenbuhl et al (57). Perhaps recruiting control data in this manner is not the ideal method but in the 78 above mentioned study by Jenney et al (24), they used the same control population recruitment protocol and did report a significant difference between their patients and controls in pulmonary function and exercise capacity. The advantage of recruiting controls as friends or siblings of the patient is the camaraderie and motivation observed amongst them during test sessions. It also helped to ensure adherence to the study. Also, the groups are then similarly matched for socioeconomic status and psychological background. When comparing the 12 week data to the literature norms by Krahenbuhl (57), there was a significant difference between the healthy control means for the He(Ex) in regards to both the absolute and relative oxygen uptake and for the He(C) in relative oxygen uptake only. When comparing both patient groups, Ca(C) and Ca(Ex) to the same literature norms, there was a significant difference again in both the absolute and relative measures of aerobic capacity. It is clear that patient values for aerobic fitness are significantly lower than healthy control literature norms. It has been difficult to compare the 12 week study of patient and control data to other studies in the literature due to the differences in mean ages and the fact that this study combined the male and female data. In this study the Ca(C) were 10.6 years old and the Ca(Ex) were 11.8 years, whereas in the study by McKenzie et al (61), their mean age was 12.1 years for the females and 13.9 years for the males. There are no other studies that have used the same population, age range or exercise protocol to make further comparisons. The anaerobic capacity measures that were studied did not demonstrate a significant difference between groups in either the twelve month or twelve week study. These tests are not dependent on oxygen delivery and therefore are not affected by the organ damage previously described. Deficiencies observed are peripheral in nature and will result in poor muscular strength and endurance and are caused by muscle atrophy and deconditioning. When comparing the twelve month healthy control values to those expected based on age and sex specific values reported in the literature by Blimkie et al (58) there was not a significant difference between the control data in this study and the published norms. In the twelve week study there was a significant difference for the He(Ex) but not for the He(C) group, again the difference is due to the large variance seen 79 in the He(C) subjects. When comparing the two cancer populations, Ca(C) and Ca(Ex), to the literature norms there was no significant difference in either the twelve month or twelve week study. This again could be due to the large variance seen in the cancer groups or the fact that musculoskeletal problems are not limiting the patients' exercise tolerance. In the training program, only one-quarter of the exercises were anaerobic in nature and thus provided too little of a training stimulus to demonstrate significant changes in anaerobic test measures. Another possibility for the nonsignificance found between groups, is the small number of patients studied and the possibility of a selection bias in the study. It is possible that the patients who agreed to participate in the study were relatively fit, whereas the less fit patients refused to enter the study. Even though recruitment letters were sent out to all eligible participants, only 26% agreed to participate and it is possible that only children and their parents who were interested in exercise and its rehabilitative benefits entered the study. Patients who were very sedentary and had even more intensive therapies may have been under represented because of child and/or parental reluctance to enter the study due to fear and/or over-protection by the parents. This is in contrast to work done by Sharkey et al (63) who reported that their cancer patient self-selection may have been biased towards the more severely affected subjects entering their study, hence resulting in findings opposite to this study. None of the aforementioned studies have examined deconditioning as a factor in the exercise response. Rehabilitation studies with adults who have survived cancer have found favorable results after a training period (19, 144, 145). The only study to examine the effects of a supervised rehabilitation program in pediatric survivors of malignancy was done by Sharkey et al., (63). They studied 10 patients who were all childhood survivors of cancer, all were postpubertal, and the average age was 19 ± 3 years. They found significant reductions in spirometry measures of F E V I and FVC, total exercise time, peak oxygen uptake and ventilatory anaerobic threshold, with mild reductions in peak heart rate and cardiac index at baseline measures. Al l 10 patients participated in a 12 week, twice weekly, hospital-based rehabilitation exercise program. The post-conditioning data demonstrated that there was no significant change in spirometry measures or cardiac 8 0 index, but total exercise time increased an average of 13% with a trend toward improvement in peak oxygen uptake and ventilatory anaerobic threshold. They concluded that deconditioning explained part, but not all of the abnormalities observed in surviving patients of childhood cancer. Their study differs from the twelve week training study in many ways. The mean age of the cancer patients in their study was 19 + 3 years with the time at diagnosis being 8 ± 4 years, whereas in the present study the Ca(Ex) mean age was 11.8 (0.6) years and time at diagnosis was 6.4 ± 2.4 years. The time since completion of treatment in this study was 5.3 years, while theirs was 8 to 10 years. Al l of the children in their study were treated with a mean cumulative anthracycline dosage of 349 ± 69 mg/m2 and 9 of 10 received radiation (range 18 to 55 Gy). In this study, only 5 of 19 received anthracyclines with a mean cumulative dosage of 206 mg/m2 and 12 of 18 patients in our study received radiation therapy with a mean of 20 Gy (range 10 to 48.6 Gy). The other primary difference was the lack of a control group for comparison of training effects. They based their findings solely on pre- and post-rehabilitation results of the patient population and past studies of normal values from their laboratory. Without the use of control groups for comparison it makes their study difficult to compare to the present findings. If direct comparisons to the literature norms were made without utilizing control groups in the twelve week study, there would have been a significant difference in aerobic capacity. Neither study found a change in spirometery or cardiac measures over the 12 week training period but their post-rehabilitation results did show an increase in total exercise time with a trend toward increasing oxygen uptake. There was also a trend, although non-significant, to increase oxygen uptake in the Ca(Ex) group in this study. The reason there was not a significant difference in pre to post-rehabilitation results in this study was due to the large variability in the Ca(Ex) population. When examining the raw data, 6 of the 10 patients in this study did increase their peak VO2 (mr'kg'1min"') by 2.1 mf'-kg'-min'1 or more (not surprisingly, these were the same subjects that attended most of the training sessions) but 4 subjects either leveled off or actually decreased. The individual improvements may have been masked by the averaging of the groups over a broad range of values. One of the four was found to have a recurrence of his cancer a few weeks after 81 the program finished, and this is the same subject whose scores all decreased by the end of the test sessions. The results of the exercise rehabilitation program did not demonstrate a significant difference in exercise tolerance after 12 weeks of training. In the past, there was considerable skepticism regarding the ability of children to improve maximal aerobic power with physical training before puberty (64). A suggested reason for such low trainability is that children are active even when not taking part in a regimented training program, so that a training program would add little to their fitness. Studies indicating that children do not sustain high-intensity exercise for periods of time sufficient to improve fitness weaken this argument. Gilliam et al. (65) showed that 6 to 7 year old boys and girls produced heart rates over 160 bpm for 21 and 9 min per day, respectively, and these higher rates typically came in intermittent bursts. They conclude that even moderately active children seldom exercise sufficiently to levels that would improve cardiovascular fitness. Although both cross-sectional and longitudinal studies show conflicting results in regards to the trainability of children, comprehensive reviews by Rowland (66) and Vaccaro and Mahon (67), conclude that when the aerobic training regimens conform to guidelines established for adults, prepubescent children are trainable. In adults, physiologic changes that accompany a properly designed training program can be assumed to result from the program itself. In contrast, growth and maturation are major factors to consider in any longitudinal study of children and adolescents (68). Training programs that would be expected to stimulate average improvements of 15-30% VC^max in young adults have typically produced increases in the range of only 5-10% in prepubertal children (69). In a review by Pate and Ward (70), they were able to find only 12 training studies in children under 13 years of age that met the criteria of proper experimental design with adequate training protocols and statistical analysis. Eight of the twelve studies showed a clear improvement in relative VC»2max in the experimental group. This increase averaged 10.4% (range 1.3-20.5%). The average increase in the control groups was 2.7% (range 3.3-9.9%). They concluded that 8 2 prepubescent boys can physiologically adapt to endurance exercise training, but to a lesser extent than post-pubescent boys. In a recent meta-analysis of exercise and VO^max in children 13 years and under by Payne and Morrow (71), they conclude that with a pretest-posttest design, the typical child demonstrates a VO^max increase of approximately 2.07 ml"1kg"1min"1. They suggest that the aerobic benefit of training is small-to-moderate for this age group and perhaps the chief training benefits should be to initiate activity behavior and lifestyle changes for children rather than seeking or expecting significant improvements in VChmax. In the twelve week study the mean increase was 3.1 mr1-kg"1min"1 in the Ca(Ex) subjects but only 1.3 mr1kg"1min"1 for the He(Ex). The Ca(Ex) did meet the average increase of 2.07 mf'-kg'1 •min" observed by the above meta-analysis. Also, all families were telephoned six months after the program finished and nine of the ten children were reported to be more active and had incorporated exercise into their daily routine more so than prior to the start of the exercise program. Katch (64) proposed the "trigger hypothesis" in which he suggests that there is a critical period toward the end of childhood that usually occurs during puberty. Prior to this critical period the effects of physical conditioning are minimal or nonexistent. This hypothesis assumes that for training adaptations to occur, certain physiological precursors must exist. A study by Borms (72) examined the time of peak height velocity (PHV) and its relationship to increases in aerobic capacity and found that improvements were small prior to P H V but significant thereafter. This study had both pre and postpubertal children in the training program and the difference in maturative ages and ability to increase aerobic capacity with training more than likely influenced the results. Most of the later studies with pediatric cardiac rehabilitation programs (30, 73, 74, 75) have shown beneficial results from participation in training programs. These studies have shown improvements in maximal aerobic capacity, increased treadmill time, increased ventilation, and increased cardiac output. In comparison to this study, they do have similar age ranges (7 to 17 years), they include various disease types, and similar training intensities of 60% to 80% of maximal heart rate, but very few have control groups, healthy and/or non-exercising cardiac controls. Without the use of control groups, it 83 makes direct comparison between studies hard to interpret the various findings. Again, if control groups were not used in this study and direct comparisons were made to the literature norms, there would have been a significant difference in aerobic capacity. Limitations to Training Studies: Rowland (66) points out that studies that have shown no improvement in V02max with training may have methodological design problems. Some of the weaknesses in these studies include: 1. a heterogeneous pediatric population, in regards to age, sex and activity status. Children with chronological versus maturational age differences are often included together in the same study. 2. attrition and compliance are often not addressed, resulting in only the highly motivated individuals being selected in the study. 3. adequate training guidelines are often not adhered to (i.e. inadequate duration, intensity, and frequency). 4. lack of improvement may be attributed to the athletic involvement of the subjects prior to the training programs and hence the pre-training VC^max are already high. Improvements in VC^max with endurance training in adults is inversely related to the level of aerobic fitness at the onset of training. Therefore, some studies may not show significance due to high initial levels of fitness. 5. studies either have no control groups or control groups that are not truly matched in regard to activity levels and seldom are levels of activity throughout the training program monitored by both groups. To address each of these concerns individually, the twelve week did try to match the patient and control groups the best we could considering the nature of the disease and its treatments. This was a heterogeneous pediatric population, in regards to gender, age, primary disease, extent of disease, and the multitudes of treatments received. It is obvious that there were confounding effects of different maturational ages. The age range and gender distribution in the twelve week study was Ca(Ex) 7.7 to 13.9 years, (5 M , 5F) and 84 He(Ex) 7.6 to 17.6 years, (21 M , 17 F). Age and gender were used as covariates in the statistical analysis because of this reason. The primary problem was both prepubertal and postpubertal children's results were treated together due to the small subject pool and hence the overall training effect may have been lost, if in fact, training changes for pre- and postpubertal children do occur. The identification of individual factors used in the treatment of cancer, which may be responsible for impairment of exercise capacity, is difficult because of the interaction of so many of the variables and the fact that they are rarely administered in isolation. The inclusion/exclusion criteria were based on some commonalties in the treatments received so as to establish some consistent baseline treatment requirements. Participation was restricted to those patients who had received intensive chemotherapy which had required hospitalization, as the hypothesis was that the general physical debilitation associated with chemotherapy, radiation, and a sedentary lifestyle may account for the observed physiological changes. The exercise program would therefore be of major interest to these children and their parents. Mechanical and neurological causes for poor exercise performance, and similarly, patients who had received agents with known side-effects of major organ dysfunction were excluded. Of these agents, Bleomycin is known to cause specific disorders of pulmonary function in larger dosages. Therefore, only patients with low dose Bleomycin were admitted to the study. The side-effects of anthracyclines on cardiac function is well known and therefore exclusion of those patients who have evidence of significant cardiac dysfunction associated with anthracycline dosages was necessary. Patients who had radiation therapy to the chest, due to the potential thoracic damage that has been identified with radiation therapy to this areas, were also excluded. Patients had to be able to perform all of the tests both cognitively and biomechanically and so the established age criteria was 7 years of age and over. To further match the patient and healthy groups by activity levels, the parents were asked to complete an activity questionnaire described by Bar-Or (41) in order to quantify the activity level of each subject. The patients and controls did not significantly differ in total number of hours reportedly engaged in physical activity at the beginning of the study, and all children were as active or more active than his/her friends or siblings. The natural 85 inclination of children is to be active and the questionnaire revealed that the cancer patients were as active as their controls at the beginning of the study. The attrition rate for this study was extremely low with only 2 children having to leave the study due to time constraints or injury at school. Along with this, there was an 88% compliancy rate for the He(Ex) (32 of 36 sessions) and 78% for the Ca(Ex) (28 of 36 sessions) for attending the exercise sessions. This rate compares favorably with results published in the literature (76), it has been argued that 80-85% is the maximum adherence rate to be expected for structured exercise programs, even in populations with good facilities and favorable attitudes towards exercise (77). The difference in number of days attending training sessions would have affected the results and hence another factor that may have contributed to the lack of difference observed between the two groups. The American College of Sports Medicine (ACSM) training guidelines (56) were followed throughout the program. The aerobic exercise programs ran 3x/week for 12 weeks and heart rates were monitored every 15 minutes to ensure adequate training intensity. The target zone was between 70% to 85% of the maximum exercise heart rate for all healthy children and started at 60% for the first 3 weeks for the cancer patients before moving up into the 70% to 85% range. Cancer patients are often deconditioned and can benefit from lower intensities (20% to 60% of maximum heart rate) which may not be as threatening or fatiguing (169). Other clinical populations, such as cardiac rehabilitation, programs begin the first 2-3 weeks at intensities of 60% before progressing to 70-80% of maximal heart rate (30). When examining the He(Ex) pre-training V02tnax they did not have high initial levels of fitness, in fact in comparison to the healthy normative data in the literature, the initial oxygen uptake values are low. Therefore the lack of improvement can not be attributed to the subjects high initial levels of fitness. However, the heterogeneity of the two healthy groups in regards to athletic ability was substantial. Healthy children and adolescents who volunteered for the study were highly motivated and committed to the research. Some of the subjects were competitive school athletes with high initial VC^max values and these did not change throughout the course of the study. Some subjects were active in physical education classes and some recreational activities but were not 86 competitive athletes. These differences in initial conditioning are a substantial limiting factor to finding an increase in aerobic capacity. Even though the obvious difference in activity levels was evident at the start of the study, the commitment to the School Boards who volunteered to participate in the research, and by the children and parents who volunteered, all subjects were retained throughout the length of the research. However, when an age and activity matched control subset group from the larger data was studied, there was still not a significant difference in aerobic, anaerobic or pulmonary function measures between the patients and the healthy control groups. 87 P S Y C H O L O G Y It is known that for healthy children, physical activity is psychologically beneficial, especially for the development of positive self-esteem (78, 79). In children who have survived cancer, normal participation in sports and recreational activity may be limited by central and peripheral impairment (61), or by apprehension on the part of the child or his/her parents, friends, teachers or health care providers who may prevent the child from participating in regular physical activity. Looking at the psychosocial health of these children is therefore an important aspect of acute and long-term survival. There were no significant differences between the patient and healthy control populations in either the twelve month or twelve week training studies in any of the psychological measures, nor were there any consistent patterns of observation in any of the groups. The observed differences between the groups are not significant, largely because there is so much variation within the subjects. However, the mean scores of all groups fall within a normal range, albeit often at the lower end of the average range, when compared to healthy norms developed by Harter (52). Consequently, for the majority of patients there may have been little room for improvement. It appears, that in this particular group of cancer patients, they are functioning with a healthy self concept. It is interesting that the two cancer groups scored consistently higher on athletic competence than the two healthy groups in the twelve week study. Even though they did have lower aerobic and anaerobic capacity measures, they perceived themselves to be doing well in their athletic pursuits: This could be another indicator of a self selected group of patients who were previously interested in exercise and its benefits, and who were relatively fit prior to beginning the study. One very important aspect of this study is the fact that a valid psychosocial instruments was used, whereas, several studies in cancer and cardiac rehabilitation failed to used any objective measures (63, 73, 74, 75). Most reports in the literature center around anecdotal reports from parents and children to report changes observed due to training programs. Hopefully, further studies in the area of rehabilitation with chronically ill populations, will use valid measures for comparison of populations. 8 8 Anecdotally, both the children and the parents of healthy and cancer patients in this study, reported that the training program made a significant difference in endurance, strength, self-esteem, and team building skills of the child. Both groups reported feeling more motivated toward physical activity in general and expressed their desire to continue exercising after the program. In particular, the patient training group expressed wishes to have the program continue throughout the year. They felt it was an essential component of the recovery process and should be made available to all children recovering from cancer. One interesting comment that was repeated often by the parents, was that their child was now starting to feel "whole" again. The surgeries and therapies had compartmentalized the child into specific body parts leaving the child feeling fragmented. The exercise program which provided both physical and social support for the children and their families, and the child was able to re-gain a sense of self. Perhaps this is the most important outcome of the program. Reports from the non-exercising, cancer control subjects in this study also expressed their improvement in self-esteem and increased physical activities in their lives. This is most likely due to the Hawthorne Effect as seen in earlier studies in our lab by McKenzie (61). The Hawthorne Effect is characterized by an awareness on the part of the subjects of special treatment created by artificial experimental conditions. So just by being a part of the study, the subject's behavior can be altered. As McKenzie states "the improvement reported is simply because we paid attention to these subjects, tested their functional capacities, explained the significance of these tests to the patients and their parents, and generally took an interest in these individuals." Sonstroem (78), points out that global self-esteem appears to be a relatively stable trait, and for significant changes to be seen, training programs must be longer in duration. He concludes, that pre-post designs of short duration seem incapable of either affecting or assessing permanent psychological growth. If self-esteem enhancement is hypothesized as an outcome of fitness changes, it should adhere to new A C S M guidelines (56), which recommend longer program durations of 15-20 weeks as minimum standards for obtaining the full benefit of training. Most clinical trials utilize 12 week studies and for comparison purposes this length of time was selected for the training program. 89 CARDIOLOGY Exercise can expose cardiovascular abnormalities not evident at rest and may be used to determine the adequacy of cardiac status. The degree of impairment to exercise and the assessment of interventions may be documented objectively by echocardiography. In both the twelve month and twelve week study there was not a significant difference between the patient and healthy control groups in any of the cardiac measures. There was a similar pattern of response to exercise, in most indices, but the patient groups were reduced in magnitude. This visible trend of patients performing below healthy control levels was evident throughout all measures. The lack of significance may be due to the large variability in the data, a small patient population and possible measurement error. Indices of myocardial contractility (LVFS, ET, M A F V ) demonstrated a continual improvement as exercise workload increased in all groups in both studies. At rest all indices were similar in both studies. Systolic blood pressure and heart rate response demonstrated normal patterns of increase with the increase in exercise workload in all groups. The maximal cardiac and stroke indices in these two studies was hard to compare to literature values since the subjects exercised in a semi-supine position and only to 75% of their predetermined V0 2max. However, Rowland et al (80) had a similar mean age and used a similar exercise testing protocol (except they exercised their subjects to maximal effort) when studying healthy controls and children with myocardial dysfunction. The reported resting value for CI (2.82 1/min/m2) in the healthy controls, observed in both the twelve month and twelve week studies, is reduced when compared to their study value of 3.65 1/min/m2. There was a 2 to 2.5 times increase in cardiac index from rest to 75% maximal oxygen uptake in all groups, in both studies, with similar patterns of response to exercise observed. Stroke volume response to exercise was similar to that described in the literature for healthy children and young adults for the twelve month study (80, 81, 82). A increase in stroke volume was noted early in exercise to the 25% maximal oxygen uptake level, and 90 then a leveling off in both groups as the workload progressed. Thereafter, little further increase in stroke volume was noted, and further increases of cardiac output were dependent on heart rate. However, in the twelve week study variable patterns of response to exercise and recovery were noted with inconsistent patterns observed. Difficulties measuring SI as exercise intensity increased were found, especially at the highest workload due to excessive upper body movement and respiratory interference. An increase in stroke volume appears to be the principal factor responsible for improvement in VO*2max with endurance training (83). There was not an increase in either V0 2max or stroke volume with training in this study, in either the healthy control or patient data. It has been suggested that the measurement of aortic root diameter represents the greatest potential source of error in cardiac output and stroke volume measurements by the Doppler technique since this value is squared to obtain aortic cross-sectional diameter (84, 85). An error of 1 mm in this measurement can be expected to produce variability as high as 10% in derived stroke volume. The best correlation and least variability for cardiac output, in children, were obtained using the aortic valve annulus diameter as reported by Morrow et al (86) (r = 0.94) and (r=0.98) by (87). The coefficient of variation for repeated estimations of aortic cross-sectional area from repeated measurements of aortic diameters was 4.3%, corresponding to a likely range of errors in aortic cross-sectional area (and hence stroke volume and cardiac output) of around + 9%. The same echocardiography technician performed all of the measurement in this study and a reliability test on repeated measures of aortic root diameter in this study were found to be within 2.7 to 6.4% for all measures. This range of error is in agreement with the literature (89, 90, 91, 92). Al l aortic root diameters, in this study, were measured at the aortic valve annulus and values were compared with published normal standards by Snider et al (88). Rowland et al (89) found coefficients of variation of 8.5% for stroke volume and 8.1% for cardiac output using Doppler echocardiography in adult men at maximal exercise. Nicolsi et al (90) found a 6.8% interobsever and 5.9% intraobserver variability when using Doppler. Meijboom et al (91) and Barron et al (92) have reported percentage errors of less than 5% for both intra-and interobserver variation using Doppler measures. Although the aortic diameter increases 2% to 3% when the upright position is assumed, 91 no further increase in aortic diameter have been shown to occur with exercise up to 80% of maximal oxygen consumption. Christie et al (93), points out that assuming that the aorta is circular in both postures, stroke volumes calculated with supine aortic diameter measurements will on average be 6% to 9% smaller than those calculated with upright diameter estimates. In this study the aortic root was measured in the supine position, and therefore could have stroke volume values that are 6% to 9% lower than those that would have been calculated the aortic root had been measured in the semi-supine position. Driscoll (94) reports that the other factor to take into account is the inherent variability of cardiac output with repeated measures is reported to be 10%. The combination of the measurement error at the aortic valve annulus and the inherent variability in cardiac output, implies that increases in excess of these variations must be demonstrated to prove a central training effect did occur. This increase in cardiac output was not found in the present study after a twelve week training program. Seear et al (55), agreed that the potential error in measuring cardiac output limited its usefulness. They proposed that aortic size would match the increasing cardiac output as the child grew thus maintaining a constant arotic flow velocity at all ages during resting conditions. They found the normal mean aortic flow velocity (MAFV) to be constant at 28.4 ± 4.8 cm/s. In both of the present studies in the semi-supine rest position, the M A F V was found to be within this range for all groups. The M A F V pattern of response to exercise was identical in all groups in both studies. A two fold increase in mean flow was consistently observed. One potential problem was the use of 2 minute intervals at the 25%, 50%, and 75% of V0 2max workloads when testing in the semi-supine position using echocardiography. The ideal test time would have been 3 minutes to ensure that indeed a steady state had been achieved at each increase in workload. When a pilot study was conducted with patient groups, the children were unable to sustain 3 minutes at 75%maxV02, in fact, 2 minute stages were difficult in many cases. Measurements were started at the one minute mark and were completed by 2 minutes thus allowing the child to proceed onto the next stage. Work by Donald et al (95) indicates that 2 minutes is an adequate time period for cardiac output to achieve a steady state. It is possible in this 92 study, that cardiac output values have not reached a steady state when recorded, thus affecting the maximal values recorded at each stage. The studies in the literature are quite varied in their results with a few finding subtle cardiac abnormalities and others observing very significant cardiac damage in children who have survived cancer. Both Weesner et al., (96) and Yeung et al., (97) studied long-term survivors of childhood cancer who underwent exercise echocardiography to evaluate the late anthracycline-induced cardiac toxicity. Both studies found normal cardiac function at rest and observed that patients who had not received anthracyclines had a greater increase in FS and Doppler aortic peak flow velocity than patients receiving anthracyclines. They found no significant differences in work performed, or increase in FIR or BP with exercise between the groups. They concluded that many of the children who had received anthracycline may have suffered subclinical myocardial damage. These studies are similar to both the twelve month and twelve week study in that the mean anthracycline dosages are relatively low and the mean time since completion of therapy is similar. The primary difference is the lack of a healthy control group in both of the literature studies in which to make comparisons to this study. In the twelve month study, FS is reduced in magnitude in the patients versus the healthy controls, with both groups demonstrating similar patterns of response to exercise. There was a visible trend demonstrating the increase in FS was less in the cancer patients than in the healthy controls until the twelve month test where FS values are similar in response. The reason for not attaining a significance difference is due to the very large variation in the patient data. In the twelve week study, FS is similar at rest and at the 75% workload in all four groups but the pattern of response to exercise varies between the patient and healthy controls initially but is similar by week twelve. The following three studies are in contrast to our research findings. Larsen et al., (98), reported the results of using exercise testing to assess patients before and after bone marrow transplantation. They found multiple abnormalities including an increase in systemic vascular resistance, and reductions in total exercise time, peak oxygen uptake, ventilatory anaerobic threshold, cardiac index and stroke volume index response to exercise, compared to healthy controls. This is similar to Johnson et al (99), who studied 93 patients treated for malignancy. They found a reduced oxygen uptake and maximal workload, smaller increases in cardiac index for submaximal exercise, and a blunted stroke index response were noted for the patients when compared to the healthy controls. Steinherz et al., (100) studied patients who had been treated for leukemia or a solid tumor and found the overall incidence of abnormal cardiac status was 21%. There was an increase of poor cardiac function with increased total cumulative dose of anthracyclines and also the length of follow-up, with increasing cardiomyopathy the later the follow-up examinations (i.e. 15% had cardiomyopathy at 4-9 years post-anthracycline, vs 47% of patients at 15-20 years post-anthracycline examination). They concluded that the incidence of abnormal cardiac function appears to increase with the length of follow-up, particularly in patients treated with higher total cumulative doses. These studies support the work of Lipshultz et al, (13) and Leandro et al, (101) who propose that the length of follow-up when entering the study may effect the results. Lipshultz et al., (13) studied long-term survivors of childhood leukemia on average of 6.4 years post treatment who had been treated with adriamycin. They found that 41% had a depressed FS and left ventricular function and/or afterload was abnormal in 58.7% of the subjects. They noted hypertrophy in association with reduced wall thickness and interstitial fibrosis in myocardial biopsy specimens from children treated with anthracyclines. They conclude that late-onset anthracycline-induced cardiac failure may be precipitated by the myocytes' inability to compensate adequately in accordance with the demand of growth or other cardiac stress. This was as a result of chronically elevated afterload owing largely to progressive thinning of the left ventricular wall with increasing age and growth, presumed secondary to myocyte loss during anthracycline therapy, all of which results in inadequate left ventricular mass and depressed left ventricular performance. The results from a study by Leandro et el. (101)_support this theory. They studied long-term childhood survivors of malignancy who had a mean time off chemotherapy of 7.2 years. They found left ventricular mass and mass index were significantly reduced, FS was decreased and end-systolic wall stress was much higher in the patients than the controls. They concluded that the results suggest a pattern consistent with a thin-walled, compliant left ventricle with reduced muscle mass performing under above-normal levels of wall stress. 94 One possible explanation for the differences observed in the aforementioned studies and the present two studies, is the amount of time since completion of therapy may significantly affect the results. Truesdell et al (102) reports this late decompensation observed may occur 10 to 14 years after completion of treatment. Studies, such as the two present ones, performed earlier after completion of therapy, may not find significant differences at this stage of growth of the heart. Lipshultz et al (13), identified four factors that appear to influence the frequency of cardiac abnormalities years after treatment with anthracyclines 1) cumulative dosage of anthracyclines, 2) mediastinal radiation, 3) age at diagnosis, 4) length of time since completion of therapy. The children in both of the present studies received less intensive dosages of anthracyclines, no mediastinal radiation, were older at the time of diagnosis in the twelve month study (means age of 11.8 years) but were younger in the twelve week study (mean age of 6.4 years), and the time since completion of therapies was 7 months in the twelve month study and 5.3 years in the twelve week study. It appears that our study population had very low identifiable risk factors that would predispose them to cardiac abnormalities. It would be interesting and very valuable information to follow these children for the next 8 to 10 years to see if decompensation does occur later in life. 95 C O N C L U S I O N From the results of these studies, there were no significant differences between the cancer patients and the healthy control groups in physiology, psychology, or cardiology measures in both the twelve month and twelve week studies. Visible trends were observed with the cancer patients consistently demonstrating lower performances in all physiological and cardiology measures. This is in contrast to few studies the literature. It has been suggested that the younger the child at diagnosis, the greater the cumulative dose of anthracyclines, treatment with mediastinal radiation, and time since completion of treatment is when entering the study, are four of the primary reasons for the differences in our studies. The children in these studies were older at diagnosis, had less intensive anthracycline dosages, no patient received mediastinal radiation as part of their therapy, and the time since completing treatment was relatively soon. Another significant finding was that the healthy controls in both studies were not representative of the aerobic normative data cited in the literature. It appears the healthy controls were relatively unfit and perhaps shared the same exercise habits as their friends or siblings, the cancer patients. When comparing the cancer patients, in both studies, to the literature norms, there was a significant difference in aerobic measures of V02max, but not for anaerobic measures. The other possibility, for not finding significance, is that there was a patient selection bias, in that only patients who were interested in exercise and its benefits, and who were relatively fit to begin with volunteered for the study. The less fit patients may have refused to be in the study, and/or fear and overprotection on the part of the child and/or his/her parent may have prevented the child from entering the study. Lipshultz et al (18) suggest that the progressive thinning of the left ventricular wall secondary to myocyte loss during anthracycline therapy, is unable to keep pace with the demands of somatic growth resulting in late-onset anthracycline-induced cardiac failure. This late decompensation may occur 10 to 14 years after treatment. This study was performed fairly recently after the completion of treatments in the patient groups and there may not have been sufficient damage detected yet at this early stage of growth in the 96 child's life. This study did however, establish a framework for assessing ventricular function in this population that will serve as a reliable measure of progressive decompensation if it is to occur in later years. It would appear that the majority of children and adolescent patients who were followed in this study are functioning remarkably well both physically and psychologically compared to their healthy controls. As survival rates continue to increase, so must the quality of life for these individuals. Cure of the malignancy, clearly of major importance, may not be a sufficient end point for determining protocol success. Exercise is often overlooked as a valuable component in the diagnosis and management of this disease. Exercise testing can contribute significantly to the clinical assessment and design of the rehabilitation program for this population. Regular exercise can provide physical as well as psychological benefits to the child. The longitudinal monitoring of the physical and emotional health of children once treatment for a malignancy is complete, provides a clear picture of the rate of recovery of the various systems and provides a complete look at the child. The rehabilitation program was fun, it provided social support and education for the child who has survived cancer and for the family. It helped to alleviate fears and concerns about the appropriate levels of exercise the child could engage in and gave the child a sense of feeling "whole" again. They were acting like normal children and adolescents in a supportive and safe environment. Exercise seems to be one of the easiest, least expensive and most applicable tools we have to offer cancer patients once treatment for the malignancy is complete and recovery is begun. 97 R E C O M M E N D A T I O N S 1. Begin the rehabilitation program during the treatment phase. Often children diagnosed with leukemia are treated for 2 to 3 years and become inactive during this time. A rehabilitation program during the maintenance phase of treatment would enable them to avoid the deconditioning that presents during this time. 2. Call all families who were sent letters of participation and either conduct interviews or group focus sessions to find out why their child was unable to participate in the exercise rehabilitation program. This would identify some of the barriers td exercise and provide more information for recruitment of subjects and providing increased access for all children. 3. Longitudinal studies that followed the children from recently out of treatment to 10 to 15 years post completion of therapies. This would give information regarding the rate and prevalence of decompensation that may occur in cardiac measures as the child increases somatic growth. 4. It would be important to add more diagnostic psychological assessments to the testing procedures to ensure a complete look at the child and family dynamics. 5. An interesting area to study would be the effects of the treatments for cancer on the skeletal muscle composition, physiology and response to therapies and rehabilitation interventions. This would give a complete look at central and peripheral limitations to the exercise response. 6. The use of functional outcome measures would further help in the assessment of damage from treatment arid the response to rehabilitation programs. 7. In this study we examined children who received less intensive therapies, it would be 98 useful to study children who had more intensive treatments. This would give a more complete look at the spectrum of treatment outcomes and responses to a exercise challenge test. 99 APPENDIX ONE - REVIEW OF LITERATURE The following areas are addressed in the review of the literature: the side effects of chemotherapy and radiation to the heart, lung and musculoskeletal systems; studies looking at the effects of cancer and its treatments; healthy training studies and the effects of exercise programs; outcomes of cardiac rehabilitation programs; the psychological research with chronically ill populations; and the use of echocardiography/Doppler measures to examine exercise parameters. Chemotherapy Attempts have been made to determine the short and long-term effects of radiation and chemotherapy on various organ systems. Clinical evidence suggests that the interaction between certain drugs and radiation therapy is synergistic (103, 104) but other data suggest the effects are additive, at least at low and moderate doses of the anthracyclines (105, 106). Regardless of the mode of interaction, it is clear that the use of cardiac radiation and Adriamycin (sequentially or concomitantly) increases the risk to the patient of developing cardiac disease following doses of each agent ordinarily considered safe (106, 107). The anthracycline antibiotics contains some of the most valuable antiumor agents, and one of them Adriamycin (Doxorubicin ™) has the broadest spectrum of activity of any available cancer chemotherapeutic agent. While it is one of the most powerful antitumor agents it is also the one which most commonly results in significant cardiotoxicity. Adriamycin cardiotoxicity affects 2 to 27% of patients receiving this drug and therefore presents a formidable clinical problem (8). Endomyocardial biopsy has been used to identify the characteristic myocardial lesion as a result of anthracycline therapy. It has been shown that there is a direct relationship between the amount of drug given and the amount of morphologic damage (9). The degree of morphological damage and the resulting myocardial dysfunction are also related, but in a more complex, parabolic, nonlinear fashion. This means that there is a "threshold" for the amount of damage that must occur 100 before clinical heart failure is observed (9). There appears to be a large range of variability among different subjects in the severity of morphologic damage per amount of drug administration. Because of this variability, some patients can safely receive more than the usual empirical limit of 450 to 550 mg/m2, but others may have to be limited at lower doses (10). Mediastinal radiation and other chemotherapeutic agents, including cyclophosphamide and ifosamide, may enhance the cardiotoxic effects of anthracyclines and potentially lower the critical cumulative anthracycline dose to approximately 350 to 400 mg/m2 (9, 103). Abnormalities noted may indicate impending cardiac failure include prolongation of the corrected QTc interval and a decreased fractional shortening and decreased ejection fraction by echocardiogram. The mechanism of action is not exactly known, but there are effects on the myocardial sarcolemma, mitochondrial function, nucleus, sarcoplasmic reticulum, and also the myofibrils. Anthracyclines may induce biochemical changes capable of producing significant cellular damage. These changes may be due to: 1) conversion of doxorubicin to a toxic metabolite; 2) interaction with cell membranes; 3) release of vasoactive substances; 4) changes in contractile protein; 5) generation of reactive oxygen radicals; and 6) immunological alterations (15). The clinical effects of these drugs can be divided into acute, subacute, and chronic (12). The acute symptoms closely follow a dose and can involve dysrhythmia, pericardial effusion, and acute decrease in contractility with resultant cardiac failure (12). The subacute clinical manifestations can occur from days to up to 2 years after the last dose, with a peak onset of cardiac failure at 1-3 months after cessation of therapy (108). The chronic effects of anthracyclines are more significant clinically and have been more thoroughly evaluated (8, 11, 12, 13). Over a period of time, ventricular dysfunction occurs on the basis of a myopathic insult to individual cells. This can present initially as right or left ventricular dysfunction, but usually ultimately leads to biventricular failure (9). The clinical presentation is that of congestive cardiomyopathy, with elevated filling pressures and decreased cardiac output. Occasionally, the clinical presentation may be one of a restrictive myopathic process presenting with a normal sized heart and low cardiac output; 101 these are usually cases in which a mixed etiology of Adriamycin cardiomyopathy and radiation-induced heart disease can be demonstrated (11). Clinical symptoms are often delayed several months after the last dose of the agent, because of the time necessary for the full exposure of the cytotoxic effects of the drug (14). Morphologically there are two main types of myocyte injury seen ultrastructurally in anthracycline cardiotoxicity (11). The first is myofibrillar loss within individual myocytes. Initially, the cell may be only partially affected, but then the whole cell shows myofibrillar loss, with only Z-band remnants remaining around the cell margin. The nuclei appear unaffected and are not enlarged. The mitochondria are seen to contain compact cristae, although they are often smaller than in the surrounding unaffected myocytes. The second type of myocyte injury show vacuolar degeneration and coalescence of the swollen sacrotubular system and are often referred to as "Adria cells". These changes also occur with preservation of the nucleus and the mitochondria. These two types of myocyte-degenerative change can be seen one at a time in any biopsy, or both types of change may be seen in the same biopsy. The ultimate effect of Adriamycin cardiotoxicity is diffuse myocardial fibrosis, however, heart failure often occurs before extensive fibrosis develops. Diffuse myocardial fibrosis can therefore be considered a common endpoint in both radiation and Adriamycin cardiomyopathy (109), but the pathway to fibrosis is different for each. In radiation, it occurs through endothelial damage, causing microvascular deficit and resulting in ischemia. The damage with Adriamycin occurs in myocytes that are eventually replaced by fibrous tissue (109). The long-term effects of anthracyclines are usually irreversible (102). As ventricular contractility diminishes, the ventricle dilates to maintain cardiac output. A heart with ventricular dilatation is unable to compensate further when metabolic demands increase. Since myocytes do not proliferate after age 6 months, all myocardial growth in childhood is a result of increased myocyte size. Anthracycline-induced myocyte death will, therefore, stimulate hypertrophy of other myocytes in order to generate (or maintain) a normal adult cardiac output (13). Lipshultz et al., (13) studied long-term survivors of 102 childhood leukemia evaluated 1-15 years (mean of 6.4 years post treatment) who had been treated with doxorubicin. They found that 41% had a depressed FS and left ventricular function and/or afterload was abnormal in 57 of 97 patients (58.7%). They noted hypertrophy in association with reduced wall thickness and interstitial fibrosis in myocardial biopsy specimens from children treated with anthracyclines. They conclude that late-onset anthracycline-induced cardiac failure may be precipitated by the myocytes' inability to compensate adequately in accordance with the demand of growth or other cardiac stress. This is as a result of chronically elevated afterload owing largely to progressive thinning of the left ventricular wall with increasing age and growth, presumed secondary to myocyte loss during anthracycline therapy, all of which results in inadequate left ventricular mass and depressed left ventricular performance. The results from a study by Leandro et el. (101) agree with Lipshultz (13). They studied 29 long-term childhood survivors of malignancy, with a mean age of 15 ± 4.3 years and who had a mean time off chemotherapy of 7.2 + 3.2 years, and 19 matched controls. Eighteen patients received only adriamycin therapy at a mean dose of 335 mg/m2 (range 200 to 490 mg/m2), 8 received combined anthracycline (mean dose 294 mg/m2) and radiation (mean dose 32 Gy) and 3 received radiation alone (mean dose 25 Gy). They used 2-dimensional echocardiography, doppler flow velocity, and radionuclide angiography to study systolic and diastolic functions at rest. They found that left ventricular mass and mass index were significantly reduced, fractional shortening was decreased and end-systolic wall stress was much higher in the patients than the controls. The stress-velocity index was also decreased in 6 of the 28 patients. They concluded that the results suggest a pattern consistent with a thin-walled, compliant left ventricle with reduced muscle mass performing under above-normal levels of wall stress Other recent studies to investigate the effects of anthracycline therapy in children treated for cancer include Weesner et al., (96) who studied twenty long-term survivors of childhood cancer who underwent exercise echocardiography to evaluate the late anthracycline-induced cardiac toxicity. Ten patients mean age of 14 years, who had received anthracyclines with a mean dose of 291 mg/m2 and were 7 years after treatment and ten patients mean age of 16 years, who had not received anthracycline as part of their 103 pharmaceutical regimen and were 8 years after treatment. Both groups had normal cardiac function at rest. Patients who had not received anthracyclines had a greater increase in M -mode shortening fraction (38 + 8% vs 52 + 11%), velocity of circumferential fiber shortening (1.5 + 0.5 vs 1.8 ± 0.5) and Doppler aortic peak flow velocity in comparison to patients receiving anthracyclines. There were no significant differences in work performed, or increase in heart rate or blood pressure with exercise between the groups. They suggest that there are a number of subtle abnormalities in myocardial function which become apparent only after exercise even in patients who are asymptomatic with normal resting cardiac function. In a study by Yeung et al., (97) twenty-nine children who had been treated for malignancies, underwent echocardiography measurements while exercising to exhaustion. Group A consisted of 19 patients with a mean age of 10.6 ± 4.3 years who had received anthracycline (mean total dose 230 + 119 mg/m2) as part of their chemotherapy, and group B of 10 patients with a mean age of 13.3 ± 4.9 years who had received other cytotoxic drugs, neither group had mediastinal irradiation. The time since completion of therapies ranged from 1 mo. to 72 mos. They measured heart rate, blood pressure, and left ventricular dimensions before and after exercise on a bicycle for a maximum of 10 minutes. Al l children showed normal fractional shortening (FS) at rest, but the increase in FS on exercise was significantly lower in the children who had received anthracyclines than in those who had not. However, there were no significant differences between the groups in heart rate, systolic or diastolic blood pressure at rest or exercise, and exercise times were similar between groups. They concluded that many of the children who had received anthracycline may have suffered subclinical myocardial damage. Lipshultz et al., (110) studied sixty-five patients who were evaluated with echocardiography 0 to 13 years (median 6.7 yrs) after they received 45 to 576 mg/m2 (median 319 mg/m2) of doxorubicin for acute leukemia in childhood. They measured FS and rate-adjusted velocity of circumferential fiber shortening as indexes of contractility and end systolic wall stress as an index of afterload. By comparing these measurements, they identified an abnormal relationship between the velocity of circumferential fiber shortening and end systolic wall stress, demonstrating abnormal cardiac function in 36 of 104 65 (55%) of their patients. In addition, there was a progressive increase in the afterload measurements in 13 of 16 of their patients studied serially, indicating deteriorating status. Steinherz et al., (100) studied 270 patients, ages 2-23 years of age, with a median of 10 years of age at the end of therapy, who were free from recurrence for 4 years (median of 8 years post-therapy) and had received > 200 mg/m2 (median of 435 mg/m2) of doxorubicin therapy. The patients had been treated for leukemia or a solid tumor. Al l patients had echocardiography performed at resting conditions. The overall incidence of abnormal cardiac status for the 270 patients was 21% (58/270). Thirty-four patients had mild cardiomyopathy (FS = 25-29%), 9 patients moderate (FS = 21-24%), and 15 patients had severe cardiomyopathy (FS = 11-20%). There was an increase of poor cardiac function with increased total cumulative dose of anthracyclines and also the length of follow-up, with increasing cardiomyopathy the later the follow-up examinations (i.e. 15% had cardiomyopathy at 4-9 years post-anthracycline, vs 47% of patients at 15-20 years post-anthracycline examination). They concluded that the incidence of abnormal cardiac function appears to increase with the length of follow-up, particularly in patients treated with higher total cumulative doses. Those patients with abnormal contractility on early testing, and especially those with early clinical symptoms, are at higher risk and may decompensate with longer follow-up. Silber et al., (111) studied 151 patients, the mean age during study was 15.5 ± 4.5 years, mean time since last treatment was 4.7 ± 4.0 years, and they were at least 1 month beyond their last does of anthracycline (mean dose of 307 mg/m2) and mean radiation dose to the heart (19.6 ± 8.65 Gy). They found that females were more likely to have abnormally low ejection fractions or cardiac indices than their male counterparts, after adjusting for cumulative dose of anthracycline and age at treatment. The authors give a few possible explanations as to why there is the observed difference between genders. One idea, is that females in their study were more "out of condition" than their male counterparts. Physical activity levels may have differed between the sexes both during and after cancer treatment, and therefore the girls performed lower than boys. Other possibilities are that the female heart may be more susceptible to cardiac damage from the anthracyclines or they may have a different metabolism or volume of distribution for 105 anthracyclines than males. They found postpubertal girls had an increased risk for cardiomyopathy versus girls prepubertal or under 12 years old. It has been shown that doxorubicin does not achieve high concentrations in fat and that obesity has been shown to slow the metabolism of doxorubicin (112). They speculate that if females with the same body surface area have more fat than males, and if anthracyclines do not distribute into fat, then equivalent meter-squared doses may lead to higher concentration of anthracycline in the hearts of females than males. Larsen et al., (98), reported the results of using exercise testing to assess 51 patients before and after bone marrow transplantation; whose mean age was 15 ± 4 years (range 7 to 32), mean survival time post-transplantation was 3.9 years and who had been treated with anthracyclines, mean of 282 ±106 mg/m2 (range 84 to 665 mg/m2). They found multiple abnormalities including an increase in systemic vascular resistance, and reductions in total exercise time, peak oxygen uptake, ventilatory anaerobic threshold, cardiac index response to exercise, and stroke volume index compared to healthy controls. Finally, Johnson et al (99), studied the effect of low-dose anthracycline therapy on the circulatory response to moderate exercise. They studied 13 patients, mean age 13+4 years, who had completed therapy 4.5 + 1.9 years (range 2 to 9 years) prior to the study, and 15 age-matched control subjects who completed maximal and subsequent submaximal exercise testing. The patients had a cumulative dose of anthracyclines of 292 + 119 mg/m2 (range 76-500 mg/m2). Results indicated that reduced oxygen uptake and maximal workload, smaller increases in cardiac index for submaximal exercise, and a blunted stroke index response were noted for the patients when compared to the healthy controls. Radiation Therapy Cardiac Effects The chronic adverse cardiac effects of radiation therapy (RT)have been the subject of study since the 1940's. Clinical conditions noted following RT include pericarditis with chronic effusion and pancarditis that includes myocardial fibrosis with or without endocardial fibroelastosis, cardiomyopathy, coronary artery disease (CAD), valvular injury, and conduction defects. The histological hallmark of these injuries is fibrosis in the interstitium with normal appearing myocytes and capillary and arterial narrowing (113). 106 Radiation-induced heart disease (T3JHD) is the spectrum of clinical and pathological alterations of the heart occurring after therapeutic mediastinal irradiation (113). Most RIHD patients have developed their disease after treatment for lymphomas (especially Hodgkin's disease). The morphologic alteration that occur in the heart and pericardium following exposure to ionizing radiation are closely dependent upon dose, irradiated volume, and time after exposure (114). With clinically evident radiation-induced heart disease (RIHD) the most common manifestation is pericardial disease (115). The parietal pericardium develops variable degrees of fibrosis that replaces the outer adipose tissue. There is always fibrinous exudate both on the surface of the pericardium facing the heart and in the stroma of the fibrotic pericardium. Injury to the myocardium is characterized by patches of diffuse fibrosis. These fibrotic patches vary in size but never occupy the entire myocardium (115). The fibrosis is made of a network of collagen fibers that separate individual myocytes or groups of myocytes. There are few data specific to the clinical effects of cardiac irradiation in children. Among 120 children treated at Stanford with greater than 40 Gy for Hodgkin's disease, 13% developed cardiac damage. (116). Another series of 28 children treated with 30 Gy (average dose) showed pericardial thickening in 43% but no functional abnormalities (117). Among 12 patients treated at the Mayo Clinic with 19.5 to 55 Gy (median dose 35 Gy) for Hodgkin's disease, 33% had abnormal echocardiography and 50% had abnormal exercise studies (23). In children treated for Hodgkin's with 55 Gy or more, 40% developed RIHD in a study done by Stewart et al., (114). The authors concluded that in children and adolescents treated for Hodgkin's disease, both the risk and severity of coronary heart disease appears to be higher and they may have a high prevalence of subclinical functional abnormalities Although often asymptomatic, such patients may have low cardiac reserve and may not tolerate cardiovascular stress (118, 119, 120). Adriamycin is also used to treat some patients with Hodgkin's disease and may have additive or synergistic cardiotoxicity in combination with radiotherapy. 107 Pulmonary Effects Both radiation therapy and chemotherapy can acutely and chronically affect lung function resulting in pneumonitis and pulmonary fibrosis. Radiation therapy appears to be the most important risk factor, especially with larger doses. The mechanism for respiratory damage in young children is different from that in the adult or adolescent. In the child, impairment by cytotoxic therapy of proliferation and maturation of alveoli can lead to chronic respiratory insufficiency. Inhibition of growth of the thoracic cage (i.e., muscle, cartilage, and bone) can limit chest-wall compliance, with resultant restrictive problems (121). Chemotherapeutic agents associated with pulmonary injury include bleomycin, carmustine, busulfan, cyclophosphamide, and methotrexate. The onset of side effects may be insidious, with symptoms developing from months to years after therapy. Bleomycin shows a slightly different mechanism, producing a decrease in pulmonary diffusion capacity which may be detected on pulmonary function tests while the patient is still receiving therapy. Restrictive pulmonary disease and arterial hypoxemia may also develop (121). Histologically, lesions in the lung due to irradiation are most likely present in all patients, even after very small doses of radiation (121). The effects of lethal radiation doses on the lung parenchyma become evident within weeks to months after exposure. There is exudation of proteinaceous material into the alveoli, leading to impairment of gas exchange. An infiltration of inflammatory cells and desquamation of epithelial cells from the alveolar wall occur (122). Soon the interstitial edema forms collagen fibrils which leads to thickening of the alveolar septa. These exudative changes may resolve in a few weeks to a few months. Clinically, acute pneumonitis usually occurs 1 to 3 months after the completion of radiation or drug therapy. During the period when clinical pneumonitis would occur, some radiologic abnormalities can be found in about 50% of all irradiated patients (123). No gross abnormalities in lung function usually occur before 4 to 8 weeks after completion of a course of RT. Restrictive changes gradually develop and progress with time (123). Restrictive patterns are generally found after RT or chemotherapy injury with reductions in the vital capacity, lung volumes, and total lung capacity. Combined 108 obstructive restrictive patterns may be seen in which lung volumes are reduced, but the fibrotic injury also reduces airway patency (23). Acute radiation pneumonitis can develop and is characterized by damage to the type II pneumocyte ,which produces surfactant and maintains patent alveoli, and to the endothelial cell. Changes in the surfactant system that lead to alterations in alveolar surface tension and low compliance are most likely to direct result of the radiation (124, 125) although it has been postulated that the change indirectly results from exudation of plasma proteins (126). Endothelial cell damage results in changes in perfusion and permeability of the vessel wall. In the first few days to weeks after irradiation, ultrastructural alterations in the capillary endothelial lining become evident. The cells become pleomorphic and vacuolated and may slough, thereby producing areas of denuded basement membrane and occlusion of the capillary lumen by debris and thrombi (123, 127). The late lung injury is characterized by progressive fibrosis of alveolar septa, which become thickened by bundles of elastic fibers. The alveoli collapse and are obliterated by connective tissue (128). With chemotherapeutic agents the mechanism of cell toxicity appears to include formation of free radicals and lipid peroxidation of phospholipid membranes. This may also be the mechanism by which cyclophosphamide and mitomycin damage the capillary endothelium (129). Permeability increases, resulting in interstitial edema. Thereafter, swelling and necrosis of type I pneumocytes occur with resulting fibrosis. Pneumonitis may insue and lead to the development of chronic pulmonary fibrosis that is characterized by the enhanced production and deposition of collagen and other matrix components (121). Musculoskeletal Effects There is little information on the pathophysiology of damage to growing muscle and bone by cytotoxic drugs. Direct damage to the developing musculoskeletal system from cytotoxic therapy is most often caused by irradiation during periods of rapid growth. Permanent damage may be produced by doses greater than 20 Gy but the results are more severe during periods of greater bone growth, (less than age 6 years or at puberty), (130). The cells most sensitive to irradiation appear to be the chondroblast, particularly the very 109 active ones in the epiphyseal plate, (131). Osteoblasts are damaged only by high doses of radiation, but radiation quickly increases vascularity of the bone, particularly in the metaphysis. The increased vascularity increases the resorption of bone, thereby increasing the porosity and demineralization of the immature metaphsis (132). The effect on bone growth is attributed to the loss of proliferating cells at the growth plate, the decreased ability of surviving cells to synthesize matrix, and/or the production of an abnormal matrix that fails to calcify (133). Progressively ischemic bone is susceptible to stress, and fractures may occur. Repair from trauma or infection is also limited resulting in poor healing of irradiated bone. Irradiation of the spine may lead to spinal shortening or kypho-scoliosis, short stature and increased susceptibility to fractures. Irradiation of lesions of the limbs, especially when coupled with chemotherapy, may result in severe deformities; orthopedic procedures may be required to correct discrepancies in limb length. In addition to direct skeletal effect cranial irradiation may also lead to growth retardation secondary to decreased production of growth hormone by the pituitary gland (130). The most common clinical presentation is radiation damage in the small vessels in muscles, preventing the full development of the muscle because of relative ischemia. Higher doses can give rise to atypical fibroblasts that lay down excessive fibrin in the tissues, causing fibrosis (132). Hypoplasia, or a diminished development of the muscle, is the most common late effect secondary to irradiation of developing muscle tissues. The muscles treated tend to be smaller and functionally not as strong as the patient's non-irradiated muscle tissues. The differences in strength are often not significant and for the majority of patients it is more of a cosmetic problem than a functional one. However, at times these tissues can develop marked fibrosis, which can produce stiffness, a decrease in range of motion of a joint, and pain (132). Late effects can involve any organ system. Findings may range from simple laboratory abnormalities to life-threatening complications. Table 16 classifies some of the late effects among long-term survivors of childhood cancer. 110 Table 16. Late Effects of Chemotherapy Drugs Potential Organ Damage Anthracyclines Doxorubicin (Adriamycin) Duanorubicin (Daunomycin) Actinomyocin Bleomycin Cyclophosphamide Isofosphamide Cisplantinum Cardiotoxicity Lungs - fibrosis, impaired diffusion capacity, Gonadal Damage - infertility, sterility, early menopause Bladder - hemorrhagic, cystitis, bladder cancer Kidney - renal tubular scarring Bone Marrow - secondary A M L Lungs - pulmonary fibrosis, loss of lung volume Cardiotoxicity Kidney - decreased glomerular filtration rate renal tubular scarring, total renal failure Ears - hearing loss Gonadal Damage Methotrexate Liver - hepatitis, hepatic fibrosis, cirrhosis Kidney - renal tubular scarring CNS - learning impairment Lung - pneumonitis Gastrointestinal - vasculitis with diffuse collagen deposition and fibrosis Osteoporosis, bone pain Vincrisitine Neurotoxicity - diminished reflexes foot drop, and muscle weakness Gonadal Damage - infertility, sterility Steroids Obesity, cataracts, osteoporosis increased susceptibility to fractures L-asparaginase Radiotherapy Liver toxicity Lungs - pneumonitis, pulmonary fibrosis Heart - pericarditis, RIHD, CHF Decelerated or decreased growth in bones, or in glands responsible for growth-related hormones Osteoporosis Gonadal damage - infertility, sterility CNS - learning disabilities A M L = Acute Myeloblastic Leukemia, RIHD= radiation-induced heart disease, CHF = congestive heart failure, CNS = central nervous system 111 Cancer Studies Exercise testing and training have now become an important tool in the evaluation and treatment of disease in children and adolescents. It can yield information on the functional severity and natural history of a disease. On the other hand, it can help assess the effects of such therapeutic interventions as a rehabilitation program. Bar-Or (16) states that children with a chronic illness often display a subnormal exercise capacity. This is a result of two main causes: 1) hypoactivity which leads to detraining and, 2) specific pathophysiological factors that limit one or more exercise-related functions. Disease or illness can directly induce hypoactivity. It is important to realize that a hypoactive, unfit child, often enters a vicious circle of further hypoactivity and detraining. This lack of physical activity places these children and adolescents at risk for early development of cardiovascular disease and other illnesses associated with hypoactivity. And it can also negatively affects their quality of life. In children treated with RT and chemotherapy exercise tolerance may be impaired. The mechanisms responsible for the exercise impairments are multifactorial. First, the disease process itself may involve specific pathological factors that limit exercise-related function (16). Secondly, the treatment protocols are complex and invasive and may take several years to complete. As new classes of drugs were synthesized or discovered, it was soon found that each had its own spectrum of toxicity's. Most shared myelosuppression, but organ-specific complications that are relatively drug-specific were soon identified (134). A third factor is a significant change in the level of physical activity during the course of the disease or treatment. Peripheral limitations due to muscle disuse, atrophy, and deconditioning could also contribute to the exercise impairment. Limited or restricted exercise prior to, during and following treatment may impair peripheral muscular and/or aerobic function, and the patient's and the family's residual fears surrounding the stress associated with exercise may also play important roles. Al l factors could potentially cause the following exercise limitations: a compromised cardiovascular system may be unable to deliver the oxygenated blood to the 112 exercising muscles; anemia may limit the oxygen-carrying capacity of the circulating blood; insufficient oxygenation resulting in low arterial oxygen content could also be caused by respiratory deficiencies, such as lung fibrosis; and abnormal muscle may be unable to process the delivered oxygen for energy production. Many cancer patients experience fatigue and an impairment of physical performance during the course of their illness. In fact, in several studies with adults, this problem affects up to 70% of cancer patients during chemotherapy and radiotherapy or after surgery (135, 136, 137). Furthermore, up to 30% of cancer survivors experience a loss of energy for years after cessation of treatment (136, 137). Besides affecting the individuals functional capacity it is also a significant contributor to decreased quality of life in cancer patients (138, 139). Fatigue has been linked to a number of factors, including nutritional status, sleep disturbances, biochemical changes secondary to disease and treatment, psychosocial factors and level of activity (140). How all of this may affect exercise tolerance in the cancer patient is not yet fully understood. Saltin et al., (141) states that bedrest and disuse, which frequently accompany cancer treatment, have been shown to cause many deleterious effects. These include a reduction in maximal oxygen consumption, elevation of resting heart rate, reduction in plasma volume, development of orthostatic hypotension, impaired lung volumes, psychological effects and various musculoskeletal impairments including muscular weakness and osteoporosis. These problems are exacerbated by adverse responses to surgery, radiotherapy, and chemotherapy. The final factor is the psychological impact of a chronic disease. This is significant and may influence the ability of the child to participate in recreational, leisure or school exercise programs. A disease such as cancer can drastically change a child's normal lifestyle (142). The child may no longer have the energy, or feel well enough to play as he or she used to. Exclusion from regular activities at school or with playmates may result in a decreased self-esteem and mental outlook on life, two attributes that are important in the recovery of any disease. Exercise programs provide children with an enjoyable social atmosphere as well as an improved physical well-being. 113 The following studies have investigated the potential late effects in groups of children who have survived a malignancy and its treatment. There are few studies evaluating the respiratory status of children surviving childhood cancer. Miller et al., (59) studied 29 survivors of acute lymphoblastic leukemia (ALL) and/or solid tumors The age at diagnosis in their study was 3.7 years, with the mean interval since completion of therapy being 2.9 years (range 1 to 12 years). Twenty of their patients had received radiation therapy with 5 of the 20 receiving thoracic radiation ranging from 15 to 60 Gy. They found 48% of the subjects had some abnormality of pulmonary function testing, which involved abnormal forced vital capacity (FVC) and/or total lung capacity (TLC), indicative of a restrictive pattern (1). They noted two trends in their study, namely that those patients diagnosed at younger than 3 years of age and those patients who received thoracic radiation demonstrated the highest incidence of pulmonary function abnormalities. They suggest it is possible that in the younger children, the insult of the various forms of therapy may have caused more damage to the rapidly growing lungs of the younger patients. Another potential problem is children who suffer acute respiratory problems early in life may proceed to have further respiratory problems as they get older (5). Shaw et al., (22) studied 26 adult and children survivors of A L L who had completed treatment on average of 6 .8 years prior to entering the study and whose mean age at diagnosis was 5.9 years. The mean chemotherapeutic and radiation dosages were not given, although the authors note that in the treatment of A L L , most notably methotrexate, which has well-recorded pulmonary toxicity, is used frequently for treatment in these patients. When assessing the patients respiratory status they found that 65% had one or more abnormalities for vital capacity (VC), total lung capacity (TLC), and residual volume (RV). They conclude that children who survive A L L have a high prevalence of abnormalities on pulmonary function testing, which are probably due to impairment of lung growth. Kadota et al., (23) studied twelve patients who had been treated for Hodgkin's lymphoma. Most of the children were treated with thoracic (mantle) irradiation, mean dose of 35 Gy (range 19.5 to 55 Gy), with or without chemotherapy. The patients ranged in age from 6-16 years at the time of diagnosis, were tested 9.8 years (range 7 to 12 years) 114 after their last treatment and ranged in age from 14 to 27 years old at the time of testing. All subjects had echocardiography and standard pulmonary function tests along with a maximal 3 minute incremental cycle protocol exercise test. Results of pulmonary function studies were normal in six patients. Restrictive lung disease (exemplified by a total lung capacity of 62 to 80% of the predicted value) was noted in 5 patients. All five had normal carbon monoxide diffusing capacities. Their results showed abnormal pulmonary function tests and reduced exercise times and maximal oxygen uptake in 9 of 12 long-term surviving patients. Echocardiography revealed abnormalities in 4 of the 12 patients which included thickened mitral valve cusps and the Doppler analysis revealed the presence of tricuspid insufficiency. None of the children had received Bleomycin or anthracyclines. Initially all patients but one were asymptomatic. In a study by Jenny et al., (24) 70 survivors of A L L and 146 age and sex matched control subjects , ages (6-30 years) were tested for spirometry and exercise capacity. The median age at diagnosis was 5.8 years (range 1.5 to 14.9) and the average time since completion of chemotherapy was 4.2 years (range 0.6 to 18.5). They found a significant reduction in F E V I , FVC, TLC and transfer for carbon monoxide (DLCO) identifying a restrictive impairment of lung function. There was a mild but significant reduction of both maximal and submaximal indices of exercise capacity. Ejection fraction and fractional shortening were significantly lower in patients treated for leukemia. The authors concluded the observed changes were due to the treatment for the disease, specifically the irradiation and chemotherapeutic agents. Pihkala et al., (25) studied 30 patients aged 8 to 25 years treated for pediatric malignancy who had received chest irradiation (RT) ± chemotherapy. The mean interval since RT was 7 (range, 2 to 13) years. The median RT dose for mediastinum and/or lungs was 25Gy (range, 10 to 51) Gy. The median cumulative dose of anthracyclines was 250 mg/m2 (range, 0 to 480) mg/m2. Cardiac function and exercise tolerance were elevated by electrocardiography, echocardiography, radionuclide cineangiography, and exercise test with gas exchange analysis. They found the patients differed from normal controls in systolic indices of myocardial function. In echocardiography, the left ventricular contractility was abnormal in 14/30 patients. In radionuclide cineangiography, the left 115 ventricular ejection fraction was subnormal in 6/30 patients, and in 9/30 patients the rise in ejection fraction during exercise was inadequate (<5%). In exercise testing, the mean maximum workload attained was 2.7+0.7 watts/kg and the mean maximum oxygen consumption was 35.4±9.7 ml/min/kg. Both variables were <80% of predicted values in 11 patients. The L V wall stress/afterload was elevated, i.e., >60g/cm2, in 5/30 patients (17%) and in 3/38 individuals (8%) in the control group. The mean wall stress was 50 ± 9 g/cm2 in the patients and 44 ± 9 g/cm2 in the control group. They concluded that the patients tested were clinically asymptomatic but had a high frequency of subnormal systolic myocardial function. Hovi et al., (143) evaluated the muscle strength of 43 young female childhood survivors of leukemia compared with 69 healthy age-matched women. Their mean age was 19 years (average 14 to 30 years old), and the women had been off therapy for 1 to 19 years (average 8 years). They measured maximal isometric strengths for elbow flexion, knee extension, and hand grip in a dynamometer chair. Dynamic muscular endurance of the trunk flexors was assessed by the sit-up test. The dynamic muscular endurance of the arm extensors was assessed by the pushup test. They found muscle strength tests to be significantly lower with elbow flexion and knee extension there was a significant difference between groups in both of the endurance tests. Grip strength, however, was greater in the patients. They concluded that subnormal muscle strength persists even years after therapy for leukemia. Rehabilitation studies using adults that have survived cancer have found favorable results after a training period. One of the first reports on the effects of exercise on cancer patients was reported by Buettner and Gavron (144). They studied 17 subjects, 7 experimental and 10 controls, all of whom had been diagnosed as having had cancer within the previous five years. The experimental group exercised 3x/week for 8-weeks and the aerobic training program resulted in an improvement in estimated maximum oxygen uptake, resting heart rate, and skinfold thickness in men and women with a history of cancer within the previous five years (4). Mac Vicar and Winnngham (19) reported On the effects of a 10-week cycle ergometer program on patients with Stage II breast cancer undergoing chemotherapy. 116 Patients were randomly assigned to exercise or nonexercise groups. A third group of healthy, exercising, age-matched women was used for comparison. The results showed a 40% improvement in VO^max as well as maximum workload and test time. These data show that patients with Stage II breast cancer not only are able to tolerate aerobic training but respond in a manner similar to that of healthy adults. Dimeo et al, (145) studied 16 patients, who had recently received high dose chemotherapy followed by autologous peripheral blood stem cell transplantation, and brought them through a hospital-based rehabilitation program of treadmill exercise 5x/wk for 6 weeks. They found an improvement in maximum physical performance (calculated in MET's) and a reported decrease in fatigue and limitations to daily activities due to low physical performance. The only study to examine the effects of a rehabilitation program in pediatric survivors of malignancy was done by Sharkey et al., (63). They studied 10 patients who were all childhood survivors of various cancers, all were postpubertal, and the average age was 19 + 3 years, while age at diagnosis was 8 + 4 years. All subjects had completed treatment for at least 1 year prior to entering the study, with cumulative anthracycline dosage ranging from 225 to 450 mg/m2. Nine of the ten patients received radiation as part of their therapy with cumulative radiation dosage ranging from 18 to 55 Gy. They found significant reductions in spirometry measures of FEVi and FVC, in total exercise time, peak oxygen uptake and ventilatory anaerobic threshold, with mild reductions in peak heart rate and cardiac index before cardiac rehabilitation. All 10 patients then participated in a 12 week, twice weekly, hospital-based rehabilitation exercise program that was modeled after a pediatric cardiac rehabilitation program designed by Vaccaro et al., (30). The post-conditioning data demonstrated that there was no significant change in spirometry measure or cardiac index, but total exercise time increased an average of 13% with a trend toward improvements in peak oxygen uptake and ventilatory anaerobic threshold. However, these indexes remained substantially reduced compared with those of normal subjects in their lab. They concluded that deconditioning explained part, but not all of the abnormalities observed in surviving patients of childhood cancer. 117 Past studies from our laboratory support these findings. McKenzie et al., (20) studied 29 children, ages 8 to 18 who had been successfully treated for solid tumors. The time since their last treatment varied form 6 months to 15 years with an average of 3.4 years. They found patients who had been treated for malignancy had a profound reduction in cardiorespiratory fitness and anaerobic power relative to their healthy peers. Twenty of these children from the original study were then given home rehabilitation programs as a treatment intervention and retested 8-12 months later. Again the average time off treatment was 3.5 years and repeat evaluation demonstrated no significant changes, neither positive or negative, in these patients (21). The authors conclude that these patients had an unexplained, sustained reduction in aerobic and anaerobic capacities. Prior to the study parents reported that their children were having difficulty in school, had diminished self-confidence and poor self-esteem and socialization skills prior to the laboratory testing. After the laboratory testing sessions, with few exceptions, the parents commented on a change in attitude towards school, sports, and generally most activities. The most frequent comment centered on the improvement in self-esteem and confidence that the testing seemed to have instilled in them. The authors state, "this was most likely due to the Hawthorne Effect simply because they paid attention to these subjects, tested their functional capacities, explained the significance of these tests to the patients and their parents, and generally took an interest in these individual. This effect took place in spite of no significant change in the response to repeated exercise testing". The authors conclude that it is thus possible that the psychological effects of a rehabilitative program are entirely different, or at least have different time frames to the physiological effects (21). These initial descriptive studies showed that there is a significant difference between children who have survived treatment for solid tumors and their healthy controls and that these differences are not improving with time. For a healthy child physical activity is part of their daily routine since most children have a natural tendency to be active and energetic. When the integrity of play is compromised by a disease such as cancer, the risks and benefits of exercise must be assessed. 118 In healthy individuals, maximal exercise tolerance is limited primarily by muscle and cardiovascular function. Aerobic exercise training results in changes in skeletal muscles specific to the muscles involved in training and in the cardiovascular response to exercise (26). These changes include muscle capillary proliferation, increase in myoglobin levels to augment oxygen transport, and increased oxidative metabolic activity in muscle cells. Cardiovascular changes include an increase in stroke volume at rest and during exercise, increase in maximum cardiac output, and higher arteriovenous oxygen extraction with exercise. Physiologic adaptations to training include an increase in maximum VO2 and a higher anaerobic threshold (work level before the onset of anaerobic metabolism and lactic acidosis). The primary role of exercise for the cancer patient is to help prevent the loss of functional capacity. In addition, exercise may play a role in diminishing the side effects associated with treatment, including psychological burdens. It has been suggested (27) that exercise training may improve an individual's quality of life by increasing life satisfaction through the enhancement of arousal, self esteem and body image. Brown et al., (28) suggested that training may also assist in the treatment of anxiety, stress and reactive depression. These and other factors suggest that exercise training may contribute to heightened sense of well-being of the patient following training. A number of studies on other chronically ill populations have used exercise training as an intervention technique. Exercise has been shown to improve the functional capacity of patients with cardiovascular disease (29, 30, 31), diabetes mellitus (32, 33), chronic obstructive pulmonary disease (34), cerebral palsy (35), cystic fibrosis (36) and peripheral vascular disease(37, 38). In addition, epidemiological studies by Frisch et al., (39) and Paffenbarger et al., (40) suggested that regular physical exercise aids in increasing the individuals resistance to disease. It seems logical to consider an exercise training program as an adjunct therapy in cancer treatment. Exercise seems to be one of the easiest, least expensive and most applicable tool one has that we can use. Treatment of children by exercise is unique; by prescribing exercise we are signaling to the child that he can, and should, act like his healthy peers. It 119 emphasizes the child's abilities rather than disabilities. This is in contrast to therapy by medication, diet, or bed rest, where he is made to feel different from others. Moderate exercise thus shows promise as a way to delay or reverse a patient's decline in functional ability. However, no guidelines exist today for objective evaluation of functional capacity or for restorative exercise programs specifically designed for cancer patients. 120 Healthy Training Studies Functional capacity, defined as the highest metabolic rate an individual can achieve on exertion, is often used as a measure of one's ability to engage in physical activity (146). Since there is a direct relationship between oxygen uptake (VO^max) and performance of physical activity, maximal oxygen uptake is also an measure of the highest metabolic rate an individual can achieve with exertion. For this reason, a maximal exercise test is considered to be an objective physiological indicator of functional capacity. Since oxygen uptake and delivery must match the demand of working muscle, and are contingent on an effective integrated response of the cardiovascular and pulmonary systems, a maximal exercise test provides the clinician or researcher with valuable information about the effects of interventions on maximal aerobic power. In addition, the effects of aerobic exercise training are usually quantified on the basis of changes in VC^max. V02inax can be obtained directly by exercising a child to maximal exertion on a cycle ergometer or a treadmill. One of the criteria for V02inax in adults is a plateau in VO2 with an increase in exercise workload. This plateau however, is not always seen in a child and thus the highest observed oxygen uptake is referred to as the peak VO2. The peak VO2 has been frequently used as a measure of the change in the functional capacity of the cardiovascular system during exercise training in normal subjects and as a measure of the deconditioning adaptation in bed-rested subjects (147). For both children and adults, V0 2 max is expressed either as an absolute rate (L/min) or relative to some measure of body size, most notably body mass (ml"1-kg"1-min"1). The use of relative V02max reduces variability among individuals. Maintenance of functional capacity requires physical activity using large muscle groups to promote adaptation of the aerobic energy system. Inactive deconditioned skeletal muscle loses oxidative capacity and requires more oxygen for performance of comparable work than does the conditioned muscle, a factor contributing to rapid fatigue and decline in endurance (148). Disease and/or treatment(s) can inhibit the exercise response at any one of several points in the oxygen transport system. Nevertheless, within these limitations, aerobic 121 exercise training can still induce physiological adaptations in the aerobic energy system sufficient to improve functional capacity (19). The magnitude of the adaptation is determined by the intensity, frequency, and duration of exercise and the initial level of maximal oxygen uptake. Extensive experience in adult aerobic training programs has led to the identification of exercise type, duration, frequency, and intensity levels necessary to create this fitness effect: a program involving continuous activity of large muscle groups, 3-5 sessions per week for 15-60 minutes, and an intensity producing a heart rate 60-90% of maximum are well established guidelines to improving cardiovascular fitness (56). Numerous studies during the past 3 decades have established that training in normal subjects leads to an increase in peak exercise oxygen consumption (VO2). This may be achieved through both improvements in maximal cardiac output and peripheral adaptation (149, 150, 151). In normal subjects, these peripheral adaptations include an increase extraction and utilization by the systemic arteriovenous oxygen difference at peak exercise, which is attributable, in part, to a redistribution of cardiac output to working skeletal muscles (149, 150, 152). In adults physiologic changes that accompany a properly designed training program can be assumed to result from the program itself. In contrast, growth and maturation are major factors to consider in any longitudinal study of children and adolescents (68). Training programs that would be expected to stimulate average improvements of 15-30% VO*2inax in young aduks have typically produced increases in the range of only 5-10% in prepubertal children (69). In a review of training studies in children by Bar-Or, (68), he noted that only two studies had shown improvement in maximal aerobic power of more than 15%, and several investigators reported little or no change in VO^max after training. In the past, there was considerable skepticism regarding the ability of children to improve maximal aerobic power with physical training before puberty (64). A suggested reason for such low trainability is that children are active even when not taking part in a regimented training program and hence a training program would add little to their fitness 122 level. Studies indicating that children do not sustain high-intensity exercise for periods of time sufficient to improve fitness weaken this argument. Gilliam et al., (65), for instance, showed that 6 to 7 year old boys and girls produced heart rates over 160 bpm for 21 and 9 min per day, respectively, and these higher rates typically came in intermittent bursts. They conclude that even moderately active children seldom exercise sufficiently to levels that would improve cardiovascular fitness. Although both cross-sectional and longitudinal studies show conflicting results in regards to the trainability of children, comprehensive reviews by Rowland (66) and Vaccaro and Mahon (67), conclude that when the aerobic training regimen conforms to guidelines established for adults, prepubescent children are trainable. Rowland (66) reviewed eight studies that utilized standard training guidelines and measured VC^max before and after an exercise program in prepubescent children. Of the eight studies, six demonstrated a significant rise ranging from 7-26%. The mean V0 2 max elevation of 14% is consistent with the expectations of training effects in adult programs. In a review by Pate and Ward (70), they were only able to find 12 training studies in children under 13 years of age that met the criteria of proper experimental design with adequate training protocols and statistical analysis. Eight of the twelve studies showed a clear improvement in relative V0 2max in the experimental group. This increase averaged 10.4% (range 1.3-20.5%). The average increase in the control groups was 2.7% (range 3.3-9.9). They concluded that prepubescent boys can physiologically adapt to endurance exercise training, but to a lesser extent than post-pubescent boys. In a recent meta-analysis of exercise and V02tnax in children 13 years and under by Payne and Morrow (71), they conclude that research employing cross-sectional design must be interpreted cautiously. The differences observed could be a function of other variables such as self-selection, or previous training experience. Also they point out that the possibility exist that control subjects may have been more active than the researchers assumed. With a pretest-posttest design, the typical child demonstrated a V02tnax increase of approximately 2.07 ml"1kg'1min"1. They suggest that the aerobic benefit of training is small-to-moderate for this age group. 123 Katch (64) proposed what's called the "trigger hypothesis" in which he suggests that there is a critical period toward the end of childhood that usually occurs during puberty. Prior to this critical period the effects of physical conditioning are minimal or nonexistent. The trigger phenomenon is thought to be the result of "modulating effects of hormones that initiate puberty and influence functional development and subsequent organic adaptations". This hypothesis assumes that for organic training adaptations to occur, certain physiological precursors must exist. This idea goes along with the observation that early maturers are more prone to a positive training effect than their average or late maturing counterparts. A study by Borms (72) examined the time of peak height velocity (PHV) and its relationship to increases in aerobic capacity and found that improvements were small prior to PHV but significant thereafter. 124 Cardiac Rehabilitation Program Studies The idea that exercise training might prove beneficial to children with heart disease is a spin-off from the larger experience of rehabilitation programs for adults recovering from myocardial infarction or coronary bypass surgery. These programs have sought to restore physiological and psychological well-being and, as a secondary effect, to prevent subsequent coronary events. A review of pediatric cardiac rehabilitation studies are listed in Table 17 and 18. None of the studies listed in Table 17 demonstrate a significant improvement in maximal aerobic capacity after training in children with surgically repaired congenital heart disease. The children were from 1 to 16 years after corrective surgery, the programs lasted between five and nine weeks and emphasized aerobic activities at intensities of 65 to 80% MHR, or 50 to 70% maximal O2 uptake. One methodological problem was that only two of the studies included a control group (73, 153) comprised of healthy children who trained, but there were no control groups of patients who served as non-exercising controls. In all four studies there was an increase in the peak power output but not in maximal O2 uptake. Other studies, listed in Table 18, have shown improvements in maximal aerobic capacity of children with surgically repaired congenital heart disease after aerobic exercise training. In the previously mentioned studies, no measure was taken to assure that the exercise intensity was maintained at an adequate level to improve fitness and the duration of the programs was quite short. It is plausible that the children were not exercising at a high enough intensity and/or the duration of the program was not long enough to elicit a training response that would have been indicated by an increase in V02max. 125 Table 17. Training Studies in Children with Congenital Heart Disease Study Defects N Age(yr) Controls Exercise Program Results Miller et al (153) ASD, PS, CoA, VSD 5 F , 7 M 10-15. Healthy, training 5 wk, daily, 80% M H R t Peak power output, o V 0 2 max Goldberg et al. (154) TF, VSD 13 F, 13 M 7-17 None 6 wk, 3x/wk, 60-70% V02max t max work capacity, 4-HR, 1 V02submax, <->MHR, <-» VEmax, <-»Vo2max Ruttenberg et al (74) AS, TF, T G A , A V C 12 7-18 Healthy, training 9 wk, 3x/wk, walk-jog, 65-75% M H R T max workload, <-»MHR, * W 0 2 m a x Sklansky et al (155) TF 11 6-16 None 8 wk, 3x/wk, 60-80% PHR, cycle and treadmill <-» V0 2 max, <->MHR, Isubinax HR, lQ, t treadmill time A S D = atrial septal defect; PS = pulmonary stenosis; CoA = coarctation of the aorta; VSD = ventricular septal defect; TF = tetralogy of Fallot; AS = aortic stenosis; T G A = transposition of the great arteries; A V C = atrioventricular canal; F = females, M = males, M H R = maximal heart rate, V 0 2 = oxygen consumption; V E = ventilation; Q = cardiac output. 126 Table 18. Training Studies in Children with Congenital Heart Disease Study Defects N Age(yr) Controls Exercise Program Results Mathews et al (75) TF, CoA, AS, MI , P S 7 12-20 Healthy, training 1 yr, 3x/wk, 75-80% MHR, 90 min aerobic t V0 2 max, t VEmax Longmuir et al (156) VSD, ASD, CoA, AS, TF, PDA, T A , P S 27-exp 27-cont 4.7-14.3 non-exercising patient controls 2x/wk, 6 week home program during the first 3 months after surgery tfitness scores of aerobic cap, muscle strengdi, flexibility, and coordination Bradley et al (157) TF, T G A 9 4-13 None 3 months, 2x/wk, 60-80% MHR, aerobic activities t V0 2 max, t treadmill time Calzolari et al (158) TF 9 6-16 None 3 months, 3x/wk, 60-70% M H R <->MHR, tsubmax performance, texercise duration Balfour et al (159) P S , P V C , A V R , inyocariditis 6 13-20 None 3 months, 3x/wk, 70% MHR, 30-40 min, cycle and treadmill <->MHR, tV0 2 peak, texercise time Vaccaro et al (67) T G A 5 5.1-12.3 None 3 months, 2x/wk, lx/wk - home program add on wk 6, 60-70% M H R T M H R , T S B P peak, ttreadmill time, T V 0 2 peak Tomassoni etal (160) T G A , MI , TF, F O N 8 4.5-15 None 3 months, 2x/wk, lx/wk - home program add on wk 6, 60-80% M H R ttreadmill time, tcardiac output, tcardiac index Galiato et al (31) T G A , TF, FON, CoA, VSD, MI 35 4.9-10.9 None 3 months, 2x/wk, lx/wk - home program add on wk6, 60-80% M H R t V 0 2 peak, tpeak cardiac output, <->VE peak, o M H R TF = tetralogy of Fallot; CoA; = coarctation of the aorta; AS = aortic stenosis; M I = mitral insufficiency; PS = pulmonary stenosis; T G A = transposition of the great arteries; F O N = Fontan; P V C = premature ventricular contractions; A V R = aortic valve replacement; T A = tricuspid atresia; PS = pulmonary stenosis; P D A = patent ductus arteriosus; VSD = ventricular septal defect; ASD = atrial septal defect; F = females, M = males, M H R = maximal heart rate, V 0 2 = oxygen consumption; V E = ventilation; Q = cardiac output. 127 Although most of the studies have shown beneficial results from participation in pediatric cardiac rehabilitation programs, some studies have found ambiguous results, such as improvement in total treadmill time, with no improvement in VC^max. These studies have been limited by methodological problems including small sample sizes, compliance issues, absence of non-exercising controls and non-random designs. Longmuir et al., (161) re-tested 40 of the subjects from their earlier study in 1985 (156) to evaluate the long-term impact of their six week training program on the physical exercise capacity in these patients treated for various heart defects. The subjects who completed the home exercise program during the first 3 post-operative months demonstrated normal levels of physical fitness in their initial study and again 5 years later without further intervention. The children who did not receive a post-operative training program remained significantly below their healthy peers. The authors conclude, an exercise training program conducted early in the post-operative period would appear essential to the achievement of appropriate levels of physical activity for children with congenital heart defects. 128 Psychological Research with Chronically III Populations Although survival rates for childhood cancer have dramatically improved over the past 20 years, the impact from a childhood cancer has not. Cancer brings feelings of anxiety, fear, depression, and helplessness, for both the child diagnosed with cancer and the family. For a child, self-esteem appears to be a central component of success in academic achievement, classroom participation, social skills, and leadership potential (78). Failure to develop self-esteem, on the other hand, results in a vulnerability to anxiety and depression. It is known that for healthy children, physical activity is psychologically beneficial, especially for the development of positive self-esteem (78, 79). In children who have survived cancer, normal participation in sports and recreational activity may be limited by central and peripheral impairment (61). It is not known what effects such decreased participation has on the psychological health of these children. Sonstroem (78) states that "participation in regular exercise might be expected a priori to improve self-esteem; Elevated mood and feelings of well-being as well as relief of depression and anxiety - effects all related to physical activity - are also associated with a positive self-concept". In adults, chronic exercise has not been shown to promote measures of overall self-esteem in all studies. But because body image is linked to self-concept, self-esteem has been demonstrated to increase in subjects who value physical competency and increase their fitness or athletic ability through an exercise program. Gruber (162) reviewed 84 studies between 1966 and 1986 exploring the relationship of physical activity and self-esteem in elementary age children. Meta-analysis revealed that, overall, physical fitness activities were significantly related to improvements on test scores of self-concept. This held true for healthy children, as well as for those who were emotionally disturbed, mentally retarded, or perceptually handicapped, but the effect was greater in the latter three groups. The relationship of self-esteem and exercise was also more prominent when aerobic activities were utilized. 129 Sonstroem (78) also documented the scientific limitations in 16 studies of exercise and self-esteem, including adolescents and adult participants. Because the results were consistently positive, in spite of experimental shortcoming, Sonstroem concluded that participants in exercise programs report significant increases in self-esteem scores. Calfas and Taylor (163) did a review of the literature looking at the relationship among psychological variables and physical activity in youth (ages 11-21 years). They concluded that the literature suggests that physical activity in youths is psychologically beneficial, especially for self-concept and anxiety/stress variables. They recommend that adolescents should engage in moderate or vigorous aerobic activity approximately 3x/wk for total of at least 60 minutes per week. Considering the trauma experienced by a child who has survived a serious illness such as cancer, it is logical to suspect that residual psychological effects may endure long past the treatment phase of the illness. But the results of studies conflict. Fergusson (163) surveyed 18 children who had been hospitalized and treated for cancer between the ages of 2 and 5 years old. This group was selected because toddlers do not tolerate separation from their families. The children were given a battery of tests four or more years after their diagnosis. He found that, on the basis of interviews with parents and the results of psychological testing, these children were psychologically well-adjusted and lived normal, healthy lives. In contrast to Fergusson's finding, O'Malley et al., (165) reported that a relatively high proportion (59%) of the survivors of childhood cancer experienced adjustment problems after treatment for their disease. The mean age at diagnosis was 5.7 years (with a range from birth to 18 years) and the children took standardized measures of self-esteem, social adjustment, anxiety, depression, and death-anxiety, as well as projective tests. The differences in findings could have been due to the differences in populations tested and/or the different methods used by each group. Also, both studies were based on retrospective self-report data, making it difficult to draw conclusions from them. Koocher and O'Malley (166) studied the psychological consequences of surviving childhood cancer and found that the age at the time of diagnosis and length of prolonged, continuous remission of the disease were important factors that contribute to a lower 130 incidence of psychological problems. The gender of the child did not effect the psychological outcome. They also found the highest incidence of adjustment problems were seen among survivors of Hodgkin's disease and acute lymphocytic leukemia. This finding was attributed to the prolonged course of treatment and its related side effects. They concluded that survivors of childhood cancer are at greater risk for the development of long-term psychological problems than are childhood survivors of other chronic but not life-threatening disorders. He found that a number of variables tend to distinguish well-adjusted survivors from those whose adjustment may be compromised. Optimum long-term adjustment is influenced by 1) the type of cancer and the number of permanent side effects, 2) the occurrence of relapse, and 3) the developmental stage at the time of onset. List et al., (167) interviewed young adults who had cancer during adolescence and who were at least five years from diagnosis to study the psychological adjustment in this population. The focus was on issues of school attendance, academic performance, and career achievement. They found that (61%) indicated disruptions in peer relationships and decreases in participation in extracurricular activities (54%). Academic difficulties were described by 28% of the sample. Many commented that they no longer "fit in" with their peers and felt isolated and alone. Other studies have confirmed the results regarding school-related problems in children surviving cancer. These children have been described as having difficulty returning to school and maintaining attendance (168, 169). List et al., (167) state, "the findings of such high rates of school disruption among children with cancer is an important observation with far-reaching implications. School is the center of a child's life and the primary setting of influence of both academic and social development. These functions are even more critical for the child who has cancer and already feels different. Being at school and participating in the normally shared intellectual and social activities of his/her peer group helps counteract the anxiety, depression, and isolation accompanying illness, while guiding psychosocial development." In a study conducted by the Candlelighters' Childhood Cancer Foundation (142) they sent out questionnaires to young people over 14 years of age who were all off treatment. Three hundred long-term survivors of childhood cancer between the ages of 14 131 to 29 years responded from all part of the United States. Their results demonstrated three significant differences in how the survivors felt, with sixty-nine percent of subjects reporting that they felt differently from other young people, but that this was positive; only 31% mentioned the differences were negative. The most frequent difference reported (30%) was a positive one, with survivors feeling that they were more advanced or mature in their personality or psychological development than their peers. The most common negative difference reported was in regards to their physical health status and abilities. They often felt less healthy and less physically able than their peers who did not have a history of cancer. Survivors also reported life habits that included significantly less exercise than their peers. In a review by Brown et al., (28) they found that training often provides little or no improvement in the psychological well-being of people from the general population (170, 171, 172). However, findings from studies with non-clinical populations are contradictory. Some studies have found that exercise training led to enhance general well-being (173), and decreases in depression (170), tension, confusion (174), perceived stress, and anxiety (175). Persons recruited from community populations have also reported improvements in physical fitness, weight, and appearance (176), and perceived physical, psychological, or social well-being (171). They conclude that one reason for the contradictory findings is the improvements in perceived well-being, sometimes measured by a single item, have frequently not translated to documented psychological tests. There has been very little research in the area of rehabilitation programs for children with heart disease and their psychological health status. The limited studies however, indicate that exercise training is useful for improving functional work capacity and social confidence in these patients. Although the evidence is largely anecdotal, the directors of these programs report that their subjects improve in social interaction skills, become more outgoing, and have fewer anxieties surrounding physical activity (73, 74). Mathews et al., (75) observed that by the end of the cardiac rehabilitation program, parents were supporting rather than restricting their children's activities, patients' self-confidence and self-images improved, and fears of death lessened. 132 Echocardiography/Doppler Measures Echocardiography is a pain-free, non-invasive modality using high frequency ultrasound which is able to measure cardiac chamber sizes, wall thickness and assess changes on a real time basis. Using standard approaches, the left ventricular end-systolic and end-diastolic dimensions, wall thickness throughout the cardiac cycle, and ejection time may be measured from the left ventricular tracing and aortic root echocardiogram (177) . This can be performed at rest and with some difficulty during exercise but is easily performed immediately post-exercise. Wall motion may also be examined, and this technique is well established in adult cardiology in the diagnosis of coronary artery disease (178) . Doppler echocardiography is an established modification of ultrasound whereby the frequency shift of sound waves striking a moving target is quantified and analyzed, i.e. the Doppler effect (179). In this case, the moving target is the red cells in the blood. The techniques for measurement of cardiac output and stroke volume by Doppler have been validated by numerous workers both at rest (180, 181, 182) and with exercise (183, 184, 185, 186, 187). For reliable measurement of mean velocity, aortic flow must be laminar and the aortic spatial velocity profile must be flat, i.e., the velocity must be equal at all points across the vessel lumen. The mean velocity of flow multiplied by the aortic cross sectional area of the vessel (e.g. aorta which can be measured by M-mode echocardiography) has been shown to correlate well with cardiac output. Doppler echocardiography may be performed at the same time as standard echocardiography and measurement of aortic flow is performed from the suprasternal notch approach. The use of mean aortic velocity may be as accurate an indexed value as calculating cardiac output as has been shown by Seear et al., (55). Stoke volume and cardiac output are fundamental descriptors of cardiovascular function. Cardiac output is the primary indicator of the functional capacity of the circulation to meet the increased demands of physical exertion. The stroke volume is the amount of blood pumped out of the heart with each beat and is determined by the preload, 133 afterload and contractility. 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Pediatric laboratory exercise testing clinical guidelines. Human Kinetics Publishers, Champaign, IL. 1993:115-140. ISO APPENDIX TWO - Self-Perception Profile for Children (SPPC) Name Subject # Sample Sentence Really Sort of Sort of Really True True True for True for Me for Me Me for Me a) • • Some kids would rather BUT Other kids would rather • • play outdoors in their watch TV. spare time. • • Some kids feel that they BUT are very good at their school work. 2. • • Some kids find it hard to BUT make friends. • • Some kids do very well BUT at all kinds of sports. • • Some kids are happy BUT with the way they look. • • Some kids often do not BUT like the way they behave. • • Some kids are often BUT unhappy with themselves. • • Some kids feel like they BUT are just as smart as other kids their age. • • Some kids have a lot of BUT friends. Other kids worry about • Q whether they can do the school work assigned to them. Other kids find it's • • pretty easy to make friends. Other kids don't feel that • • they are very good when it comes to sports. Other kids are not happy O O with the way they look. Other kids usually like • • the way they behave. Other kids are pretty • • pleased with themselves. Other kids aren't so sure Q O and wonder if they are as smart. Other kids don't have • • very many friends. 151 9. • • Some kids wish they could be a lot better at sports. BUT Other kids feel they are good enough at sports. • 10. • • Some kids are happy with their height and weight. BUT Other kids wish their height weight were different. • 11. • • Some kids usually do the right thing. BUT Other kids often don't do the right thing. • 12. • • Some kids don't like the way they are leading their life. BUT Other kids do like the way they are leading their life. • 13. • • Some kids are pretty slow in finishing their school work. BUT Other kids can do their school work quickly. • 14. • • Some kids would like to have a lot more friends. BUT Other kids have as many friends as they want. • 15. • • Some kids think they could do well at just about any new sports activity they haven't tried before. BUT Other kids are afraid they might not do well at sports they haven't ever tried. • 16. • • Some kids wish their body was different. BUT Other kids like their body the way it is. • 17. • • Some kids usually act the way they know they are supposed to. BUT Other kids often don't act the way they are supposed to. • 18. • • Some kids are happy with themselves as a person. BUT Other kids are often not happy with themselves. • 19. • • Some kids often forget what they learn. BUT Other kids can remember things easily. • 20. • • Some kids are always doing things with a lot of kids. BUT Other kids usually do things by themselves. • 152 21. • • Some kids feel that they are better than others their age at sports. BUT Other kids don't feel they can play as well. • • 22. • • Some kids wish their physical appearance (how they look) was different. BUT Other kids like their physical appearance the way it is. • • 23. • • Some kids usually get in trouble because of things they do. BUT Other kids usually don't do things that get them in trouble. • • 24. • • Some kids like the kind of person they are. BUT Other kids often wish they were someone else. • • 25. • • Some kids do very well at their classwork. BUT Other kids don't do very well at their classwork. • • 26. • • Some kids wish that more people their age liked them. BUT Other kids feel that most people their age do like them. • • 27. • • In games and sports, some kids usually watch instead of play. BUT Other kids usually play rather than just watch. • • 28. • • Some kids wish something about their face or hair looked different. BUT Other kids like their face. • • 29. • • Some kids do things they know they shouldn't do. BUT Other kids hardly ever do things they know they shouldn't do. • • 30. • • Some kids are very happy being they way they are.. BUT Other kids wish they were different. • • 31. • • Some kids have trouble figuring out the answers in school. BUT Other kids almost always can figure out the answers. • • 32. • • Some kids are popular with others their age. BUT Other kids are not very popular. • • 133 33. • • 34. • • • 35. • • 36. • • Some kids don't do well BUT at new outdoor games. Some kids think that BUT they are good looking. Some kids behave BUT themselves very well. Some kids are not very BUT happy with the way they do a lot of things. Other kids are good at CH LZ! new games right away. Other kids think that • • they are not very good looking. Other kids often find it • • hard to behave themselves. Other kids think the way • D they do things is fine. 154 APPENDIX T H R E E - Self-Perception Profile for Adolescents (SPPA) Name Subject # Sample Sentence Really Sort of Sort of Really True for True for True for True for M e M e M e Me a) D Q Some teenagers like to B U T Other teenagers would Q D go to movies in their rather go to sports spare time. events. 1. • • Some teenagers feel that they are just as smart as others their age. B U T Other teenagers aren't so sure and wonder if they are as smart • • 2. • • Some teenagers find it hard to make friends. B U T For other teenagers it's pretty easy. • • 3. • • Some teenagers do very well at all kinds of sports. B U T Other teenagers don't feel that they are very good when it comes to sports. • • 4. • • Some teenagers are not happy with the way they look. B U T Other teenagers are happy with the way they look. • • 5. • • Some teenagers feel that they are ready to do well at a part-time job. B U T Other teenagers feel that they are not quite ready to handle a part-rime job. • • 6. • • Some teenagers feel that if they are romantically interested in someone, that person will like them back. B U T Other teenagers worry that when they like someone romantically, that person won't like them back. • • 7. • • Some teenagers usually do the right thing. B U T Other teenagers often don't do what they know is right. • • 155 8. • • Some teenagers are able to make really close friends. B U T Other teenagers find it hard to make really close friends. • • 9. • • Some teenagers are often disappointed with themselves. B U T Other teenagers are pretty pleased with themselves. • • 10. • • Some teenagers are pretty slow in finishing their school work. B U T Other teenagers can do their school work more quickly. • • 11. • • Some teenagers have a lot of friends. B U T Other teenagers don't have very many friends. • • 12. • • Some teenagers think they could do well at just about any new athletic activity. B U T Other teenagers are afraid they might not do well at a new athletic activity. • • 13. • • Some teenagers wish their body was different. B U T Other teenagers like their body the way it is. • • 14. • • Some teenagers feel that they don't have enough skills to do well at a job. B U T Other teenagers feel that they do have enough skills to do a job well. • • 15. • • Some teenagers are not dating the people they are really attracted to. B U T Other teenagers are dating those people they are attracted to. • • 16. • • Some teenagers often get in trouble for the things they do. B U T Other teenagers usually don't do things that get them in trouble. • • 17. • • Some teenagers do have a close friend they can share secrets with. B U T Other teenagers do not have a really close friend they can share secrets with. • • 18. • • Some teenagers don't like the way they are leading their life. B U T Other teenagers do like the way they are leading their life. • • 156 19. L Z I L Z I Some teenagers do very B U T well at their classwork. 20 L Z I L Z I Some teenagers are very B U T hard to like. 21. • • Some teenagers feel that B U T they are better than others their age at sports. 22. • O Some teenagers wish B U T their physical appearance was different. 23. • • Some teenagers feel they B U T are old enough to get and keep a paying job. 24. • • Some teenagers feel that B U T people their age will be romantically attracted to them. 25. • • Some teenagers feel B U T really good about the way they act. 26. D D Some teenagers wish B U T they had a really close friend to share things with. 27. • • Some teenagers are B U T happy with themselves most of the time. 28. • • Some teenagers have B U T trouble figuring out the answers in school. Other teenagers don't do D D very well at their classwork. Other teenagers are really LZI • easy to like. Other teenagers don't feel Q LZ they can play as well. Other teenagers like their (ZI LZI physical appearance the way it is. Other teenagers do not Q LZI feel they are old enough, yet, to really handle a job well. Other teenagers worry [Z] LZI about whether people their age will be attracted to them. Other teenagers don't feel Q] LZI that good about the way they often act. Other teenagers do have (Zl LZI a close friend to share things with. Other teenagers are often (Zl LZI not happy with themselves. Other teenagers almost Q LZI always can figure out the answers. 157 2 9 - L Z LZ Some teenagers are B U T popular with others their age. 3 0 - LZ LZ Some teenagers don't do well at new outdoor games. 3 1 - LZ LZI Some teenagers think B U T they are good looking. 3 2 - • • Some teenagers feel like B U T they could do better at work they do for pay. 3 3 - D • Some teenagers feel that B U T they are fun and interesting on a date. 3 4 - CZ LZI Some teenagers do B U T things they know they shouldn't do. 3 5 - D • Some teenagers find it B U T hard to make friends they can really trust. 3 6 - L Z LZ Some teenagers like the B U T kind of person they are. 3 7 - • • Some teenagers feel that B U T they are pretty intelligent. 3 8 - L Z L Z Some teenagers feel that B U T they are socially accepted. 3 9- L Z L Z Some teenagers do not B U T feel that they are very athletic. Other teenagers are not LZ LZ very popular. B U T Other teenagers are good LZ LZ at new games right away. Other teenagers think LZ LZ that they are not very good looking. Other teenagers feel that LZ LZ they are doing really well at work they do for pay. Other teenagers wonder LZ LZ about how fun and interesting they are on a date. Other teenagers hardly [ Z LZ ever do things they know they shouldn't do. Other teenagers are able LZ LZ to make close friends they can really trust. Other teenagers often LZ LZ wish they were someone else. Other teenagers question LZ LZ whether they are intelligent. Other teenagers wished LZ LZ that more people their age accepted them. Other teenagers feel that |Z) LZ they are very athletic. 158 4 0 . • • 4 1 . • • 4 2 . • • 4 3 . • • 4 4 . • • 4 5 . • • Some teenagers really BUT like their looks. Some teenagers feel that BUT they are really able to handle the work on a paying job. Some teenagers usually BUT don't go out with the people they would really like to date. Some teenagers usually BUT act the way they know they are supposed to. Some teenagers don't BUT have a friend that is close enough to share really personal thoughts with. Some teenagers are very BUT happy being the way they are. Other teenagers wish • • they looked different. Other teenagers wonder Q LZI if they are really doing as good a job at work as they should be doing. Other teenagers do go f~~) out with the people they really want to date. Other teenagers often LZI Q don't act the way they are supposed to. Other teenagers do have LZ] LZ1 a close friend that they can share personal thoughts and feelings with. Other teenagers wish (Zl LZ1 they were different. 159 £ CO to o D_ CM 7 -iri co CO O) h- CD CJ) CM OO c\i c\i CM cs] tt (O IfJ-r <D CO CO CO CO T - O CN cd in d CJ> lO CN lO T J * T J " LO CO 00 CO T — CO T J " LO LO CO Is- . 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