Physical Activity in Children During Hematopoietic Stem Cells Transplantation (HSCT)

BACKGROUND Hematopoietic stem cell transplantation (HSCT) is a potentially curative option for many diseases, such as hematologic malignancies and refractory solid tumors among children and adolescents. This procedure led to considerable improvement in survival rates, but also contributed to the development of late effects. Due to the severity of conditioning regimen, length of isolation and hospitalization period, weakness related to immunosuppression and drug toxicities, physical, cognitive and psychosocial functions are severely impaired. HSCT recipients may report impairments in cardiorespiratory fitness (fatigue), muscle bulk and strength, immunologic recovery, neuropsychological functions, functional abilities and autonomy with an undeniable decline of quality of life (QoL). Recently pediatric oncological research attentions have been directed to reduction of the impact of these side effects and to improvement of QoL, both during and after cancer treatment. The published studies about the effects of rehabilitation care, in pediatric population undergoing HSCT show how rehabilitation, which consists in structured and adapted different therapeutic activities, is safe and feasible. In particular studies conducted on the inpatient phase for HSCT report how the execution of a low intensity level of activity doesn't have any bad effect on immunological recovery, positively affects BMI, gives benefits on general health status, improves QoL, protects from depressive symptoms by promoting a healthy lifestyle during survivorship. Moderate exercise in a chronic graft-versus-host disease (cGVHD) murine model receiving total body irradiation (TBI) and immunosuppression can reduce clinical severity scores, blood interleukine-4 (IL-4) and tumor necrosis factor α levels while increasing survival, physical fitness, circulating B220 and cluster of differentiation 4 (CD4) lymphocytes. Finally, rehabilitation can improve immune function which has an impact on cancer control. Pediatric Oncohaematology Department of "Regina Margherita" Children's Hospital in Turin ["A.O.U. Città della Salute e della Scienza"] is one of the most important structure in Italy for pediatric HSCT. In the year 2016, 47 patients underwent HSCT: 25 of them were less than 11 years old and 22 were older than 11 years. In 2017, until the month of August, 25 patients were transplanted: 12 of them were less than 11 years old and 13 were older than 11 years. The in-patient phase lasted for a medium time of 40 days. From a recent review of the Department, in the period between March 2010 and November 2015, 207 children and adolescent patients benefited of a rehabilitation treatment, 42 of these during and after hospitalization for HSCT. However, to date rehabilitation programs have been implemented in a purely personalized perspective thus ignoring primary methodological issues (e.g., absence of a control group) which would allow an appropriate evaluation of outcomes generalizable to the target population. Therefore, rigorous interventions are mandatory in order to prevent future long-term treatment effects, to improve general health state of these patients and to share evidence-based guidelines for the optimal design for rehabilitation care in pediatric oncology.

EXPERIMENTAL PROJECT Starting from literature data on benefits of participation to a rehabilitation program for subjects undergoing HSCT, the current research intends to propose a project in a prevention perspective aim at the promotion of healthy life style for children and adolescents.

Procedures According to the difficulties reported in other studies that had both exercise group (EG) and control group (CG) patients recovery at the same time, and since this led to inevitable contamination between these two groups, investigators established that eligible patients who provided consent will be assigned to one of the two groups according to a "cluster time" selection model. The study it has been approved by the hospital's Ethical Committee. Written informed consent will be obtain from the participants or from their parents/guardians for patients under eighteen.

Exercise Intervention The study is presented to eligible patients and to their caregivers by a Development Neuro and Psychomotor Therapist in an interview. The interview regards: 1) problems that may occur during the HSCT procedure; 2) the importance of rehabilitation during the recovery to limit side effects; 3) presentation of the study design and procedures; 4) submission of the informed consensus. After having obtained the consensus, patients are assigned to the EG or the CG, according to the methodology previously explained. Subjects receive information booklets containing practical rehabilitation instructions, expressed in both text and illustrations, differentiated by the three identified age ranges (0-4, 5-12, 13-18). The content of booklets varies between EG and CG, since in the first case it contains both exercise and RCI, while for CG it regards only on RCI.

EXPERIMENTAL GROUP: The intervention consists in a standardized PE and RCI. PE is done 5 days/week (2 days in autonomy by the patient with parents support and 3 days supervised). Each session lasts 30 minutes and this is supervised by one therapist for all patients. Children aged less than 5 years make activities directed to sustain and promote their neuro-psychomotor development and muscle strength (e.g. to sit in the infant seat, playing in sitting position without support, playing on the floor and to crawl). Patients belonging to the other two age ranges are enrolled in an exercise programme (EP) composed by three different types of exercises, each carried out for 10 minutes per session: muscle strength exercises for upper and lower extremities preceded by warming up, aerobic exercises and stretching. For children aged 5-12 years activities are based principally on games (e.g. games with the ball, with circles and bricks, etc.), while structured exercises are proposed to adolescents (e.g. using weights, treadmills or exercise bikes); in both groups, the active videogames of Nintendo Wii(™) Fit is used to promote aerobic training. The EP is done only if the patient had platelets > 20000 and Hb > 8.0. Patients belonging to the upper age ranges also benefit from RCI, which has to be followed daily, and where some practical advice are given on how to adopt an active lifestyle during the recovery (e.g., getting up to go to the bathroom, getting up to move to the window to talk with visitors, sit on chair to have school lessons).

Parents record daily their child's EP and RCI activities in appropriate grids, and adolescents filled them in themselves.

CONTROL GROUP: Parents of children who belonged to the 0-4 years old age range CG receive a booklet with some RCI on how to reduce the time spent in bed and to propose different kinds of activities useful to sustain their development, according to the functional level of their child. Children who aged more than 5 years and adolescents of the CG receive the same part of the pamphlets given to the EG, containing written and illustrated indications of the RCI. The RCI has to be followed daily. Parents are required to record in appropriate grids their child's daily activities and adolescents filled them in themselves. The therapist goes 3 times/week to check that the diary has been filled in correctly.

EXPECTED RESULTS (experimental group vs control group): - Stable level of gross motor skills, functional motility, resistance to the walking and muscular strength from T0 and T1; - Stable level in passive articular movement in tibial artery dorsiflexion from T0 and T1; - Stable level of muscular elasticity from T0 and T1; - High perception of QoL and less fatigue from T0 and T1; - Improvement in immune functions; - Positive association between food intake and program participation.

FUTURE APPLICATIONS TO HEALTH The current project seeks to obtain not only important health and clinical benefits for patients undergoing HSCT in terms of late diseases reducing (e.g., obesity), but it will also underline new important association between exercise and biological system useful to find new insight for antitumor mechanisms. Also the need to improve several rehabilitation issues will be showed. For instance, the project will allow to focus on the importance that all patients have access to rehabilitation options. Actually, there is currently a gap between what investigators know from research, and what health care professionals, are implementing in pediatric cancer care. In Italy, for instance, the possibility to benefit of rehabilitation care is still poor because of the absence of services and facilities in several centres of pediatric oncology. So, to pay attention to these unmet needs will be the first step towards the reduction of the financial burden of hospitalization because of late effects problems and secondary disease some of which can be prevented with an appropriate rehabilitation program.