Effects of physical exercise for children and adolescents undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis

Lago, Aline Simone Dias do; Zaffarani, Caroline; Mendonça, Juliana Fernandes Barreto; Moran, Cristiane Aparecida; Costa, Dirceu; Gomes, Evelim Leal de Freitas Dantas

doi:10.1016/j.htct.2020.07.013

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Hematology, Transfusion and Cell Therapy

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Review article • Hematol., Transfus. Cell Ther. 43 (03) • Jul-Sep 2021 • https://doi.org/10.1016/j.htct.2020.07.013 copy

Effects of physical exercise for children and adolescents undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Hematopoietic stem cell transplantation (HSCT) is a treatment that requires long periods of hospitalization. The mobility restrictions result in physical, functional and psychological impairments. Physical exercise is a therapy that can restore physical and functional capacities; however, it is necessary to understand the effects of its practice in post-HSCT individuals. The purpose of this systematic review (SR) was to assess the impact of physical exercise in children and adolescents undergoing HSCT. The SR was conducted following the PRISMA guidelines through search in the electronic databases Embase, Lilacs, PEDro, PubMed and SCOPUS, without limitation of dates and languages. Randomized or non-randomized clinical trials with children and adolescents who underwent HSCT, aged between 3 to 19 years old, who participated in a regular physical activity program, were assessed. After removing duplicates and selecting studies according to the eligibility criteria, seven parallel studies incorporating hospitalized and discharged participants undertaking aerobic and strengthening exercises were included in this study. The main outcomes analyzed were exercise capacity, quality-of-life, body composition and freedom. Five studies comprised the meta-analysis regarding the effects of the distance walked in the 6-min walk test and quality-of-life. Physical exercise is considered to be safe, feasible and efficacious to prevent the decline of the quality-of-life in children and adolescents undergoing HCST, as well as a considerable improvement in physical capacity.

Keywords:
Hematopoietic stem cell; transplantation; Children; Physical exercise; Quality of life; Bone marrow transplantation

Study	Group	type	Frequency	Duration	Variables	Results
Chamorro-Vina et al.¹¹11 Chamorro-Vina C, Ruiz JR, Santana-Sosa E, Gonzalez VM, Madero L, Perez M, et al. Exercise during hematopoietic stem cell transplant hospitalization in children. Med Sci Sports Exerc. 2010;42(6):1045–53.	Exercise (EG)	In-hospital	5 × ∼50 min per week	3 weeks	• Immune cells (blood counts of leukocytes, monocytes, lymphocytes, and lymphocyte subpopulations	The immune cells measurement showed no significant responses pre- and post-transplantation in both groups. However, the post-transplant decrease was more abrupt in the CG than that in the EG.
	n = 7 Control (CG)	Exercise program (EP) EG: aerobic and resistance exercises			• Anthropometric variables (body mass, body mass index and estimated fat-free mass)	Significant effect of the EG versus time for all anthropometric variables (weight, body mass index, body fat, and fat-free mass), indicating an increase over the hospitalization period in the EG compared to CG.
	n = 13	CG: non-exercise program
Dubnov-Raz et al.¹³13 Dubnov-Raz G, Azar M, Reuveny R, Katz U, Weintraub M, Constantini NW. Changes in fitness are associated with changes in body composition and bone health in children after cancer. Acta Paediatr. 2015;104:1055–61.	EG	Home-based EP	3 × 60 min per week,	6 months	• Physical fitness	No differences found between the groups in changes in physical fitness indexes, body composition or mental health. Significant correlations were found in bone density and lean body mass in all participants.
	n = 12	EG: endurance, strengthening and stretching training.			• Body composition
	CG n = 12	GC: non-exercise program			• Bone density • Mood • Quality-of-life (QoL)
Kabak et al.¹⁴14 Kabak VY, Duger T, Cetinkaya DU. Investigation of the effects of an exercise program on physical functions and activities of daily life in pediatric hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2016;63:1643–8.	EG	Combined in-hospital and home-based EP	7 × (20–40) min per week.	1 month	• Physical function	The study determined that the exercise program had positive effects in physical function and functional performance in the EG, in contrast with the worsened performance in the CG. Regarding ADL, no difference was found between the two groups.
	n = 11	EG: strengthening, endurance, stretching, and relaxation exercises.			• Functional performance
	CG	CG: non-exercise program			• Activities of daily life (ADL)
	n = 11				• 6MWT
Chamorro-Vina et al.¹¹11 Chamorro-Vina C, Ruiz JR, Santana-Sosa E, Gonzalez VM, Madero L, Perez M, et al. Exercise during hematopoietic stem cell transplant hospitalization in children. Med Sci Sports Exerc. 2010;42(6):1045–53.	EG	Combined in-hospital and home-based EP	5 × (20–60) min per week	10 weeks	• Immunological recovery	Significant increase in NKCC concentration eight times greater than that found initially among EG.
	n = 3	EG: aerobic exercise strength training, stretching exercises
	CG	GC: non-exercise program
	n = 3
Wallek et al.¹⁶16 Wallek S, Senn-Malashonak A, Vogt L, Schmidt K, Bader P, Banzer W. Impact of the initial fitness level on the effects of a structured exercise therapy during pediatric stem cell transplantation. Pediatr Blood Cancer. 2018;65(2).	EG	In-hospital EP	5 × (40–60) min per week	Up to hospital discharge	• 6-min walking distance (6MWD)	Intergroup comparison revealed significant differences between the two groups. The EG increased their 6MWD by +8%, whereas both CGs presented a decline in the 6MWD. At discharge, the EG achieved 80% of healthy reference values.
	n = 27	EG: endurance training, muscle strengthening and ﬂexibility training
	CG	GC: non-exercise program
	n = 27
Senn-Malashonak et al.¹⁵15 Senn-Malashonak A, Wallek S, Schmidt K, Rosenhagen A, Vogt L, Bader P, et al. Psychophysical effects of an exercise therapy during pediatric stem cell transplantation: a randomized controlled trial. Bone Marrow Transplant. 2019;54(11):1827–35.	EG	In-hospital EP	5 × (30–60) min	Up to hospital discharge	• Maximal isometric knee extension strength (KES)	KES, 6MWD, and HGS significantly decreased in the CG, while there were no changes in the IG. Preto post-changes in 6MWD and HGS differed significantly between groups. QoL declined in both groups.
	n = 35	EG: resistance, endurance, and ﬂexibility training			• Hand grip strength (HGS)
	CG	GC: mental and relaxation training			• 6MWD
	n = 35				• QoL • Medical parameters
Yildiz Kabak et al.¹⁹19 Yildiz Kabak V, Cetinkaya DU, Kuskonmaz B, Cetin N, Duger T. Effects of multimodal exercise on clinical status and patient-reported outcomes in children undergoing hematopoietic stem cell transplantation. Pediatr Hematol Oncol. 2019;36(7):410–21.	EG	Combined in-hospital and home-based EP	5 × (30–60) min	Up to hospital discharge	• Depression	Pain intensity and days with pain were lower in IG (p < 0.05).
	n = 15	EG: resistance, endurance, and ﬂexibility training		And 1 month after discharge	• Pain	QoL declined in both groups.
	CG	CG: non-exercise program			• Fatigue	Level of depression and Fatigue were lower in IG.
	n = 11				• QoL • Parents QoL

Study	Chamorro-Vina et al.¹¹11 Chamorro-Vina C, Ruiz JR, Santana-Sosa E, Gonzalez VM, Madero L, Perez M, et al. Exercise during hematopoietic stem cell transplant hospitalization in children. Med Sci Sports Exerc. 2010;42(6):1045–53.	Dubnov-Raz et al.¹³13 Dubnov-Raz G, Azar M, Reuveny R, Katz U, Weintraub M, Constantini NW. Changes in fitness are associated with changes in body composition and bone health in children after cancer. Acta Paediatr. 2015;104:1055–61.	Kabak et al.¹⁴14 Kabak VY, Duger T, Cetinkaya DU. Investigation of the effects of an exercise program on physical functions and activities of daily life in pediatric hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2016;63:1643–8.	Chamorro-Vina et al.¹¹11 Chamorro-Vina C, Ruiz JR, Santana-Sosa E, Gonzalez VM, Madero L, Perez M, et al. Exercise during hematopoietic stem cell transplant hospitalization in children. Med Sci Sports Exerc. 2010;42(6):1045–53.	Wallek et al.¹⁶16 Wallek S, Senn-Malashonak A, Vogt L, Schmidt K, Bader P, Banzer W. Impact of the initial fitness level on the effects of a structured exercise therapy during pediatric stem cell transplantation. Pediatr Blood Cancer. 2018;65(2).	Senn- Malashonak et al.¹⁵15 Senn-Malashonak A, Wallek S, Schmidt K, Rosenhagen A, Vogt L, Bader P, et al. Psychophysical effects of an exercise therapy during pediatric stem cell transplantation: a randomized controlled trial. Bone Marrow Transplant. 2019;54(11):1827–35.	Yildiz Kabak et al.¹⁹19 Yildiz Kabak V, Cetinkaya DU, Kuskonmaz B, Cetin N, Duger T. Effects of multimodal exercise on clinical status and patient-reported outcomes in children undergoing hematopoietic stem cell transplantation. Pediatr Hematol Oncol. 2019;36(7):410–21.
Eligibility criteria were specified	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Subjects were randomly allocated to groups (in a crossover study, subjects were randomly allocated an order in which treatments were received).	No	No	No	Yes	No	No	Not reported
Allocation was concealed.	No	Yes	Yes	Yes	No	Yes	Yes
The groups were similar at baseline regarding the most important prognostic indicators.	Yes	Yes	Yes	Yes	Yes	Yes	Yes
There was blinding of all subjects.	No	No	No	No	No	No	No
There was blinding of all therapists who administered the therapy.	No	No	No	No	No	No	No
There was blinding of all assessors who measured at least one key outcome.	No	No	No	No	No	No	No
Measures of at least one key outcome were obtained from more than 85% of the subjects initially allocated to groups.	Yes	Yes	Yes	Yes	Yes	Yes	Yes
All subjects for whom outcome measures were available received the treatment or control condition as allocated or, Not being the case, data for at least one key outcome was analyzed by “intention to treat”.	No	No	No	No	No	No	No
The results of between-group statistical comparisons are reported for at least one key outcome.	Yes	Yes	Yes	Yes	Yes	Yes	Yes
The study provides both point measures and measures of variability for at least one key outcome	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Total/10	4	5	5	6	4	5	5

Certainty assessment							No. of patients			Effect	Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Exercise	Non-exercise	Relative (95% CI)	Absolute (95% CI)
Quality of life (follow-up: mean 3 months)
2						Randomized trials	Serious^a a No blind studies.	Not serious	Not serious	Not serious	None	25	22	–	MD 11.5 higher (2.21 higher than 20.8 higher)	⊕⊕⊕○MODER-ATE	IMPORTANT
6MWT covered distance in percentage of the predicted value (follow-up: mean 3 weeks)
2						Randomized Serious^a a No blind studies.	Not serious	Not serious	Not serious	None	62	62	–	MD 12.59 higher (7.14 higher than 18.03 higher)	⊕⊕⊕○MODER-ATE	IMPORTANT

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[1] *Correspondent author at: Rua Vergueiro, 235/249 — Liberdade, São Paulo, SP, Brazil. E-mail address: evelimgomes@uni9.pro.br (E.L. Gomes).