Plain language summary
Physical exercise training interventions for children and young adults during and after treatment for childhood cancer
Childhood cancer is much less common than adult cancer at around 144 to 148 cases per one million children (Cancer Research UK 2011; National Cancer Institute 2012). An intensive treatment, including combined treatment modalities such as surgery, chemotherapy, radiotherapy, or a combination, is often needed for cure. These treatment modalities are frequently accompanied by adverse events, such as nausea, serious infections, organ damage (heart, lung, kidney, liver), decreased bone density, but also decreased muscle strength and physical fitness.
In the past, children were advised to recover in bed, and to take as much rest as needed. Nowadays, it is considered that too much immobility may result in a further decrease of physical fitness and physical functioning. These adverse effects might be prevented or minimised by introducing a physical exercise training intervention during, or shortly after, childhood cancer treatment.
This review includes four randomised controlled trials and one clinical controlled trial that evaluated the effects of a physical exercise training programme in children during cancer treatment. Childhood acute lymphoblastic leukaemia (ALL) is the most common type of childhood cancer. For that reason, researchers often focus on this type of cancer. In total 131 participants with ALL were included in the analysis. The results of the review show that physical exercise training interventions can be performed in children with this type of cancer and that there are some small benefits on body composition (percentage of fat mass, muscles, and bones), flexibility, and cardiorespiratory fitness (endurance capacity). However, the evidence for a benefit on physical fitness of these interventions is limited due to methodological limitations of the included studies. More studies assessing the effects of exercise on body composition, muscle functioning, daily activity, psychological functioning, or a combination of these, are needed. Furthermore, the current findings do not provide enough evidence to identify the optimal physical exercise training programme for children with cancer, neither do they provide information on the characteristics of people who will, or will not, benefit from such a programme. These important issues still need to be clarified.
Interventions d'exercice physique pour enfants et jeunes adultes pendant et après un traitement pour cancer infantile
Les cancers de l'enfant sont beaucoup moins fréquents que les cancer de l'adulte : environ 144 à 148 cas par million d'enfants (Cancer Research UK 2011; National Cancer Institute 2012). Un traitement intensif, notamment la combinaison de modalités de traitement telles que la chirurgie, la chimiothérapie et la radiothérapie, est souvent nécessaire pour les guérir. Ces modalités de traitement produisent souvent des effets indésirables, tels que des nausées, des infections graves, des dommages aux organes (cœur, poumon, rein, foie), une diminution de la densité osseuse, mais aussi une baisse de la force musculaire et de la condition physique.
Dans le passé, on recommandait que les enfants gardent le lit et se reposent autant que nécessaire. De nos jours, il est considéré que trop d'immobilité peut entraîner une baisse supplémentaire de la condition physique et du fonctionnement physique. Ces effets indésirables peuvent être évités ou minimisés par l'introduction d'une intervention d'exercice physique pendant, ou tout de suite après, le traitement du cancer infantile.
Cette revue comprend quatre essais contrôlés randomisés et un essai clinique contrôlé qui avaient évalué les effets d'un programme d'exercice physique pour enfants en cours de traitement anticancéreux. La leucémie lymphoblastique aiguë (LLA) infantile est le type de cancer le plus commun chez l'enfant. C'est pourquoi les chercheurs se concentrent souvent sur ce type de cancer. Au total, 131 participants atteints de LLA ont été inclus dans l'analyse. Les résultats de la revue montrent que des interventions d'exercice physique peut être pratiquées chez les enfants atteints de ce type de cancer et que cela est de quelque bénéfice pour la composition corporelle (pourcentage de graisse, de muscles et d'os), la souplesse et la condition cardiorespiratoire (la capacité d'endurance). Toutefois, les preuves d'un bénéfice de ces interventions sur la condition physique sont entachées par les limitations méthodologiques des études incluses. De nouvelles études sont nécessaires qui évalueront les effets de l'exercice sur la composition corporelle, le fonctionnement musculaire, l'activité quotidienne, le fonctionnement psychologique ou une combinaison de ceux-ci. En outre, les résultats actuels ne fournissent pas suffisamment d'éléments probants pour identifier le programme optimal d'exercice physique pour les enfants atteints de cancer, et ils ne fournissent pas non plus d'informations sur les caractéristiques des personnes susceptibles ou non de tirer bénéfice d'un tel programme. Ces questions importantes doivent encore être clarifiées.
Notes de traduction
Traduit par: French Cochrane Centre 3rd October, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.
Resumo para leigos
Exercícios para crianças e adultos jovens durante e após o tratamento para câncer infantil
O câncer infantil é bem mais raro do que o câncer nos adultos, e afeta cerca de 144 a 148 a cada um milhão de crianças (Cancer Research UK 2011;National Cancer Institute, 2012). Tratamento intensivo, incluindo cirurgia, quimioterapia, radioterapia ou uma combinação dessas modalidades, é muitas vezes necessário para a cura. Esses tratamentos são frequentemente acompanhados por eventos adversos, tais como náuseas, infecções graves, danos em órgãos (coração, pulmão, rim, fígado), diminuição da densidade óssea, além da diminuição da força muscular e da aptidão física.
No passado, as crianças eram aconselhados a se recuperar na cama e repousar o quanto necessário. Hoje em dia, acredita-se que o excesso de imobilidade pode levar a uma redução ainda maior da aptidão física e da capacidade funcional. Esses efeitos adversos podem ser evitados ou minimizados através da introdução de exercícios físicos durante ou logo após o tratamento do câncer infantil.
Esta revisão inclui quatro estudos clínicos randomizados e um estudo clínico controlado que avaliaram os efeitos de um programa de treinamento físico para crianças em tratamento de câncer. A leucemia linfoblástica aguda (LLA) é o tipo mais comum de câncer infantil. Por essa razão, os pesquisadores muitas vezes se concentram mais nesse tipo de câncer. No total, 131 participantes com LLA foram incluídos na análise. Os resultados da análise mostram que o treinamento físico pode ser realizado em crianças com esse tipo de câncer e que ele leva a algumas pequenas vantagens sobre a composição corporal (percentual de gordura, músculos e ossos), flexibilidade e aptidão cardiorrespiratória (resistência/capacidade). No entanto, a evidência para um benefício na aptidão física dessas intervenções é limitada devido às limitações metodológicas dos estudos incluídos. São necessários mais estudos que avaliem os efeitos do exercício sobre a composição corporal, o funcionamento muscular, a atividade diária, o funcionamento psicológico, ou uma combinação destes desfechos. Além disso, as evidências atuais não são suficientes para apontar qual seria o programa de treinamento físico ideal para crianças com câncer, nem para dizer quais participantes irão se beneficiar com esse tipo de programa. Essas importantes questões ainda precisam ser esclarecidas.
Notas de tradução
Tradução do Centro Cochrane do Brasil (Rhayssa Espósito).
Description of the condition
Only a small percentage of the total population suffer from childhood cancer; approximately 144 to 148 cases per million children (Cancer Research UK 2011; National Cancer Institute 2012). However the impact of childhood cancer is significant. Many studies report a decreased physical fitness (aerobic capacity and muscle strength) and a poor social functioning, in patients and survivors of acute lymphoblastic leukaemia (ALL), which is the most common type of childhood cancer (Aznar 2006; Hartman 2009; Hovi 1993; Marchese 2004; Moyer-Mileur 2009; San Juan 2008; Warner 1998; Warner 2008; Wright 1998; Wright 2005) and also in childhood cancer patients in general (Arroyave 2008; Cox 2008; De Caro 2006; Hartman 2008; Ness 2005; Ness 2009; Winter 2009). In addition, a considerable number of survivors of childhood cancer suffer from motor function disability (Geenen 2007; Van Brussel 2006). Motor function disability in patients or survivors of childhood cancer is mostly related to negative motor signs, such as insufficient muscle activity, or muscle weakness (Hartman 2008; Wright 2005). A reduced daily energy expenditure and lower levels of physical activity have been described as the most important cause of this reduced state of physical fitness in childhood cancer patients (Warner 2008).
Positive effects of exercise training on physical fitness have been reported in studies with adult cancer patients (Cramp 2008; Oldervoll 2004; Schmitz 2005; Watson 2004). It is hypothesised that similar results are possible in children with cancer, or survivors of childhood cancer (Moyer-Mileur 2009).
Description of the intervention
The intervention under consideration was a physical exercise training programme, introduced within the first five years following the diagnosis of childhood cancer. The exercise training should aim to increase physical fitness by aerobic, anaerobic, strength, or mixed fitness training.
How the intervention might work
Cancer and cancer treatment induce lean tissue degeneration and can, therefore, potentially cause abnormalities in the cardiac and skeletal muscle (Schneider 2007). A decline in protein synthesis and protein degeneration by cancer and its treatment, can reduce muscle mass, the muscle fibre cross-section, and muscle extensibility. This can result in a decreased oxidative enzyme activity and a decreased number of proteins necessary for metabolism (Schneider 2007). Cancer patients often experience muscle weakness, a decreased functional capacity, decreased flexibility, reduced mobility, and diminished health-related quality of life (HRQoL) (Hartman 2008; Schneider 2007). In addition, a decreased psychosocial functioning and HRQoL as a result of cancer has impact on a person's motivational drive and can result in a poorer self perception of one's ability to perform physical activity (Warner 2008; Wright 1998).
Physical activity can prevent or diminish the negative effects of a sedentary life-style such as obesity, poor skeletal health, fatigue, and poor mental health, thereby increasing HRQoL of the individual. Increasing physical activity is possible by adopting a less inactive life-style and increasing sports participation. Beneficial effects of physical activity during or shortly after cancer therapy are an increase in muscle mass and plasma volume, improved lung ventilation and lung perfusion, and also an increased cardiac reserve, which can lead to a higher concentration of oxidative muscle enzymes.
This was seen in the study by Dimeo et al (2001); the children with cancer who received cancer treatment with glucocorticoids in combination with resistance exercises, showed less muscle mass loss than the children who did not receive the additional physical exercise training intervention (Dimeo 2001).
Why it is important to do this review
Despite the positive results of exercise interventions in adult cancer patients, the evidence for benefits in childhood cancer patients is limited. Studies within the population of childhood cancer patients and survivors have been initiated and the first data have been published. However, the number of participants in the various publications is small and the variety in type of cancer limited, making it difficult to draw conclusions. In making healthcare management decisions, participants and clinicians must weigh the benefits and drawbacks of supportive care. Pooled data can help in this decision-making process.
The purpose of this Cochrane review is to summarise the existing literature on the effectiveness of physical exercise training interventions in children with cancer, implemented within the first five years from diagnosis and to provide a best-evidence synthesis or meta-analysis of the reported results.
To evaluate the effect of a physical exercise training intervention on the physical fitness (e.g. aerobic capacity, muscle strength, or functional performance) of children with cancer within the first five years from their diagnosis (performed either during or after cancer treatment), compared to a control group of childhood cancer patients who did not receive an exercise intervention.
To determine whether physical exercise within the first five years of diagnosis has an effect on fatigue, anxiety, depression, self efficacy, and HRQoL and to determine whether there are any adverse effects of the intervention.
Summary of main results
Several studies have investigated the effects of exercise interventions on physical fitness in adult cancer patients, showing different benefits. Less frequent are studies assessing these effects in a childhood cancer population, particularly not when looking at RCT or CCT study designs.
This review included five studies. All these studies investigated the effects of a physical exercise training intervention programme of at least four weeks' duration, in children with cancer. They all aimed to improve physical functioning or psychosocial well-being, and had enrolled children with ALL. The five included studies included limited participant numbers and some lacked a well-designed exercise intervention. Therefore the outcomes of this review should be interpreted with care.
Cardiorespiratory fitness was studied by the use of the nine-minute run-walk test, the timed up-and-down stairs test, and the 20-m shuttle run test. Only the 20-m shuttle run test showed significantly better scores in the intervention group compared with the control group (P value = 0.05, no further information available).
For BMD, a statistically significant difference in favour of the exercise group was identified (SMD 1.07; 95% CI 0.48 to 1.66; P value < 0.001). BMI was assessed in two studies. In contrast with the results of one of these studies (SMD 0.90; 95% CI 0.32 to 1.48), the pooled data did not show a statistically significant difference between the combined population in the intervention and control group.
Flexibility was assessed in three studies and each study used different test methods. No (statistically significant) difference between the study groups was identified in two studies, whereas in another study a statistically significant difference in favour of the exercise group was found (SMD 0.69; 95% CI: 0.12 to 1.25; P value = 0.02).
The study of Macedo 2010 focused on muscles of the lung. In this study an inspiratory muscle training programme aimed to increase inspiratory or expiratory muscle strength. No significant effects where found for either inspiratory or expiratory muscle strength. Two other studies using either the knee and ankle strength changes measured by hand-held dynamometry or the number of completed push-ups (with knees on the ground) and a peripheral quantitative computed tomography of the tibia to determine the muscle mass identified no statistically significant differences in muscle strength/endurance.
No statistically significant differences between the study groups were found for the level of daily activity, HRQoL, or fatigue. In addition, only one study reported no complications attributed to the physical exercise intervention programme, whereas the other studies did not address this item.
None of the included studies evaluated the outcomes of activity energy expenditure, time spent exercising, anxiety and depression, or self efficacy.
It should be noted that the exercise interventions were not the same and the quality and quantity of the evidence was limited.
For the future it will be best to assess the effects of one type of exercise intervention in more childhood cancer subgroups. This can be done in well-designed studies with large sample sizes.
Overall completeness and applicability of evidence
This review provides evidence for modest but positive effects of physical exercise training interventions for children with cancer. These modest effects could be due to small sample sizes, various interventions, and different outcome measures that were used in the studies included in this review. As a result, only data for BMI could be pooled; therefore, the results of the analysis were instable and weak. Although the meta-analysis and sensitivity analysis outcome on BMI were robust, the patient population was unintentionally homogeneous since ; all included children had ALL. The results of this review, therefore, are not applicable for other types of childhood cancer.
The RevMan analyses results of this review are very different to the analysis performed by the authors of some of the studies, which led to different conclusions. For Macedo 2010, Hartman 2009, and Marchese 2004, the differences were due to different methods of analysis. In this review we assessed the final outcome differences between the study groups (Analysis 4.1; Analysis 4.3; Analysis 4.4) and found no changes over time.
The included studies all had supervised interventions with a duration and intensity in which it was possible to have a physiological response (Hartman 2009; Macedo 2010; Marchese 2004; Moyer-Mileur 2009; Yeh 2011). From literature it is known that supervised exercise interventions in children are more effective compared to non-supervised programmes (Faigenbaum 2010). It is also known that a well-designed exercise programme consists of four parameters: mode (type of exercise), intensity, frequency, and duration (ACSM 2010; Ganley 2011). It would be advisable for new studies to first determine if the planned programme includes all elements of these parameters. This will increase the quality of the trials and also increase the comparability.
Appropriate statistical methods are important. The use of incorrect statistical methods can diminish the likelihood of demonstrating the real effects, also in high-quality interventions. In this review only one of the included studies used a power calculation (Hartman 2009). In the included studies the authors used a Chi2 test or the Mann-Whitney U test (Hartman 2009; Moyer-Mileur 2009), the Kruskal-Wallis (Moyer-Mileur 2009), and the paired sample T-test (Macedo 2010) to assess baseline (pre-score) differences between the study groups. The baseline scores were reported as group average (Hartman 2009; Macedo 2010; Marchese 2004; Yeh 2011), but also per study participant (Moyer-Mileur 2009). These baseline differences might have had a large impact on the results and conclusions of this review. It would have been preferable for all authors to have corrected for baseline differences in their analyses. However this was not done. To increase the quality of evidence of this review we hoped to be able to pool all raw data (baseline and end of study data) in one database. This would have given us the possibility to correct for these differences. Yet, not all researchers responded to our request for additional information.
To investigate changes between participants and changes over time the paired sample T-tests (Hartman 2009; Macedo 2010), Friedman two-way test (Moyer-Mileur 2009), the mixed-effects model (Yeh 2011), and repeated measure analyses (Hartman 2009; Marchese 2004) were used in the included studies. The mixed-effect model and repeated measure analyses are more specific than comparing group mean changes. Therefore, the results of the studies using the better statistical methods are possibly better than the ones using simple statistical techniques. However, in this review we were not able to use this information in the outcome.
Quality of the evidence
By grading the evidence according to the GRADE criteria (Guyatt 2008) the overall quality of the studies varied between low and very low. Due to risk of bias, inconsistency, indirectness, imprecision, possible publication bias, or a combination of these, the qualities of the studies were downgraded. None of the articles was eligible for upgrading. The quality of the evidence is summarised in the 'Summary of findings' table (Summary of findings for the main comparison). The small numbers of participants in the trials was the main reason for the low-quality scores. This is often the case in studies in a paediatric population, and in cases of newly introduced interventions. More and larger well-controlled studies are needed to improve the quality and the quantity of evidence. This also shows the need for a core-set of outcome measures in exercise-related research in childhood chronic conditions (Van Brussel 2011).
This review included five studies, all with small numbers of participants. Between the studies there is a considerable degree of heterogeneity on mode and intensity of the exercise interventions. Only BMI was assessed in two different studies with no substantial heterogeneity (I2 = 48%). None of the other more important outcome measures were assessed in more than one study. This prevented further pooling of the data.
Potential biases in the review process
The search strategies for MEDLINE/PubMed, EMBASE/OVID, CENTRAL were formulated by the Cochrane Childhood Cancer Group. In addition, two other databases were searched by the use of a search strategy we developed ourselves: CINAHL and PEDro. The PEDro database was difficult to search. Although it is possible that we missed one or two studies from this database, due to the great overlap between results of the different databases it is very unlikely that studies were missed.
Agreements and disagreements with other studies or reviews
In 2010, a review on childhood cancer and physical activity was published by Winter 2010. This review included 28 studies, and almost half had an uncontrolled study design. In eight studies healthy controls were used. Of the four RCTs included in that review, one study included long-term childhood cancer survivors (mean 12 years from diagnosis). Another RCT offered a two- to four-day intervention, which therefore did not match with the inclusion criteria of this Cochrane review (Hinds 2007). The two remaining RCTs of the review by Winter 2010 are also included in this Cochrane review (Hartman 2009; Marchese 2004). A second review on exercise interventions for childhood cancer patients was performed by Huang 2011. They included many of the same studies, but also the study of Chamorro-Vina 2010, which again introduced an intervention of less than four weeks. Both reviews concluded that results are promising, but that there is a need for more and larger RCTs. Both reviews stated that only a subgroup of the childhood cancer population was tested, since almost all studies concerned children with ALL. These findings are consistent with our findings.
We would like to thank Edith Leclercq for developing and running the search strategy for CENTRAL, MEDLINE, and EMBASE. We would like to thank Bart Bartels, MSc for translating the Portuguese article and Dr. Annelies Hartman for providing additional data, the results of her study population, and her comments in the reviewing process. Also, we would like to thank Dr. Mariska Leeflang for her remarks, as well as the third external review author. In addition we would like to mention that the editorial base of the Cochrane Childhood Cancer Group is funded by Stichting Kinderen Kankervrij (KIKA), Foundation Children Cancer-free.
Appendix 1. Search strategy for MEDLINE/PubMed
1. For children the following MeSH headings and text words were used:
infant OR infan* OR newborn OR newborn* OR new-born* OR baby OR baby* OR babies OR neonat* OR perinat* OR postnat* OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar* OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric* OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school* OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy OR schools, nursery OR infant, newborn
2. For cancer and childhood cancer the following MeSH headings and text words were used:
cancer OR oncology OR oncolog* OR neoplasms OR neoplas* OR carcinoma OR carcinom* OR tumor OR tumour OR tumor* OR tumour* OR cancer* OR malignan* OR hematooncological OR hemato oncological OR hemato-oncological OR hematologic neoplasms OR hematolo* OR bone marrow transplantation OR bone marrow transplant* OR lymphoma OR (((leukemia OR leukemi* OR leukaemi* OR (childhood ALL) OR AML OR lymphoma OR lymphom* OR hodgkin OR hodgkin* OR T-cell OR B-cell OR non-hodgkin OR sarcoma OR sarcom* OR sarcoma, Ewing's OR Ewing* OR osteosarcoma OR osteosarcom* OR wilms tumor OR wilms* OR nephroblastom* OR neuroblastoma OR neuroblastom* OR rhabdomyosarcoma OR rhabdomyosarcom* OR teratoma OR teratom* OR hepatoma OR hepatom* OR hepatoblastoma OR hepatoblastom* OR PNET OR medulloblastoma OR medulloblastom* OR PNET* OR neuroectodermal tumors, primitive OR retinoblastoma OR retinoblastom* OR meningioma OR meningiom* OR glioma OR gliom*) OR (pediatric oncology OR paediatric oncology)) OR (childhood cancer OR childhood tumor OR childhood tumors)) OR (brain tumor* OR brain tumour* OR brain neoplasms OR central nervous system neoplasm OR central nervous system neoplasms OR central nervous system tumor* OR central nervous system tumour* OR brain cancer* OR brain neoplasm* OR intracranial neoplasm*) OR (leukemia lymphocytic acute) OR (leukemia, lymphocytic, acute[mh])
3. For physical exercise training therapy the following MeSH headings and text words were used:
exercise OR exercises OR exercis* OR Exercise, Physical OR Exercises, Physical OR Physical Exercise OR Physical Exercises OR Exercise, Isometric OR Exercises, Isometric OR Isometric Exercises OR Isometric Exercise OR Warm-Up Exercise OR Exercise, Warm-Up OR Exercises, Warm-Up OR Warm Up Exercise OR Warm-Up Exercises OR Exercise, Aerobic OR Aerobic Exercises OR Exercises, Aerobic OR Aerobic Exercise OR exercise therapy OR Therapy, Exercise OR Exercise Therapies OR Therapies, Exercise OR physical therapy modalities OR Modalities, Physical Therapy OR Modality, Physical Therapy OR Physical Therapy Modality OR Physiotherapy (Techniques) OR Physiotherapies (Techniques) OR Physical Therapy Techniques OR Physical Therapy Technique OR Techniques, Physical Therapy OR exercise test OR exercise tests OR muscle stretching exercise OR muscle stretching exercises OR physical therapy OR physical therapies OR strengthen* OR stretch* OR physiotherapy[text] OR physiotherap*[text] OR stability training OR training* OR exercise movement technique OR exercise movement techniques OR Movement Techniques, Exercise OR exercise movement technic OR Exercise Movement Technics OR pilates based exercise OR pilates-based exercise OR Pilates Based Exercises OR Pilates-Based Exercises OR Exercises, Pilates-Based OR pilates OR physical exercise OR gymnastics OR gymnastic OR gymnastic* OR swimming OR locomotion OR locomotions OR locomotion* OR treadmill OR walking OR running OR aerobic OR aerobics OR aerobic* OR cycling OR jogging OR Exertion OR disability of function[text] OR occupational therapy OR occupational therapies OR functional therapy[text] OR functional therapies[text] OR training program OR physical education and training OR Physical Education, Training OR Physical Education OR Education, Physical OR fitness OR cardio training OR weight lifting OR power training OR muscle training OR rowing OR sports OR jump OR jumping
4. For outcome the following MeSH headings and text words were used:
quality of life OR Qol OR condition* OR physical fitness OR Fitness, Physical OR Physical Conditioning, Human OR Conditioning, Human Physical OR Conditionings, Human Physical OR Human Physical Conditioning OR Human Physical Conditionings OR Physical Conditionings, Human OR physical effort OR physical skill OR physical activity OR muscle strength OR muscular strength OR lung function OR pulmonary function OR vital capacity OR Depression OR Depressive Disorder OR Depression, involutional OR fear OR recovery of function OR physical endurance OR range of motion OR VO2 OR VO(2peak) OR ventilatory threshold OR heart rate OR endurance OR activity energy expenditure OR DXA scan OR activity participation OR mets score OR DeltaMetS OR Wingate anaerobic test OR steep ramp test OR dynamometer OR Six Minute Walk Distance OR 6MWD OR lateral step up OR Sit-to-Stand OR ten repetition maximum OR minimum chair height OR muscle power OR gross motor function OR GMFCS OR GMFM OR incremental shuttle walking OR sit-and-reach
5. For RCTs and CCTs the following MeSH headings and text words were used:
(randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab]) AND humans[mh] (Higgins 2011)
1 AND 2 AND 3 AND 4 AND 5
[tiab]=title or abstract
[*]=1+ more characters
[RCT]= randomised controlled trial
[CCT]= controlled clinical trial
Appendix 2. Search strategy for EMBASE/OVID
1. Forchildren the following Emtree terms and text words were used:
1. infant/ or infancy/ or newborn/ or baby/ or child/ or preschool child/ or school child/
2. adolescent/ or juvenile/ or boy/ or girl/ or puberty/ or prepuberty/ or pediatrics/
3. primary school/ or high school/ or kindergarten/ or nursery school/ or school/
5. (infant$ or newborn$ or (new adj born$) or baby or baby$ or babies or neonate$ or perinat$ or postnat$).mp.
6. (child$ or (school adj child$) or schoolchild$ or (school adj age$) or schoolage$ or (pre adj school$) or preschool$).mp.
7. (kid or kids or toddler$ or adoles$ or teen$ or boy$ or girl$).mp.
8. (minors$ or (under adj ag$) or underage$ or juvenil$ or youth$).mp.
9. (puber$ or pubescen$ or prepubescen$ or prepubert$).mp.
10. (pediatric$ or paediatric$ or peadiatric$).mp.
11. (school or schools or (high adj school$) or highschool$ or (primary adj school$) or (nursery adj school$) or (elementary adj school) or (secondary adj school$) or kindergar$).mp.
13. 4 or 12
2. For childhood cancer the following Emtree terms and text words were used:
1. (leukemia or leukemi$ or leukaemi$ or (childhood adj ALL) or acute lymphocytic leukemia).mp.
2. (AML or lymphoma or lymphom$ or hodgkin or hodgkin$ or T-cell or B-cell or non-hodgkin).mp.
3. (sarcoma or sarcom$ or Ewing$ or osteosarcoma or osteosarcom$ or wilms tumor or wilms$).mp.
4. (nephroblastom$ or neuroblastoma or neuroblastom$ or rhabdomyosarcoma or rhabdomyosarcom$ or teratoma or teratom$ or hepatoma or hepatom$ or hepatoblastoma or hepatoblastom$).mp.
5. (PNET or medulloblastoma or medulloblastom$ or PNET$ or neuroectodermal tumors or primitive neuroectodermal tumor$ or retinoblastoma or retinoblastom$ or meningioma or meningiom$ or glioma or gliom$).mp.
6. (pediatric oncology or paediatric oncology).mp.
7. ((childhood adj cancer) or (childhood adj tumor) or (childhood adj tumors) or childhood malignancy or (childhood adj malignancies) or childhood neoplasm$).mp.
8. ((pediatric adj malignancy) or (pediatric adj malignancies) or (paediatric adj malignancy) or (paediatric adj malignancies)).mp.
9. ((brain adj tumor$) or (brain adj tumour$) or (brain adj neoplasms) or (brain adj cancer$) or brain neoplasm$).mp.
10. (central nervous system tumor$ or central nervous system neoplasm or central nervous system neoplasms or central nervous system tumour$).mp.
11. intracranial neoplasm$.mp.
12. LEUKEMIA/ or LYMPHOMA/ or brain tumor/ or central nervous system tumor/ or teratoma/ or sarcoma/ or osteosarcoma/
13. nephroblastoma/ or neuroblastoma/ or rhabdomyosarcoma/ or hepatoblastoma/ or medulloblastoma/ or neuroectodermal tumor/ or retinoblastoma/ or meningioma/ or glioma/ or childhood cancer/
3. Forcancer the following Emtree terms and text words were used:
1. (cancer or cancers or cancer$).mp.
2. (oncology or oncolog$).mp. or exp oncology/
3. (neoplasm or neoplasms or neoplasm$).mp. or exp neoplasm/
4. (carcinoma or carcinom$).mp. or exp carcinoma/
5. (tumor or tumour or tumor$ or tumour$ or tumors or tumours).mp. or exp tumor/
6. (malignan$ or malignant).mp.
7. (hematooncological or hemato oncological or hemato-oncological or hematologic neoplasms or hematolo$).mp. or exp hematologic malignancy/
4. For physical excercise training therapy the following Emtree terms and text words were used:
1. (exercise or exercises or exercis$).mp.
2. exp exercise/
3. (physical exercise or physical exercises).mp.
4. exp isometric exercise/
5. (isometric exercise or isometric exercises).mp.
6. (warm up exercise or warm up exercises or warm-up exercise or warm-up exercises).mp.
7. exp aerobic exercise/
8. (aerobic exercise or aerobic exercises).mp.
9. exp kinesiotherapy/
10. (exercise therapy or exercise therapies).mp.
11. (physical therapy modality or physical therapy modalities).mp.
12. exp pediatric physiotherapy/ or exp physiotherapy/
13. (physiotherapy or physiotherapies).mp.
14. (physical therapy technique or physical therapy techniques or physical therapy or physical therapies).mp.
15. exp exercise test/
16. (exercise test or exercise tests).mp.
17. exp stretching exercise/
18. (muscle stretching exercise or muscle stretching exercises).mp.
19. (strengthen$ or stretch$).mp.
20. exp muscle exercise/ or stability training.mp. or exp muscle training/
22. (exercise movement technique or exercise movement techniques).mp.
23. (exercise movement technic or exercise movement technics).mp.
24. (pilates-based exercise or pilates based exercise or pilates-based exercises or pilates based exercises).mp.
25. pilates.mp. or exp pilates/
26. physical exercise.mp.
27. (gymnastic or gymnastics or gymnastic$).mp.
28. exp swimming/ or swimming.mp.
29. exp locomotion/
30. (locomotion or locomotions or locomotion$).mp.
31. exp treadmill/ or exp treadmill exercise/
33. walking.mp. or exp walking/
34. exp running/ or running.mp.
35. cycling.mp. or exp cycling/
36. jogging.mp. or exp jogging/
37. (aerobic or aerobics or aerobic$).mp.
39. disability of function.mp.
40. exp occupational therapy/
41. (occupational therapy or occupational therapies).mp.
42. (functional therapy or functional therapies).mp.
43. training program.mp.
44. (physical education and training).mp.
45. physical education.mp. or exp physical education/
46. fitness.mp. or exp fitness/
47. cardio training.mp.
48. weight lifting.mp. or exp weight lifting/
49. power training.mp.
50. muscle training.mp.
51. rowing.mp. or exp rowing/
52. sports.mp. or exp sport/
53. exp jumping/ or (jump or jumping).mp.
5. For outcome the following Emtree terms and text words were used:
1. exp "quality of life"/
2. (quality of life or QoL).mp.
3. general condition improvement/
5. physical fitness.mp. or exp fitness/
6. (human physical conditioning or human physical conditionings).mp.
7. physical effort.mp.
8. physical skill.mp.
9. physical activity.mp. or exp physical activity/
10. (muscle strength or muscular strength).mp. or exp muscle strength/
11. lung function.mp. or exp lung function/
12. pulmonary function.mp.
13. vital capacity.mp. or exp vital capacity/
14. depression.mp. or exp depression/
15. depressive disorder.mp.
16. involutional depression.mp. or exp involutional depression/
17. fear.mp. or exp fear/
18. recovery of function.mp. or exp convalescence/
19. physical endurance.mp. or exp endurance/
20. range of motion.mp. or exp "range of motion"/
21. (VO2 or VO2peak).mp.
22. (VO adj 2peak).mp.
23. ventilatory threshold.mp.
24. heart rate.mp. or exp heart rate/
25. exp endurance/ or endurance.mp.
26. exp energy expenditure/ or activity energy expenditure.mp.
27. exp dual energy X ray absorptiometry/ or DXA scan.mp.
28. activity participation.mp.
29. mets score.mp.
30. (mets or DeltaMetS).mp.
31. Wingate anaerobic test.mp.
32. exp Steep Ramp Test/ or steep ramp test.mp.
33. dynamometer.mp. or exp dynamometer/
34. (Six Minute Walk Distance or 6MWD).mp.
35. lateral step up.mp.
37. ten repetition maximum.mp.
38. minimum chair height.mp.
39. muscle power.mp.
40. (gross motor function or GMFCS or GMFM).mp.
41. incremental shuttle walking.mp.
6. For RCTs and CCTs the following Emtree terms and text words were used:
1. Randomized Controlled Trial/
2. Controlled Clinical Trial/
8. drug therapy.sh.
11. 9 and 10
1 and (2 or 3) and 4 and 5 and 6
[mp]=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name
[RCT]= randomised controlled trial
[CCT]= controlled clinical trial
Appendix 3. Search strategy for Central Register of Controlled Trials (CENTRAL)
1. For children the following text words were used for searching Title, Abstract, or Keywords:
infant OR infan* OR newborn OR newborn* OR new-born* OR baby OR baby* OR babies OR neonat* OR perinat* OR postnat* OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar* OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric* OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school* OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy
2. For childhood cancer the following text words were used for searching Title, Abstract, or Keywords:
(leukemia OR leukemi* OR leukaemi* OR (childhood ALL) OR AML OR lymphoma OR lymphom* OR hodgkin* OR T-cell OR B-cell OR non-hodgkin OR sarcoma OR sarcom* OR Ewing* OR osteosarcoma OR osteosarcom* OR wilms tumor OR wilms* OR nephroblastom* OR neuroblastoma OR neuroblastom* OR rhabdomyosarcoma OR rhabdomyosarcom* OR teratoma OR teratom* OR hepatoma OR hepatom* OR hepatoblastoma OR hepatoblastom* OR PNET OR medulloblastoma OR medulloblastom* OR PNET* OR neuroectodermal tumors, primitive OR retinoblastoma OR retinoblastom* OR meningioma OR meningiom* OR glioma OR gliom* OR pediatric oncology OR paediatric oncology OR childhood cancer OR childhood tumor OR childhood tumors OR cancer or neoplasms or tumor or cancers or neoplasm or tumors)
3. For cancer the following text words were used for searching Title, Abstract, or Keywords:
cancer OR oncology OR oncolog* OR neoplasms OR neoplas* OR carcinoma OR carcinom* OR tumor OR tumour OR tumor* OR tumour* OR cancer* OR malignan* OR hematooncological OR hemato oncological OR hemato-oncological OR hematologic neoplasms OR hematolo* OR bone marrow transplantation OR bone marrow transplant* OR leukaemia OR lymphoma
4. For physical excercise training therapy the following text words were used for searching Title, Abstract, or Keywords:
exercise OR exercises OR exercis* OR Physical Exercise OR Physical Exercises OR Isometric Exercises OR Isometric Exercise OR Warm-Up Exercise OR Warm Up Exercise OR Warm-Up Exercises OR Aerobic Exercises OR Aerobic Exercise OR exercise therapy OR Exercise Therapies OR physical therapy modalities OR Physical Therapy Modality OR Physiotherapy (Techniques) OR Physiotherapies (Techniques) OR Physical Therapy Techniques OR Physical Therapy Technique OR exercise test OR exercise tests OR muscle stretching exercise OR muscle stretching exercises OR physical therapy OR physical therapies OR strengthen* OR stretch* OR physiotherapy OR physiotherap* OR stability training OR training* OR exercise movement technique OR exercise movement techniques OR exercise movement technic OR Exercise Movement Technics OR pilates based exercise OR pilates-based exercise OR Pilates Based Exercises OR Pilates-Based Exercises OR pilates OR physical exercise OR gymnastics OR gymnastic OR gymnastic* OR swimming OR locomotion OR locomotions OR locomotion* OR treadmill OR walking OR running OR aerobic OR aerobics OR aerobic* OR cycling OR jogging OR Exertion OR disability of function OR occupational therapy OR occupational therapies OR functional therapy OR functional therapies OR training program OR physical education and training OR Physical Education OR fitness OR cardio training OR weight lifting OR power training OR muscle training OR rowing OR sports OR jump OR jumping
5. For outcome the following text words were used for searching Title, Abstract, or Keywords:
quality of life OR Qol OR condition* OR physical fitness OR Human Physical Conditioning OR Human Physical Conditionings OR physical effort OR physical skill OR physical activity OR muscle strength OR muscular strength OR lung function OR pulmonary function OR vital capacity OR Depression OR Depressive Disorder OR involutional depression OR fear OR recovery of function OR physical endurance OR range of motion OR VO2 OR VO(2peak) OR ventilatory threshold OR heart rate OR endurance OR activity energy expenditure OR DXA scan OR activity participation OR mets score OR DeltaMetS OR Wingate anaerobic test OR steep ramp test OR dynamometer OR Six Minute Walk Distance OR 6MWD OR lateral step up OR Sit-to-Stand OR ten repetition maximum OR minimum chair height OR muscle power OR gross motor function OR GMFCS OR GMFM OR incremental shuttle walking OR sit-and-reach
1 and (2 or 3) and 4 and 5
[*]=1+ more characters
Appendix 4. Search strategy for CINAHL
1. For children the following the following MeSH headings (MH) and text words were used for searching Title, Abstract, or Keywords:
"schoolage" OR (MH "Schools+") OR "peadiatric" OR "paediatric" OR "pediatric" OR (MH "Puberty+") OR "juvenile" OR "underage" OR "under age" OR ("teenager") or (MH "Adolescence+") OR "adolescent" OR "kids" OR "kid" OR "schoolchild" OR ("child*") or (MH "Child") ("newborn") or (MH "Infant, Newborn+") OR ("infant") or (MH "Infant+")
2. For cancer and childhood cancer the following the following MeSH headings (MH) and text words were used for searching Title, Abstract, or Keywords:
(MH "Central Nervous System Neoplasms+") OR "childhood tumour" OR "childhood tumor" "childhood cancer" OR (MH "Meningioma") OR (MH "Retinoblastoma") OR (MH "Neuroectodermal Tumors+") OR (MH "Ameloblastoma") OR (MH "Teratoma") OR (MH "Rhabdomyosarcoma") OR (MH "Neuroblastoma") OR (MH "Nephroblastoma") OR (MH "Osteosarcoma+") OR (MH "Sarcoma, Ewing's") OR (MH "Sarcoma+") or (MH "Osteosarcoma") OR (MH "Lymphoma+") OR (MH "Leukemia+") OR (MH "Bone Marrow Transplantation+") or (MH "Bone Marrow Neoplasms") OR "hemato oncological" OR ("malignancy") or (MH "Hematologic Neoplasms+") OR "tumour" OR "tumor" OR (MH "Carcinoma+") OR (MH "Neoplasms+") OR ("oncology") or (MH "Oncology+") or (MH "Pediatric Oncology Nursing") or (MH "Oncologic Care") OR ("cancer") or (MH "Neoplasms")
3. For physical exercise training therapy the following the following MeSH headings (MH) and text words were used for searching Title, Abstract, or Keywords:
("sports") or (MH "Sports+") or (MH "Amateur Sports") or (MH "Aquatic Sports") (MH "Rowing") or (MH "Ergometry") OR ("muscle training") or (MH "Muscle Strengthening") OR "power training" OR (MH "Weight Lifting") OR ("cardio training") or (MH "Athletic Training") or (MH "Athletic Training Programs") OR ("fitness") or (MH "Physical Fitness") OR (MH "Physical Education and Training+") OR "training program" "functional therapies" OR "functional therapy" OR (MH "Occupational Therapy+") or (MH "Pediatric Occupational Therapy") OR "disability of function" OR (MH "Exertion") OR (MH "Cycling") or (MH "Ergometry") OR (MH "Running") or (MH "Running, Distance") OR (MH "Walking") or (MH "Sports") OR (MH "Treadmills") OR (MH "Locomotion") or (MH "Movement") OR (MH "Swimming") OR (MH "Gymnastics") OR ("pilates") or (MH "Pilates") OR (MH "Therapeutic Exercise+") or (MH "Aerobic Exercises") or (MH "Arm Exercises") or (MH "Back Exercises") OR (MH "Stretching") OR (MH "Exercise Test+") or (MH "Exercise Test, Cardiopulmonary") or (MH "Exercise Test, Muscular+") OR "physiotherapy" OR ("exercise therapy") or (MH "Therapeutic Exercise+") or (MH "Exercise Therapy: Ambulation (Iowa NIC)") or (MH "Exercise Therapy: Balance (Iowa NIC)") or (MH "Exercise Therapy: Joint Mobility (Iowa NIC)") or (MH "Exercise Therapy: Muscle Control (Iowa NIC)") OR ("physical therapy") or (MH "Physical Therapy+") or (MH "Pediatric Physical Therapy") or (MH "Physical Therapy Practice, Evidence-Based") or (MH "Physical Therapy Practice, Research-Based") OR "therapies" OR (MH "Aerobic Exercises+") or (MH "Therapeutic Exercise+") OR (MH "Warm-Up Exercise") (MH "Isometric Contraction") or (MH "Isometric Exercises") OR ("physical") or (MH "Education, Physical Therapy") or (MH "Home Physical Therapy") or (MH "Pediatric Physical Therapy") or (MH "Physical Activity") OR ("exercise") or (MH "Exercise+") or (MH "Abdominal Exercises") or (MH "Aerobic Exercises+") or (MH "Anaerobic Exercises") or (MH "Aquatic Exercises") or (MH "Arm Exercises") or (MH "Back Exercises")
4. For outcome the following the following MeSH headings (MH) and text words were used for searching Title, Abstract, or Keywords:
"shuttle walking test" or ("repetition maximum") or (MH "Anaerobic Threshold") (MH "Rising") OR("lateral step up") or (MH "Step") OR ("six minute walking distance") or (MH "Running, Distance") or (MH "Walking+") OR(MH "Dynamometry") OR "steep ramp test" OR ("anaerobic test") or (MH "Achievement Tests") OR "wingate" OR (MH "Basal Metabolism") or (MH "Glucose Metabolism Disorders") OR (MH "Leisure Participation (Iowa NOC)") or (MH "Play Participation (Iowa NOC)") OR ("DXA scan") or (MH "Biometrics") OR (MH "Energy Metabolism+") or (MH "Activities of Daily Living+") or (MH "Human Activities+") OR ("endurance") OR (MH "Heart Rate+") or (MH "Heart Rate Variability") OR (MH "Respiratory Muscles") OR "VO2" OR "Vo2 peak" OR (MH "Range of Motion") or (MH "Range of Motion (Saba CCC)") or (MH "Motion Therapy, Continuous Passive") or (MH "Motion") OR (MH "Physical Endurance+") OR (MH "Recovery") or (MH "Functional Assessment") OR (MH "Fear+") OR (MH "Depression+") OR ("lung function") or (MH "Respiratory Function Tests+") or (MH "Functional Status") OR ("muscle strength") or (MH "Muscle Strength+") or (MH "Muscle Strengthening+") or (MH "Exercise Test, Muscular+") OR ("physical skill") or (MH "Exercise Test") or (MH "Motor Skills") or (MH "Social Skills") or (MH "Social Skills Training") OR (MH "Exertion") or (MH "Education, Physical Therapy") or (MH "Home Physical Therapy") OR (MH "Physical Fitness+") or (MH "Fitness Centers") OR (MH "Conditioning (Psychology)") or (MH "Conditioning, Cardiopulmonary") OR (MH "Quality of Life+") or (MH "Health and Life Quality (Iowa NOC) (Non-Cinahl)+")
5. For RCTs and CCTs the following MeSH headings and text words were used: (MH "randomized controlled trial") or (MH "controlled clinical trial") or (MH "randomized") or (MH "placebo") or ("drug therapy") or (MH "randomly+") or (MH "trial") or (MH "groups+") and (MH "human")
1 and 2 and 3 and 4 and 5
[MH] = MeSH headings: exploding retrieves all documents containing any of the subject terms below the term selected.
[+] = related terms are also taken into the search: In case of a plus sign (+) next to a narrower or related term, there are narrow terms below the term.
[RCT]= randomised controlled trial
[CCT]= controlled clinical trial
Appendix 5. Search strategy for PEDro
1. For children the textword "paediatrics" was used in <Subdiscipline> field
2. For cancer and childhood cancer the textwords "cancer" OR "oncolog" OR "neoplasm" OR "carcinom" or "tumor" OR "malignan" were used in the <Abstract & Title> field
3. For physical exercise training therapy the textword "exercise" was used in the <Abstract & Title> field and combined (with OR) with the textwords "fitness training" OR "hydrotherapy, balneotherapy" OR "neurodevelopmental therapy, neurofacilitation" OR "skill training" OR "strength training" in the <Therapy> field
4. For RCTs and CCTs the textword "clinical trial" was used in the <Method> field
1 and 2 and 3 and 4
For outcome no search terms were defined
Differences between protocol and review
The review differed from the protocol on a number of aspects.
Instead of using the Cochrane Childhood Cancer Group module for the risk of bias, we used the latest update, which was described in the Cochrane Handbook for Systematic Reviews of Interventions of March 2011 to assess the risk of bias of the included studies (Higgins 2011).
The study of Hartman 2009 included children at diagnosis who were aged one to 18 years. In the protocol we reported our intention to include studies with participants older than three years of age. We opted to change this because some of the studies introduced a tailored exercise programme that could be adjusted for the child's age. To see changes in outcomes a child needs to be trainable, co-operative, and testable. For intensive training, which we had in mind when writing the protocol, children aged less than three years will not be able to complete the exercises. However, the study of Hartman 2009 did not assess the effect of a structured intensive training programme, but included physiotherapy sessions with exercises that were appropriate for all ages.
We added possible tests that could have been used to assess the primary outcome.
Finally, we added the clinical trial database as resource for the search of ongoing trials (www.clinicaltrials.gov). We also searched the clinical trial database for missed studies.