Article

Combined Aerobic and Resistance Exercise Interventions for Children and Adolescents With Cancer: A Systematic Review and Meta-Analysis

Rui-Chen Ma

Han-Bing Lu

Jin Li

Zhen-Xue Mao

Xiao-Xia Xu

pediatric cancer, aerobic exercise, resistance exercise, systematic review, meta-analysis
ONF 2023, 50(2), 252-262. DOI: 10.1188/23.ONF.252-262

Problem Identification: Systematic reviews in adults with cancer have shown the benefits of combined aerobic and resistance exercise (CE) interventions on physical and psychological fitness. However, data on the efficacy of CE interventions for children and adolescents are limited and discordant.

Literature Search: The PubMed®, Embase®, Cochrane Central Register of Controlled Trials, Web of Science, and China National Knowledge Infrastructure electronic databases were searched from inception to April 19, 2022.

Data Evaluation: Nine randomized controlled trials met the inclusion criteria. A quantitative synthesis method was used to investigate the effects of CE interventions on fatigue, cardiorespiratory fitness, physical activity levels, and health-related quality of life.

Synthesis: This systematic review and meta-analysis indicates that CE interventions have beneficial effects on the fatigue, cardiorespiratory fitness, and physical activity levels of this population.

Implications for Practice: Healthcare providers should implement CE interventions during hospital care and recommend home-based CE interventions to patients who have barriers to performing hospital-based sessions.

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    It is estimated that about 300,000 children and adolescents aged 0–19 years around the world are diagnosed with cancer every year (Miller et al., 2020; Ward et al., 2014). With the improvement of treatment techniques, the five-year postdiagnosis survival rates of this patient population have exceeded 80% (Miller et al., 2020). However, this increase in survival carries an enhanced risk of treatment-related late effects, which can deteriorate survivors’ functional capacity and health-related quality of life (HRQOL) (Braam, van der Torre, et al., 2016; Ospina et al., 2021). Cancer treatment requires repeated and prolonged hospitalizations, which directly affect the physical activity (PA) levels of patients (Mueller et al., 2018). It is reported that, compared with the prediagnosis levels, the habitual PA levels of patients with childhood cancer during hospitalization and at home decreased significantly (Götte et al., 2014). Although the physical impairment of children and adolescents with cancer may be caused by many reasons, physical inactivity is one of the important contributors (Braam, van Dijk-Lokkart, et al., 2016). Physical inactivity, particularly bed rest, will further reduce poor cardiorespiratory fitness (CRF), aggravate (cancer-related) fatigue, and affect activities of daily living. Therefore, implementing evidence-based rehabilitation interventions tailored to the pediatric oncology population to attenuate negative physical and mental side effects is a major issue.

    Exercise is increasingly regarded as an important part of supportive care for individuals with cancer and cancer survivors, albeit focusing more on adults than on children so far. Aerobic exercise and resistance training are common exercise therapies (Xi et al., 2021). Aerobic exercise is a form of exercise that mainly depends on the process of aerobic energy generation; that is, it needs free oxygen to meet the demands of aerobic metabolism. Resistance exercise is a form of PA that contracts muscles to resist external resistance (Bekhet et al., 2019). Aerobic exercise is the most effective way to improve CRF and body composition, and resistance exercise increases muscle mass and strength, leading to better aerobic response (Xi et al., 2021). It has been reported that combined aerobic and resistance exercise (CE) interventions have beneficial effects on blood oxygenation, the supply of oxygenated blood to working muscles, and the ability of muscles to consume oxygen and generate strength during contraction (Morales et al., 2021). In systematic reviews of adults with cancer, the positive effects of CE interventions on CRF, PA levels, fatigue, and HRQOL have been reported (Batalik et al., 2021; Fukushima et al., 2021; Nakano et al., 2018; Piraux et al., 2018). Considering that pediatric cancer has a different histologic and clinical presentation from that of adults (Silva Santos et al., 2020), it is necessary to assess the effectiveness of CE interventions for a variety of populations with childhood cancer.

    Several systematic reviews have investigated the benefits of exercise interventions for children and adolescents with cancer, but the effects of exercise to this population are not yet convincing because these reviews include different exercise types (aerobic and/or strength exercises), have insufficient study designs (nonrandomized study), or are combined with other nonexercise interventions (e.g., psychosocial training, nutritional intervention). Considering that the results of randomized controlled trials (RCTs) yield the highest quality of evidence and types of exercise should be distinguished when examining the effects of exercise on cancer-related symptoms (Nakano et al., 2018), the purpose of this meta-analysis is to systematically and objectively assess the effectiveness of CE interventions on CRF, PA levels, fatigue, and HRQOL in children and adolescents diagnosed with cancer by synthesizing the evidence from RCTs.

    Methods

    This systematic review and meta-analysis was conducted and reported using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (Liberati et al., 2009).

    Search Strategy

    The authors conducted a literature search in PubMed®, Embase®, Cochrane Central Register of Controlled Trials, Web of Science, and China National Knowledge Infrastructure databases for related studies from inception to April 19, 2022. The search strategies were conducted using the following combinations of search terms to find relevant articles: ([title] “cancer” or “carcinoma” or “tumor” or “neoplasm” or “oncology” or “leukemia”) and ([title] “children” or “adolescents” or “pediatric” or “childhood”) and ([title] “exercise” or “training” or “sport” or “physical activity” or “rehabilitation”). Besides the electronic search, a thorough manual search of reference lists from relevant reviews and articles was conducted to find additional relevant studies.

    Study Selection

    Studies meeting each of the following criteria were included:

    • Study design: prospective RCTs
    • Population: children (aged 4–12 years) and adolescents (aged 13–19 years) with solid or hematologic cancer
    • Interventions: Exercise program mainly includes aerobic exercise and resistance exercise.
    • Comparators: no formal exercise interventions
    • Outcomes: Studies included at least one of the following outcomes: CRF, PA levels, fatigue, or HRQOL.
    • Articles: full-text articles that were published in peer-reviewed journals
    • Language: studies published in English or Chinese

    The exclusion criteria were as follows: (a) protocols, theses, duplicate studies, and conference summaries and (b) CE interventions combining exercise training with other irrelevant interventions such as physical therapies, psychosocial intervention, or nutrition support. Two reviewers selected the studies independently. Different opinions finally reached a consensus through discussion with another reviewer.

    Data Extraction

    The following study characteristics were extracted: first author, year of publication, country, patient characteristics (e.g., age, sample size, type of cancer), intervention details (e.g., frequency, duration, intensity, control), and evaluated outcomes. The data were independently extracted by two authors using Microsoft Excel 2010, and disagreements in this process were resolved by discussing with the fourth author to reach a consensus.

    Risk-of-Bias Assessment

    The Cochrane Collaboration risk-of-bias tool (Higgins & Green, 2008) was used to determine the risk of bias of the included studies, including (a) sequence generation, (b) allocation concealment, (c) blinding of participants and personnel, (d) blinding of outcome assessors, (e) incomplete outcome data, (f) selective outcome reporting, and (g) other biases. Each potential source of bias was graded as low, high, or unclear. Two authors assessed the studies independently, and different opinions were discussed among authors. Poor-quality studies were not excluded because of the limited number of studies.

    Statistical Analysis

    All statistical analyses were conducted using RevMan, version 5.3. To clarify the effect sizes, the authors constructed forest plots. All data are expressed as mean and standard deviation (SD). Considering that some of the included studies had more than one follow-up time point, the data in the forest plots were selected from the first time point after the interventions because the effect sizes at the end of the intervention periods are regarded as the most relevant (Frost et al., 2019; Hilfiker et al., 2018). The results were reported as the standard mean difference (SMD) with corresponding 95% confidence interval (CI). The I2 statistic was used to assess statistical heterogeneity. The authors set the no, low, moderate, and high standards to I2 values of 0%, 25%, 50%, and 75%, respectively (Higgins et al., 2003). When I2 was greater than 50%, the random effect model was used. Otherwise, the authors used the fixed effect model. If the p value was less than 0.05, the results were determined to be statistically significant.

    Results

    Study Selection

    A total of 1,142 articles were retrieved from the five electronic databases, and another article was included by searching the study references manually. After the duplicate articles were excluded, 711 articles remained. Another 668 articles were excluded after reading the titles and abstracts, leaving 43 articles. Finally, this systematic review included nine RCTs (Fiuza-Luces et al., 2017; Jung et al., 2021; Lam et al., 2018; Li et al., 2018; Manchola-González et al., 2020; Saultier et al., 2021; Senn-Malashonak et al., 2019; Stössel et al., 2020; Tanir & Kuguoglu, 2013), eight of which were included in the meta-analysis. The flow diagram of the study selection process is shown in Figure 1.

    FIGURE1

    Study Characteristics

    The systematic review included participants with solid tumors and hematologic malignancies, most of which were hematologic cancers (n = 396, 65%). The nine studies were published from 2013 to 2021. A total of 610 participants were included, and the ratio of males to females was about 3:2. The age of the population ranged from 4 to 18 years, and the average age was 12 years. Among these studies, most were conducted in European countries (n = 6). All the included studies used concurrent training (i.e., aerobic plus resistance exercise), and the duration of the exercise prescriptions ranged from six weeks to six months. In most studies, CE interventions were conducted three to five days per week. The exercise programs were conducted in the following settings: inpatient, outpatient, home-based, outdoor, or mixed. Only five of the nine included studies reported the intensity of aerobic exercise, which ranged from 50% to 80% of the maximum heart rate. The timing of the intervention was mainly performed during (n = 5) and after (n = 4) cancer treatment. More details of the included studies are summarized in Table 1.

    TABLE1A

    TABLE1B

    Quality Assessment

    Table 2 shows the bias risks of the included studies. Each study reported that the patients were randomly divided into an experimental group and a control group, but the randomization process was unclear in two of the studies. Three studies clearly reported the methods for allocation concealment, and the remaining studies had insufficient information to assess. Only one study showed that participants were blinded; three studies did not provide enough information. Because of the nature of the exercise interventions, the blinding of participants and personnel is difficult. Three studies reported blinding of outcome assessor, whereas others were either high bias risk or unclear risk regarding this criterion. Six studies reported the implementation of intention-to-treat analysis, indicating that the risk of attrition bias is low. Only one study’s protocol was published online (Lam et al., 2018). In the other bias column, four studies were rated as having a high bias risk because of the lack of calculation of sample size.

    TABLE2

    Fatigue

    The fatigue outcome was measured in four studies using different fatigue inventories, and the data of three studies could be included in meta-analysis. CE interventions had a significant effect on fatigue when compared to control groups (SMD = –0.5, 95% CI [–0.73, –0.27], p < 0.001, I2 = 0%). The remaining study (Jung et al., 2021) found that outpatient CE interventions can significantly reduce the fatigue of children after clinical discharge compared with those who did not engage in exercise during the whole study period (p = not reported).

    CRF

    CRF was a part of six studies, two of which had CRF as the primary outcome (Manchola-González et al., 2020; Saultier et al., 2021). Peak oxygen uptake (VO2peak) was used to assess CRF in two studies, six-minute walking distance (6MWD)/nine-minute walking distance was used to assess CRF in three studies, and VO2peak/6MWD combination was used in one study. Using 6MWD, the improvement of CRF in the CE group was significant compared to the control groups (SMD = 0.71, 95% CI [0.43, 1], p < 0.001, I2 = 44%). The meta-analysis of VO2peak showed that CE interventions had a positive effect on CRF when compared to controls (SMD = 0.4, 95% CI [0.04, 0.77], p = 0.03, I2 = 46%).

    PA Levels

    Four studies assessed PA levels by questionnaires, and one study (Fiuza-Luces et al., 2017) used an accelerometer to assess PA levels. Overall, CE interventions led to an improvement in PA levels compared to the control groups (SMD = 0.69, 95% CI [0.08, 1.29], p = 0.03, I2 = 82%). When the authors removed the previously mentioned study that used an accelerometer to objectively measure PA, the heterogeneity reduced and the adjusted pooled estimates did not change significantly (SMD = 0.93, 95% CI [0.42, 1.44], p < 0.001, I2 = 69%).

    HRQOL

    A total of seven studies investigated HRQOL, and six of them reported total scores. There was no heterogeneity in the HRQOL factor, and the result showed that the overall effect of CE interventions on HRQOL was not significant (SMD = 0.16, 95% CI [–0.02, 0.34], p = 0.08, I2 = 0%). Tanir and Kuguoglu (2013) reported that only the worry area of HRQOL in the intervention group was statistically different from that in the control group after the intervention.

    Discussion

    In the past, healthcare providers advised children and adolescents with cancer to rest in bed as much as possible. It is currently considered that excessive rest may lead to further decline of physical functioning and physical fitness, and these side effects may be reduced by doing physical exercise during or after the treatment of childhood cancer. The current systematic review of nine RCTs with 610 participants showed that CE interventions can reduce fatigue and improve CRF and PA levels, although no unique effect on HRQOL was found. In addition, no major adverse events caused by CE interventions were found.

    Fatigue, which is generally defined as an individual’s subjective feeling of fatigue, weakness, or lack of energy that cannot be relieved by rest, is one of the most bothersome symptoms in children with cancer (Stone & Minton, 2008). Fatigue may also deprive patients of their ability to do ordinary daily activities, such as study and play, which substantially impairs their PA levels and HRQOL (Murnane et al., 2015; Spathis et al., 2017). Although the cause of fatigue has not been determined, it may be related to the low-grade inflammatory responses caused by the tumor itself and related treatments (Foulkes et al., 2020). Many studies have reported the benefits of exercise interventions in reducing fatigue, and this review reached similar results (Oberoi et al., 2018). So far, the underlying mechanisms of the benefits of exercise on fatigue have not been fully understood (Stössel et al., 2020). It is speculated that there may be direct mechanisms, such as decreased inflammation, and indirect mechanisms, such as improved sleep quality (Lanser et al., 2020).

    Cancer treatment and cancer itself are related to the physical decline of patients during and after treatment, which is reflected in the low levels of CRF or the decline of activities of daily living (Manchola-González et al., 2020). Given that CRF is one of the strongest indicators of prognosis (Maginador et al., 2020), VO2peak and walking performance were selected to reflect CRF in this study. VO2peak is considered one of the most widely accepted measures of CRF (Scott et al., 2018), and the 6MWD test is a reliable tool to assess CRF in children (Su et al., 2018). Walking distance is related to VO2peak, so 6MWD should be used when the VO2peak cannot be performed (Piraux et al., 2018). Cancer and related therapies can induce tissue degeneration, which may lead to cardiac and skeletal muscle abnormalities (Rausch et al., 2021). Exercise during and after cancer treatment can increase muscle mass and plasma volume, improve pulmonary ventilation and perfusion, and increase cardiac reserve (Foulkes et al., 2020). The present meta-analysis showed that CE interventions can improve the cardiovascular and pulmonary systems of pediatric patients with cancer.

    Previous literature indicates that most children with cancer experience a decline in PA levels after diagnosis (Lam et al., 2016). The reduction of daily energy consumption and PA levels is considered to be the most important reason for the reduced physical fitness of children with cancer (Malicka et al., 2019; Schindera et al., 2021). There is also evidence that physical inactivity will lead to further loss of cardiopulmonary function and muscle atrophy, thereby aggravating fatigue (Ozdogar et al., 2022). This review provided evidence of positive effects of CE interventions on PA levels in individuals with childhood cancer. However, the results of the analysis were instable and weak because PA levels were not objectively measured. Among the five studies that measured PA levels, only one used accelerometers to do so (Fiuza-Luces et al., 2017), and the rest used self-report questionnaires, which means that the results obtained are subject to recall and response biases (Lam et al., 2018; Li et al., 2018; Manchola-González et al., 2020; Stössel et al., 2020). Future research should use objective measurements (such as pedometers or accelerometers) to record PA levels and minimize biases.

    HRQOL is a multidimensional concept, which reflects patient-perceived evaluation of their own health, including physical, emotional, and social dimensions, as well as symptoms related to diseases or treatments (Fiteni et al., 2016). HRQOL is an important end point to determine the impact of cancer and its treatment, and it is also a crucial indicator to evaluate the effects of intervention (Duncan et al., 2017). The current findings are in line with previous systematic reviews (Morales et al., 2018) showing no positive effects of exercise training on HRQOL in childhood patients with cancer. This result diverges from that documented in samples of adult patients with cancer (Gerritsen & Vincent, 2016). In fact, HRQOL showed a trend of improvement after intervention, but the improvement had not reached statistical significance. This finding may be because HRQOL is a distal outcome and it takes longer to respond to interventions than other previously mentioned outcomes.

    Limitations

    To the best of the authors’ knowledge, this is the first systematic review and meta-analysis that included only RCTs to investigate the impact of CE interventions on children and adolescents with cancer, and the results yielded the highest quality of evidence. However, the present review still had several limitations. First, because of the limited number of included studies, the authors did not conduct the subgroup analysis and assess publication bias. Second, although the authors tried to include studies with homogeneous interventions, aerobic and resistance exercises were different in intensity, frequency, and duration among studies. Third, some studies could not be included in quantitative synthesis because of lack of the necessary data, which may be regarded as a potential bias. Finally, the long-term effects of the CE programs on this patient population remain uncertain, and they require longer study and further attention.

    Implications for Nursing

    Exercise interventions are increasingly considered an important part of supportive care for people with cancer. The results of this systematic review demonstrated the benefits of CE interventions in children and adolescents with cancer. The support and companionship from nurses is very important in motivating pediatric patients with cancer to participate in PA. The authors expect that oncology nurses will cooperate with physical therapists to implement exercise programs during hospital care, and at least base their programs on aerobic and endurance training to improve care pathways. The authors also expect that future studies will use similar measurement tools, which would allow for comparison among different studies to form clearer suggestions on exercise prescriptions.

    In addition, it may be beneficial to develop age-appropriate exercise programs for children and adolescents. Exercise programs for children need to be playful and motivating to enhance adherence, such as ball games, swimming, gymnastics, Nintendo Wii, and suitable equipment for smaller children. For adolescents, besides the common running, cycle ergometer, and dumbbell exercises, the exercise programs can be surrounded by adventure-based training, such as rock climbing and trampoline. Nurses should assist physical therapists in basic physical assessments to ensure that participants are physically fit for the exercises.

    Of note, in the current situation associated with the COVID-19 pandemic, home-based CE interventions appear to be a suitable alternative. Home-based exercise interventions could overcome some barriers that patients may encounter when exercising in inpatient or outpatient settings, which limit them from participating in traditional center-based exercise interventions under professional supervision. Considering that the effectiveness of CE interventions also depends on the adherence of the patient to this program, oncology nurses can consider providing telerehabilitation systems for patients to improve exercise adherence (Eichler et al., 2017; Pastora-Bernal et al., 2017).

    KNOWLEDGE

    Conclusion

    The findings of this review showed that CE interventions are safe and effective in improving fatigue, CRF, and PA levels of children and adolescents with cancer. However, the authors’ conclusions are limited because of the small numbers of participants and the large heterogeneity of the CE programs’ composition, patient characteristics, and measurement tools. More well-designed and multicentric studies with large sample sizes are required for further detailed meta-analysis to supplement the findings of this review.

    The authors gratefully acknowledge the Affiliated Cancer Hospital of Zhengzhou University and its staff for all their valuable support.

    About the Authors

    Rui-Chen Ma, MD, MSc, is an RN at the Affiliated Cancer Hospital of Zhengzhou University in China; Han-Bing Lu, MD, MSc, and Jin Li, MD, MSc, are graduate students in the School of Nursing at Jilin University in Changchun, China; and Zhen-Xue Mao, MD, MSc, is an RN in the Department of Nursing and Xiao-Xia Xu, MD, PhD, is the head of the Department of Nursing, both at the Affiliated Cancer Hospital of Zhengzhou University. No financial relationships to disclose. Ma and Xu contributed to the conceptualization and design. Ma, Lu, and Li completed the data collection. Ma, Lu, Li, and Mao provided statistical support and the analysis. Ma and Xu contributed to the manuscript preparation. Xu can be reached at hulibu758@126.com, with copy to ONFEditor@ons.org. (Submitted May 2022. Accepted September 23, 2022.). 

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