Limited Evidence for the Benefits of Exercise in Older Adults with Hematological Malignancies: A Systematic Review and Meta-Analysis

Simple Summary It is unknown whether different types of exercise effect physical function, quality of life, mental wellbeing, and symptoms in older patients with blood cancers. No studies specifically focusing on patients over 65 years were identified. However, across adult age groups, we found that exercise has small to moderate positive effects on physical function, aerobic capacity, muscle strength, quality of life, fatigue, pain, anxiety, and depression. These benefits were generally consistent regardless of age, except for physical function and pain, which favored younger adults. Overall, exercise improves physical function and quality of life and reduces symptoms in adults with blood cancers undergoing treatment, but the role of age remains uncertain. Abstract Older patients receiving antineoplastic treatment face challenges such as frailty and reduced physical capacity and function. This systematic review and meta-analysis aimed to evaluate the effects of exercise interventions on physical function outcomes, health-related quality of life (QoL), and symptom burden in older patients above 65 years with hematological malignancies undergoing antineoplastic treatment. This review adheres to Cochrane guidelines, with the literature searches last updated on 27 March 2024, including studies with patients above 18 years. Screening of identified studies, data extraction, risk of bias, and GRADE assessments were performed independently by two authors. Meta-analyses evaluated the impact of exercise, considering advancing age. Forty-nine studies contributed data to the meta-analyses. Five studies included patients with a mean age above 60 years, and none included only patients above 60. Exercise interventions had moderate to small positive effects on QoL global (SMD 0.34, 95% CI [0.04–0.64]) and physical function (SMD 0.29, 95% CI [0.12–0.45]). Age did not explain the variability in exercise effects, except for physical function (slope 0.0401, 95% CI [0.0118–0.0683]) and pain (slope 0.0472, 95% CI [0.01–0.09]), which favored younger patients. Exercise interventions improve physical function and QoL and reduce symptoms in adults with hematological malignancies undergoing antineoplastic treatment; however, the influence of age remains inconclusive.


Introduction
The global increase in the aging population, in tandem with the delayed onset of most hematological malignancies, has led to a higher incidence of these cancers among older individuals [1,2].Approximately half of all hematological malignancies occur in adults aged 65 years and older, and 70% of cancer-related deaths occur within this age group [3].Overall survival in adults above 75 years old with hematological cancers, particularly acute leukemia, is low [4].Older adults with hematological malignancies undergoing medical antineoplastic treatment experience challenges, including frailty and decline in physical and functional capacity, which can further burden their cancer treatment and overall recovery [5].Among older patients with solid and hematological cancers, frailty is a prevalent concern associated with suboptimal therapeutic responses, increased treatmentrelated toxicity, and overall poorer survival outcomes [6].Moreover, challenges like pain, fatigue, insomnia, and mood disturbances are prevalent among older cancer patients, significantly impacting their quality of life [7].The estimated prevalence of cancer-related fatigue (CRF) is as high as 70% in individuals above 65 years [8].This not only hinders everyday functioning but may also lead to significant disability and increased reliance on assistance for activities necessary for independent living [9].
Effective management of hematological malignancies in older patients requires a comprehensive, multidisciplinary approach that addresses both the disease and overall health and wellbeing [5,10].In addition to the benefits provided by onco-geriatric interventions, which include screening for comorbidities and frailty to improve treatment outcomes, there is an increased interest in exploring nonpharmacological clinical interventions to improve health-related quality of life (QoL) and outcomes in older adults with solid and hematological cancers [11][12][13][14][15].In recent years, growing recognition of the feasibility, safety, and potential benefits of exercise in improving clinical outcomes and QoL in patients with hematological malignancies [16,17] aligns with studies showing positive effects on physical capacity and function, psychological wellbeing, and the mitigation of fatigue and other treatment-related side effects in this patient population [18][19][20][21].To guide exercise practices in older adults, several recommendations are available for clinical and research practices, such as the International exercise recommendations for older adults from 2021 [22], the American College of Sports Medicine (ACSM) exercise guidelines for older adults from 2009 [23], recommendations from 2015 for designing exercise clinical trials for older adults with cancer [24], and the 2019 roundtable on exercise guidelines for cancer survivors, which addresses issues of older cancer patients [25].There remains, however, limited evidence supporting the benefits of exercise in older adults with hematological malignancies in these guidelines.
Consequently, there is a clear imperative to explore the impact of exercise in older adults with hematological cancers [26].Given age-related physiological changes coupled with the complexities of hematological diseases and intensive treatments, there is a need for a comprehensive investigation into the potential benefits of exercise for this population.A systematic review and meta-analysis can provide insights into the effectiveness of exercise interventions on diverse outcomes and guide clinical strategies to optimize the health and wellbeing of older patients undergoing neoplastic treatment for hematological malignancies.
The aim of this systematic review and meta-analysis was to investigate the effect of exercise interventions on physical function, QoL, and symptom burden in older adults with hematological malignancies receiving medical antineoplastic treatments.

Materials and Methods
This systematic review and meta-analysis adheres to Cochrane guidelines [27] and is registered in The International Prospective Register of Systematic Reviews (PROSPERO) database (registration no.CRD42019130979 amended 24 May 2021 and 8 August 2023) and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [28,29].

Information Sources and Search Strategy
A systematic search was conducted in March 2019 across four databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL.No randomized controlled trials exclusively including participants above 65 years with hematological malignancies were identified (Figure S1).In October 2020, the search was expanded to include individuals above 18 years old, and an additional database, Science Citation Index Expanded/Social Sciences Citation Index (SCIE/SSCI), was added (Figure S2).On 27 March 2024, an updated search was carried out in MEDLINE, EM-BASE, CENTRAL, CINAHL, and SCIE/SSCI (Figure S3).Using the PICO framework (Problems, Interventions, Comparisons and Outcomes) [30], the searches included three main areas: (1) exercise-based interventions, (2) hematological malignancies during medical antineoplastic treatment, and (3) randomized controlled trials.The searches involved a combination of MeSH/Thesaurus/indexed terms and relevant synonyms (Figures S1-S3).

Eligibility Criteria
Studies included were randomized controlled trials, randomized pilot trials, randomized crossover trials, and randomized feasibility studies with adult participants (≥18 years) diagnosed with hematologic malignancies undergoing medical antineoplastic treatment, such as chemotherapy, chemoradiation, stem cell transplantation including allogeneic hematopoietic stem cell transplantation (allo HSCT), autologous stem cell transplantation (autologous HSCT), and high-dose chemotherapy with stem cell support.Studies that included participants just prior to starting treatment and up to six months post-treatment were considered.All types of exercise-based interventions and complementary alternative medicine (CAM) such as yoga, compared to standard care were considered for inclusion, including multimodal interventions where the exercise component constituted at least 50% of the intervention sessions.Interventions could be initiated prior to, during hospitalization or outpatient clinic visits, or after discharge, including home-based training.All durations of interventions were included.For comparator(s) or control groups, all types, whether active or inactive, were considered.Studies included measured outcome effects.No restrictions were applied for language or publication date.
To identify ongoing exercise-based randomized trials, a comprehensive search was carried out in ClinicalTrials.gov,accessed on 13 November 2023, including only patients above 60 years with hematological malignancies undergoing medical antineoplastic treatment (Table S1).Information extracted includes trial identifier, author information, population characteristics (age, gender, diagnosis, treatment modalities), study design, type and duration of exercise intervention, primary outcomes, and current study status.

Outcomes
The primary outcomes were changes in physical function (e.g., 6-min walk test (6MWT)) and QoL global (e.g., The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30)).Measurements of QoL global included both generic and disease-specific patient-reported outcome measures (PROMs).
For the meta-analysis, and for each outcome, distinct measurement instruments and tests were chosen, prioritizing those most widely applied for assessing the outcomes of exercise interventions, considering validity and reliability (Table S2).For each study, a single measurement instrument was selected for each outcome.

Risk of Bias Assessment
Risk of bias for each study was independently assessed by two of six authors (STL, GK, RFL, CG, MSE, MJ) using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) [31].Any disagreements were resolved through discussions with MJ.

Certainty of Evidence
The certainty of evidence for each outcome was assessed using the Grading of Recommendation, Assessment, Development and Evaluation tool (GRADE) [32] by three authors (STL, GK, MJ) utilizing the GRADEpro Guideline Development Tool [Software] (McMaster University and Evidence Prime, 2024; Available from gradepro.org;accessed on 21 August 2024).The certainty of evidence was evaluated in five domains: study quality, inconsistency, indirectness, imprecision, and publication bias.Risk of publication bias (small study bias) was assessed using Egger's test and illustrated with a funnel plot for all outcomes, which was inspected for asymmetry.

Data Synthesis and Analysis
The effect size of each intervention was estimated as the standardized mean difference (SMD) with a 95% CI using the restricted maximum likelihood model (REML).The SMD was calculated as the difference in mean change between the intervention and control group, divided by the pooled standard deviation (SD), and adjusted to Hedges' g to account for a small overestimation of the effect in small studies.A random effects model was used for all meta-analyses, as it was expected that participants, interventions, and outcome measures might differ between studies [27].To facilitate a unified analysis across multiple outcomes, we analyzed changes in measurement scores from baseline to post-test, and studies not reporting change scores were converted to change scores by using a correlation of 0.6.Interpretation of the SMD adhered to Cohen's recommendations: small effect was defined as 0.2, moderate effect as 0.5, and large effect as 0.8 [27].
Heterogeneity was evaluated using the I 2 index, and the between-study variance as tau-square (t 2 ).Meta-regression analyses employing STATA version 18 (StataCorp 2023.Stata Statistical Software: Release 18. College Station, TX, USA) were conducted to assess potential influences of mean age of participants on effects in the meta-analysis.The number of participants for each outcome corresponds to those who completed the study with data, which may not necessarily be the same as the total number included in the studies.
In subgroup analyses, we examined covariates including mean age as a dichotomous variable (<60 years or >60 years), diagnosis (acute leukemia, lymphoma, multiple myeloma, mixed diagnoses), and antineoplastic treatment (chemotherapy, allogeneic HSCT, autologous HSCT or both, different treatments).Given the anticipated heterogeneity in exercise interventions, we categorized the exercise interventions based on type (aerobic, strength, combined aerobic and strength, either aerobic or strength exercise, CAM), timing of exercise (before, during, after treatment, or combination), delivery mode (supervised, partly supervised, unsupervised), individual or group-based, and extensiveness of intervention, and risk of bias (high risk, some concerns, and low risk).Extensiveness of exercise interventions was categorized based on number of sessions, session length, and intensity, inspired by guidelines from the American College of Sports Medicine [25,33] and two systematic reviews of exercise interventions [34,35].Each exercise intervention was categorized as less, moderate, or extensive.The categorization process was collaboratively conducted by three authors (MJ, STL, GK), with STL providing expertise as a physiotherapist.

Results
The searches identified 5550 records (Figures S2 and S3).After removing duplicates and screening, 49 studies were included , reported in 51 publications, with two of these being follow-up analyses [85,86].All studies were included in the narrative review (Figure 1).

Study Characteristics
In total, 3494 patients were included, with sample sizes ranging from 17-711 (
Subgroup analyses on QoL global showed the largest effect in the age group over 60 years (SMD 1.29), and for physical function, it was below 60 years (SMD 0.32).Results for subgroup analyses for physical function and QoL global are presented in Figures S7  and S8, respectively.

Effects of Exercise Interventions on Secondary Outcomes
The largest effects of exercise were observed in aerobic capacity, SMD 0.53 (95% CI 0.27-0.79)and in muscle strength (SMD 0.47 (95% CI 0.17-0.78)).Moderate to small significant symptom-related benefits were found in fatigue (SMD 0.44), pain (SMD 0.43), and depression (SMD 0.37), and a small non-significant effect on anxiety (SMD 0.21).Significant moderate to small effects on QoL emotional (SMD 0.33), QoL functional (SMD 0.33), and QoL physical domains (SMD 0.32), as well as non-significant on the physical activity outcome (SMD 0.32), were observed.There was a small significant effect in body composition (SMD 0.20), all favoring exercise interventions (Table 2 and Figures S9-S19).
Inclusion and exclusion criteria varied across the 49 studies.The number of individual exclusion criteria per study was mean five (range 1-17), with the most frequent exclusion criteria being cardiovascular disease (n = 24), malignancy (n = 23), musculoskeletal disorder (n = 22), and mental health challenges (n = 18).Seven studies did not report exclusion criteria [42,44,49,57,69,73,82].Despite detailed descriptions of inclusion and exclusion criteria in most studies, several did not report reasons for study exclusion (n = 14) [39,40,42,45,46,[48][49][50]61,64,66,72,77,80].In studies that reported (n = 34), the three most prevalent reasons for study exclusion were related to a) medical and health status: comorbidity, unstable conditions, adverse effects, malignancy, symptoms, low blood counts; b) physical performance: mobility challenges and frailty; and c) mental health issues: psychological instability and cognitive impairment.Some studies were not transparent, detailed, or systematic in reporting reasons for exclusion; and in some cases, it was just stated that participants did not meet inclusion criteria without providing explanation.

Quality of Evidence (GRADE)
Low to very low quality of evidence was found for a small effect on primary outcomes; physical function and QoL global, as evidence was downgraded due to high risk of bias, inconsistency, and risk of publication bias (Table 2).For secondary outcomes, only body composition showed high quality of evidence but for a small effect, while the remaining secondary outcomes ranged from very low to moderate levels of evidence.

Ongoing Studies Registered in Clinical Trials
There are currently four ongoing randomized exercise trials for older adults with hematological malignancies.Two studies recruit patients over 60 years, and the other two recruit patients over 65 and 70 (Table 4).Risk of Bias [36-86].

Quality of Evidence (GRADE)
Low to very low quality of evidence was found for a small effect on primary outcomes; physical function and QoL global, as evidence was downgraded due to high

Discussion
This systematic review and meta-analysis is a synthesis of data on the effect of exercise interventions in adults with hematological malignancies undergoing medical antineoplastic treatments.Notably, we did not find any studies that only included adults aged 65 years and older.Therefore, the scope was expanded to include all adult age groups (above 18 years), and we found exercise interventions to have significant positive benefits on outcomes, irrespective of age.Among the 49 studies analyzed, only five included a sample with mean or median age over 60 years, indicating a scarcity of evidence specifically addressing the older population with hematological malignancies.Likewise, Knowles et al. 2022 in a review of reviews of older people with cancer did not find any systematic reviews including a population over 65 years [87].Similarly, Mikkelsen et al. 2020 in a systematic review of exercise interventions in older cancer patients identified only four studies that included a sample of patients above 65 years and found inconclusive evidence regarding benefits of exercise in this age group [88].
Given the rising prevalence of hematological malignancies among older adults and the increasing demand for more comprehensive approaches to treatment and care for this population [5,10], evidence regarding exercise remains notably lacking for older adults.We identified four ongoing exercise-based randomized trials in patients with hematological malignancies above 60 years registered in clinicaltrials.gov,accessed on 13 November 2023 (Table 4.These ongoing studies, though few, highlight the growing need to understand the role of exercise in improving physical function and QoL, and mitigating symptoms in older adults undergoing antineoplastic treatment. In this review, we found exercise to have small to moderate certainty evidence across most outcomes across age groups.Likewise, several systematic reviews and meta-analyses, each with relatively few studies, also found exercise benefits in adults with hematological malignancies.Abo et al. (2021) reported moderate evidence in functional capacity, QoL global, and fatigue [20].Moore et al. (2023) found evidence for improvements in physical function [21].Yang et al. 2022 found significant improvements in QoL, emotional functioning, and pain [16].Knips et al. (2019) found low-certainty evidence on depression and anxiety and moderate evidence for fatigue [18].Research across hematological diagnoses and treatments consistently indicates that exercise positively impacts a broad range of outcomes in adults generally.However, our meta-regression analysis found that impact on QoL global favored advancing age, while physical function and pain favored younger adults.Our subanalyses, which should be interpreted with caution due to the limited number of studies included, showed that those aged above 60 had the largest effects on QoL domains (global, emotional, and physical), muscle strength, pain, fatigue, and anxiety, whereas those below 60 years showed the largest effects in physical function, aerobic capacity, QoL functional, and body composition.
Exercise interventions in our systematic review were reported as feasible and safe in 24 studies, with seven studies documenting nonserious AEs.However, one-third of the studies (n = 16) did not report on AEs.Similarly, GroBek et al.'s (2023) systematic review on the safety and feasibility of exercise interventions in patients with hematological cancer (12 studies), which includes the same studies as our systematic review, concluded that exercise is feasible and safe in the studies reporting on it, but also found a similar lack of AE reporting, and when provided, the information was often insufficient [17].We recommend systematic monitoring and adequate documentation of feasibility and safety, including AEs, especially when providing exercise to hematological patients, given the potential comorbidities.This approach would facilitate targeted delivery of exercise interventions, not only to older adults but also to specific patient populations experiencing comorbidities.
Studies included in our review did not exclude patients based on older age; however, most studies used stringent exclusion criteria that targeted comorbidities and reduced function and performance inherent to this age group.This is evident in the detailed and high number of inclusion and exclusion criteria (up to 16), but importantly, reasons for exclusion were either not reported at all or reported with lack of detail, a pattern consistent with other exercise reviews of older cancer patients [87,88].The rigorous exclusion criteria may contribute to the underrepresentation of older patients with comorbidities in exercise studies, as pointed out in several reviews [89][90][91].However, there are exceptions, as in a feasibility pilot strength training program among an older population of patients (mean 68 years) with multiple myeloma, which included those with osteolytic lesions, establishing both feasibility and safety [92].Older adults with the greatest need for exercise may not be considered suitable to participate due to strict safety criteria.This emphasizes the challenge of striking a balance between prioritizing safety and unintentionally excluding patients who could derive benefits from exercise.
Future exercise studies are likely to be designed to target the individual needs of older cancer patients, ultimately incorporating a more representative sample of patients.This will increase the generalizability of findings to the broader population of patients with hematological malignancies.Rosko et al. (2022) tested the feasibility of implementing an exercise intervention in older adults with hematologic malignancy and found a higher completion rate with in-person, physiotherapist supervision compared to at-home independent exercise.Though these older patients were motivated to follow a structured exercise program, health status changes were the main barrier to exercise [93].
In our review, adherence to exercise was predominantly high (72%).Two studies with a mean sample over 60 years reported high adherence (range 75-96%) [47,67].Slightly lower, Mazzoni et al. (2020) found exercise adherence in a mixed cancer diagnosis group was ≥50% In our review, 20 studies did not provide adherence rates.Adherence is addressed in an umbrella scoping review by Collado-Mateo et al. (2021) of 53 studies of chronic disease and older individuals and identified multiple modifiable factors influencing adherence to exercise in this population [95].Emphasizing factors that can improve adherence when planning and designing exercise interventions for the older population may improve feasibility and safety, and ultimately lead to better outcomes.
The extensiveness of exercise interventions varied across studies in this review, with moderate extensiveness (n = 32) being the most frequently designed intervention for the population with hematological malignancy.This pattern remained consistent in five studies where the mean or median age was above 60 years (n = 3).Conducting extensiveness rating across studies used in systematic reviews by Andersen et al. (2022) [34] and Ramírez-Vélez et al. (2021) [35] provides a more uniformed overview of the type of intervention that may be most beneficial for different populations.It is important to emphasize the significance of tailored exercise interventions for older adults with hematological malignancies, considering a more comprehensive supportive approach that takes individual needs and preferences into account, including not only physical and QoL outcomes but also clinical outcomes.
Although exercise recommendations for adults with cancer are available, evidence specifically for older cancer patients is limited and based on only a few studies [25].There are no evidence-based recommendations specifically tailored to older patients with hematological cancers.However, it is suggested that greater focus on exercise in the older cancer population to optimize exercise delivery, participation, safety, and efficacy is justified [26].Recognizing and understanding the benefits of exercise for older patients with hematological malignancies can be an important initiative to integrate into clinical practice.
Further research is needed on exercise interventions specifically designed for older patients with hematological cancers, including those with typical age-related comorbidities.Emphasis should be on addressing their individual needs, considering exercise types and contexts, and implementing strategies to improve recruitment accrual, minimize attrition, and enhance adherence rates.Involvement of patients in the design of these studies is important for relevance and overall quality of the study.Colton et al. (2022) captured the voices of older patients with hematological cancer, highlighting their specific needs and preferences on diet and exercise behavior [96].As per our review, Kilari et al. (2016) also emphasized the notable lack of exercise studies specifically tailored to the older cancer population.To effectively inform future practices for this population, merely extracting results and insights from studies of a wide age range is not adequate for developing exercise prescriptions for older patients with hematological cancer.Future studies should incorporate outcomes beyond physical function and PROMs such as QoL and symptom burden and should also provide knowledge on the clinical benefits of exercise including admission days, complications, and survival [24].

Strengths and Limitations
This systematic review and meta-analysis provides the largest overview of exercise studies in a total of 3494 patients with hematological cancer undergoing neoplastic treatments.Notably, no study exclusively included participants over 65 years, or even 60 years.
Consequently, drawing definitive conclusions regarding the benefit of exercise for older patients based solely on our meta-regression analysis and sub-analyses is not possible.Despite the inclusion of a large number of studies in this meta-analysis, we need to consider the substantial heterogeneity across studies, regarding variations in diagnosis groups, types of antineoplastic treatments, and the extensiveness of exercise interventions.The secondary outcomes and subgroup analyses are exploratory; therefore, interpreting results at a significance level of 0.05 can potentially pose a risk of false positive results (mass significance).We conducted three systematic searches but also acknowledge the possibility of having overlooked relevant studies in these repeated searches.

Conclusions
Exercise in adults with hematological malignancy undergoing neoplastic treatment provides significant benefits in physical function, aerobic capacity, muscle strength, physical activity, body composition, and QoL.Symptoms of depression, anxiety, fatigue, and pain were significantly reduced.The influence of age on the benefits of exercise remains inconclusive.The absence of studies specifically in older adults is staggering given that hematological malignancies predominantly affect the older population.Notably, there is a modest number of ongoing exercise-based randomized studies in older patients with hematological malignancy (clinicaltrials.gov,accessed on 13 November 2023), and this reflects the increasing interest and urgent need for evidence-based guidelines tailored to this population.

Supplementary Materials:
The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/cancers16172962/s1,Table S1: Search strategy on 13 November 2023, implemented in ClinicalTrials.gov,limited to randomized trials only including patients above 60 years with hematological malignancies; Table S2: Outcome measurement tests and instruments chosen for meta-analysis, prioritizing those most widely applied for assessing outcomes of exercise interventions;

Figure 1 .
Figure 1.PRISMA flowchart of study selection process.
Figure S1: Search strategy and PRISMA flow diagram for study selection (March 2019), implemented in four electronic databases, and results of total records, study population ≥ 65 years; Figure S2: Search strategy on 20 October 2020, implemented in five electronic databases, and results of total records; Figure S3: Updated search strategy on 27 March 2024, implemented in five electronic databases, and results of total records; Figure S4: Forest plot depicting the effects of exercise on physical function; Figure S5: Forest plot depicting the effects of exercise on QoL global; Figure S6: Meta-regression analyses on exercise benefits related to age for primary outcomes; physical function and QoL global; Figure S7: Subgroup analyses on primary outcome; physical function; Figure S8: Subgroup analyses on primary outcome; QoL global; Figure S9: Forest plot depicting the effects of exercise on aerobic capacity; Figure S10: Forest plot depicting the effects of exercise on muscle strength; Figure S11: Forest plot depicting the effects of exercise on body composition; Figure S12: Forest plot depicting the effects of exercise on physical activity; Figure S13: Forest plot depicting the effects of exercise on QoL emotional; Figure S14: Forest plot depicting the effects of exercise on QoL functional; Figure S15: Forest plot depicting the effects of exercise on QoL physical; Figure S16: Forest plot depicting the effects of exercise on anxiety; Figure S17: Forest plot depicting the effects of exercise on depression; Figure S18: Forest plot depicting the effects of exercise on fatigue; Figure S19: Forest plot depicting the effects of exercise on pain; Figure S20: Metaregression analyses on exercise benefits related to age for secondary outcomes; Figure S21: Subgroup analyses on secondary outcome; aerobic capacity; Figure S22: Subgroup analyses on secondary outcome; muscle strength; Figure S23: Subgroup analyses on secondary outcome; body composition; Figure S24: Subgroup analyses on secondary outcome; physical activity; Figure S25: Subgroup analyses on secondary outcome; QoL emotional; Figure S26: Subgroup analyses on secondary outcome; QoL functional; Figure S27: Subgroup analyses on secondary outcome; QoL physical; Figure S28: Subgroup analyses on secondary outcome; anxiety; Figure S29: Subgroup analyses on secondary outcome; depression, Figure S30: Subgroup analyses on secondary outcome; fatigue; Figure S31: Subgroup analyses on secondary outcome; pain.

Table 1 .
Characteristics of included studies.

Table 2 .
Cont.Rate of the certainty of evidence; GRIP: Isometric hand grip; GLQOL: Graham and Longman Quality of Life Scale; HADS: Hospital Anxiety and Depression Scale; GLTEQ: Godin Leisure-Time Exercise Questionnaire; GLQOL: Graham and Longman Quality of Life Scale; IPAQ: International Physical Activity Questionnaire; KPS: Karnofsky Performance Score; Max test: Maximal strength measurement; MFI: Multidimensional Fatigue Inventory; MPN-SAF: Myeloproliferative Neoplasm Symptom Assessment Form; NCCN Distress Thermometer: National Comprehensive Cancer Network Distress Thermometer; PASE: Physical Activity Scale for the Elderly; POMS: Profile of Mood States; PROMIS: Patient Reported Outcomes Measurement Information System; QoL: Health-related Quality of Life; RoB: Risk of Bias; SCFS: Schwartz Cancer Fatigue Scale; SF-12: Short Form Survey-12 items; SF-36: Short Form Survey-36-Items; STAI: Spielberger State Anxiety Inventory; STS: Sit to Stand; SWT: Shuttle Walk Test; TUG: Timed up and go; VO 2 Max: Volume Oxygen Maximal.
Number (no.) of participants corresponds to the number completed with data, which is not necessarily the same as the total number included in studies; * Primary outcomes; 12MWT:12 min walking test; 6MWT: 6 min walking test; 2MSC: 2 min stair climb; 2MWT: 2 min walking distance test; AAS: Active Australia Survey; Activity MET: Activity, metabolic equivalent; BodPod: Body composition tracking system; BFI: Brief Fatigue Inventory; BMI: Body Mass Index; CAM: Complementary and Alternative Medicine (e.g., yoga, qigong, relaxation, breathing exercise); CES-D: Center for Epidemiological Studies-Depression; CMSAS: Condensed Memorial Symptom Assessment Scale; DEXA: Dual energy x-ray absorptiometry; EORTC QLQ-C30: The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire; FACT-An: The Functional Assessment of Cancer Therapy-Anemia; FACT-BMT: The Functional Assessment of Cancer Therapy-Bone Marrow Transplantation; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue; FACT-F: The Functional Assessment of Cancer Therapy-Fatigue; FACT-G: The Functional Assessment of Cancer Therapy-General; FACT-General: The Functional Assessment of Cancer Therapy-General; FACT-Leu: Functional Assessment of Cancer Therapy-Leukemia; FACT-TOI: The Functional Assessment of Cancer Therapy-Trial Outcome Index; GRADE:

Table 3 .
Feasibility and adverse events.