PhD, MRes, BSc Benjamin Singh
email: benjamin.singh@hdr.qut.edu.au

PhD, BAppSci (HMS, Honours), AEP Rosa Spence

PhD, BSc, Honours Megan L Steele

PhD, BAppSci HMS Sandi Hayes

PhD, MCEP, BSc, PG Kellie Toohey

Clin Ex Phys

PG Cert Research

Cert Tertiary

Exercise for Individuals With Lung Cancer: A Systematic Review and Meta-Analysis of Adverse Events, Feasibility, and Effectiveness

Keywords: Electronic databases (CINAHL, Cochrane, Ebscohost, MEDLINE, Pubmed, ProQuest Health and Medical Complete, ProQuest Nursing and Allied Health lung, cancer, neoplasm, aerobic exercise, resistance exercise, exercise oncology

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Worldwide, lung cancer is the most commonly diagnosed cancer in males and the third most commonly diagnosed cancer in females [START_REF] Bray | Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[END_REF] , accounting for 13% of new cancer diagnoses [START_REF] Siegel | Cancer statistics[END_REF] .

Lung cancer is associated with poor prognosis (5-year survival: 19%) [START_REF] Ferlay | Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012[END_REF][START_REF] Noone | SEER Cancer Statistics Review, 1975-2015[END_REF] and is the leading cause of cancer-related death in both females and males, resulting in more deaths than breast, prostate and colon cancers combined [START_REF] Siegel | Cancer statistics[END_REF][START_REF] Jemal | Annual Report to the Nation on the Status of Cancer, 1975-2014, Featuring Survival[END_REF][START_REF] Howlader | National Cancer Institute SEER Cancer Statistics Review, 1975-2014[END_REF] . The two main types of lung cancer are Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC), with NSCLC accounting for 70% to 85% of diagnoses [START_REF] Sher | Small cell lung cancer[END_REF] . Treatment seeks to mitigate the disease and/or extend life.

However, both the disease and its treatment are associated with a range of debilitating side effects, including pain, dyspnoea, fatigue, anxiety, depression, insomnia, pain, anaemia, pneumonitis, weight loss, muscle wasting and reduced physical function.

Disease-and treatment-related side effects contribute to clinically relevant reductions in fitness, lung capacity [START_REF] Jones | Peak oxygen consumption and long-term all-cause mortality in nonsmall cell lung cancer[END_REF] and overall quality of life [START_REF] Moller | Predictors of postoperative quality of life after surgery for lung cancer[END_REF] , which in turn increase risk of developing comorbidities and mortality [START_REF] Benzo | Complications of lung resection and exercise capacity: a meta-analysis[END_REF][START_REF] Cooley | Symptoms in adults with lung cancer. A systematic research review[END_REF][START_REF] Iyer | Symptom burden and quality of life in advanced non-small cell lung cancer patients in France and Germany[END_REF][START_REF] Morias | Treatment-Related Adverse Effects in Lung Cancer Patients after Stereotactic Ablative Radiation Therapy[END_REF][START_REF] Larsson | Women's experience of physical activity following breast cancer treatment[END_REF] . Cross-sectional data suggests that impairments in quality of life [START_REF] Yang | Quality of life and symptom burden among long-term lung cancer survivors[END_REF] and presence of respiratory symptoms can persist beyond 5 years post-diagnosis for at least 30% and 60% of lung cancer survivors [START_REF] Sarna | Impact of respiratory symptoms and pulmonary function on quality of life of long-term survivors of non-small cell lung cancer[END_REF] . Further, lung cancer patients report lower physical function and inferior health outcomes compared with healthy age-matched controls [START_REF] Ostroff | Health-related quality of life among early-stage, non-small cell, lung cancer survivors[END_REF] and also experience poorer quality of life and a greater number of adverse effects compared with other cancer types (including other common cancers such as colon and prostate [START_REF] Sugimura | Long-term survivorship in lung cancer: a review[END_REF][START_REF] Schag | Quality of life in adult survivors of lung, colon and prostate cancer[END_REF][START_REF] Johnsen | Symptoms and problems in a nationally representative sample of advanced cancer patients[END_REF] ).

The respiratory system plays a vital role in the ability to perform any and all daily tasks, as it is responsible for gas exchange (ie, delivers oxygen to the blood and removes carbon dioxide from the body, which is the by-product of aerobic metabolism), with the lungs being the primary organ of the respiratory system. The known benefits of exercise training on the respiratory system include improvements in strength of the breathing muscles, lung capacity and the efficiency of gas exchange. As such, while a significant evidence base supports the role of exercise for the wider cancer population, exercise is likely particularly useful for those with lung cancer in counteracting the adverse impacts of the disease and its associated treatment on the respiratory system. Further, observational evidence suggests that the benefits of exercise may extend beyond improvements to function and quality of life. Specifically, higher levels of postdiagnosis physical activity is also associated with reduced mortality in lung cancer (HR: 0.76 [95% CI:0.60-0.97]) [START_REF] Friedenreich | Physical activity and mortality in cancer survivors: a systematic review and meta-analysis[END_REF] . Unfortunately, over one-third (36%) of lung cancer patients (stage I-IV) reduce, or stop being physically active in the 6 months following diagnosis [START_REF] Lin | Effects of Walking on Quality of Life Among Lung Cancer Patients: A Longitudinal Study[END_REF] .

The effect of exercise for individuals with lung cancer has been evaluated in RCTs and summarised in previous meta-analyses [START_REF] Cavalheri | Exercise training undertaken by people within 12 months of lung resection for non-small cell lung cancer[END_REF][START_REF] Cavalheri | Preoperative exercise training for patients with non-small cell lung cancer[END_REF][START_REF] Peddle-Mcintyre | Exercise training for advanced lung cancer[END_REF] . Findings indicate that exercise interventions lead to improvements in fitness as measured by the 6-minute walk test (mean difference, MD range= 18 to 50 metres, p<0.05 [START_REF] Cavalheri | Exercise training undertaken by people within 12 months of lung resection for non-small cell lung cancer[END_REF][START_REF] Cavalheri | Preoperative exercise training for patients with non-small cell lung cancer[END_REF] ) and quality of life (standardised mean difference, SMD=0.51, p<0.05 [START_REF] Peddle-Mcintyre | Exercise training for advanced lung cancer[END_REF] ). However, to date, reviews have only focused on studies involving patients with NSCLC, which means that previous research has predominantly involved the subgroup of patients who have higher survival (5-year relative survival: NSCLC: 23%; SCLC: 6% [START_REF] Howlader | SEER Cancer Statistics Review, 1975-2016[END_REF] ). SCLC represents 25-30% of lung cancer diagnoses and is underrepresented in the body of evidence [START_REF] Sher | Small cell lung cancer[END_REF] . Further, thorough assessment of safety and feasibility measures of exercise for those with lung cancer has not been undertaken. Therefore, the purpose of this systematic review was to evaluate the safety, feasibility and efficacy of exercise among individuals with lung cancer (including NSCLC and SCLC). Specifically, this review will evaluate: 1) the number, type and severity of adverse events (safety); and 2) trial recruitment and retention and exercise adherence rates (feasibility). Secondary outcomes of this work included the evaluation of the effect of exercise on health-related outcomes such as quality of life, aerobic fitness, fatigue, upper-body strength, lower-body strength, anxiety, depression, sleep, forced expiratory volume (FEV 1), forced vital capacity (FVC), dyspnea, pain and length of hospital stay.

Methods

Search strategy and selection criteria

An electronic database search was undertaken using combinations of MeSH and freetext words for "lung", "cancer", "physical activity" and "exercise" (see Supplementary content 1 for the full search details for all databases). The following databases were searched: CINAHL, Cochrane, Ebscohost, MEDLINE, Pubmed, ProQuest Health and Medical Complete, ProQuest Nursing and Allied Health Source, Science Direct and SPORTDiscus.

Database searches were limited to scholarly journal articles published in English-language peer-reviewed journals prior to May 1, 2020.

The Participant, Intervention, Comparator, and Outcome (PICO) framework [START_REF] Schardt | Utilization of the PICO framework to improve searching PubMed for clinical questions[END_REF] was used to develop the inclusion criteria as follows: Participants: trials involving female or male participants diagnosed with lung cancer, either awaiting, undergoing or completed surgery, chemotherapy and/or radiotherapy were eligible. Studies that involved samples with mixed cancer types (in addition to lung cancer) were excluded if the results were not reported separately for the participants with lung cancer. Intervention: RCTs designed to evaluate exercise interventions were eligible. An RCT evaluating an exercise intervention was defined as a comparative trial designed to evaluate exercise safety, feasibility and effectiveness with random allocation of participants. Exercise was considered as "any form of planned, structured, and repetitive bodily movements performed to improve or maintain fitness, performance or health" [START_REF] Howley | Type of activity: resistance, aerobic and leisure versus occupational physical activity[END_REF][START_REF] Mcneely | Effects of exercise on breast cancer patients and survivors: a systematic review and meta-analysis[END_REF] . Eligible trials were categorised into subgroups based on exercise mode (aerobic, resistance, combined aerobic and resistance or other). Any form of exercise that was not specified as aerobic or resistance was considered 'other' exercise (e.g., yoga).

Trials were eligible for inclusion irrespective of degree of intervention supervision, intervention length or exercise dose (e.g., exercise intensity). Interventions conducted at any time pre, during or following treatment were eligible. Trials that involved exercise in addition to other interventions (e.g. dietary intervention) were excluded if the results of exercise alone could not be isolated. Comparators: Studies that involved a non-exercise control or usual care group were eligible. Single-group pre-post intervention studies (with no comparison group) were ineligible.

Outcomes of interest

Safety and feasibility: Safety was evaluated by assessing adverse events. Adverse events were defined as any undesirable medical or health-related event that occurred during the trial. Adverse events were classed as either non-exercise adverse events (occurred during the trial but reported as being unrelated to exercise) or exercise-related adverse events (events which occurred during or as a direct result of exercise). Adverse events were categorised by one author (BS) based on severity using the Common Terminology Criteria for Adverse Event (Version 5 [START_REF] Institute | Common Terminology Criteria for Adverse Events (CTCAE) Version[END_REF] ) as either: grade 1 (asymptomatic or mild symptoms, clinical or diagnostic observations only and/or intervention not indicated); grade 2 (moderate, minimal, local or non-invasive intervention required and/or limiting age-appropriate activities of daily living); grade 3 (severe or medically significant but not immediately life-threatening; hospitalisation and/or prolongation of hospitalisation indicated; disabling and limiting self-care activities of daily living); grade 4 (life-threatening consequences and urgent intervention indicated), or; grade 5 (death). An adverse event was considered 'serious' if it resulted in hospitalisation, significant disability, was life threatening or resulted in death (i.e., grade 3 or higher) [START_REF]The Australian Clinical Trial Handbook. A Simple, Practical Guide to the Conduct of Clinical Trials to International Standards of Good Clinical Practice (GCP) in the Australian Context[END_REF] . To reduce the potential of under-reporting of adverse events, any withdrawal from a trial that occurred due to a health-or disease-related reason (e.g., illness, or worsening of side effects) was considered an adverse event [START_REF] Singh | A Systematic Review and Meta-Analysis of the Safety, Feasibility, and Effect of Exercise in Women With Stage II+ Breast Cancer[END_REF] . If an event caused withdrawal from a trial, or if a withdrawal occurred due to a health or medical reason, these events were categorised as grade 3 (if the severity was not specified) [START_REF] Singh | A Systematic Review and Meta-Analysis of the Safety, Feasibility, and Effect of Exercise in Women With Stage II+ Breast Cancer[END_REF] . If a trial did not report adverse events and there were no health-related withdrawals, then it was considered that no adverse events had occurred [START_REF] Singh | A Systematic Review and Meta-Analysis of the Safety, Feasibility, and Effect of Exercise in Women With Stage II+ Breast Cancer[END_REF] .

Health-related outcomes: Meta-analyses of the effects of exercise on health-related outcomes were performed for outcomes that were reported in at least two studies [START_REF] Deeks | Analysing Data and Undertaking Meta-Analyses[END_REF] . These were quality of life, aerobic fitness, fatigue, upper-body strength, lower-body strength, anxiety, depression, sleep, forced expiratory volume in one second (FEV 1), forced vital capacity (FVC), dyspnea, pain and length of hospital stay.

Data extraction

Screening of the titles and abstracts of all records that were identified during the electronic database search was undertaken by one author (BS). Screening of the reference lists of relevant articles (original studies and reviews) was also undertaken to identify potentially eligible studies. Articles that were considered potentially eligible based on the title or abstract were then retrieved in full-text and screened for eligibility. One investigator (BS) extracted the following data from each trial into tabular format: trial and participant characteristics, intervention details, adverse events, and feasibility information.

Risk of bias assessment of each trial was undertaken using the Physiotherapy Evidence

PEDro scale by two investigators (BS, KT) with a third reviewer (SH) assessing conflicts.

The scale is a valid and reliable tool for assessing risk of bias in RCTs [START_REF] Sherrington | PEDro. A database of randomized trials and systematic reviews in physiotherapy[END_REF][START_REF] Maher | Reliability of the PEDro scale for rating quality of randomized controlled trials[END_REF] and each trial was assessed in 11 domains (eligibility criteria, random allocation, concealment, baseline between-group differences, subject blinding, interventionist blinding, assessor blinding, attrition, intention-to-treat, between-group statistical comparisons and outcome reporting).

Trials with a score of six or higher (of a possible score of 10; item one not contributing to the total score) were categorized as high quality, and lower than six as low quality [START_REF] Maher | Reliability of the PEDro scale for rating quality of randomized controlled trials[END_REF][START_REF] Armijo-Olivo | PEDro or Cochrane to Assess the Quality of Clinical Trials? A Meta-Epidemiological Study[END_REF] .

Statistical analyses

Meta-analysis of adverse events: The total number of adverse events that occurred in the exercise and usual care groups were analysed using a Mantel-Haenszel random effects model. Adverse events were analysed as a count variable for the meta-analysis and the risk difference (RD) with 95% confidence intervals was calculated as the effect measure. RD was used to ensure that trials with zero adverse events could be included in the analysis [START_REF] Harrison | Effect of levosimendan on survival and adverse events after cardiac surgery: a metaanalysis[END_REF][START_REF] Hasselblad | A survey of current problems in metaanalysis. Discussion from the Agency for Health Care Policy and Research inter-PORT Work Group on Literature Review/Meta-Analysis[END_REF] . A negative value for RD indicated a lower risk of an adverse event for exercise compared with usual care. Low-grade or low-severity adverse events (i.e., grade 1-2 events) were likely to have not been comprehensively monitored or reported for non-intervention participants due to reduced contact with research staff (compared with the interventions groups). For the intervention groups, grade 1-2 events would also likely include normal responses to exercise (e.g., mild muscle soreness), rather than potentially avoidable or undesirable adverse events [START_REF] Lewis | Muscle soreness and delayed-onset muscle soreness[END_REF] .

Therefore, grade 1-2 adverse events were not included in the meta-analysis.

Feasibility: Feasibility was evaluated by calculating recruitment rate, retention rate and exercise adherence rate (as a percentage) and reported as median, minimum and maximum (due to non-normally distributed data). Recruitment, retention and exercise adherence rates were assessed to determine feasibility. Recruitment rates were calculated as the percentage of individuals who were eligible and consented to participate in the trial.

Retention rates were the percentage of enrolled participants who completed the trial.

Adherence rates were the percentage of scheduled number of exercise sessions that were completed by participants. Feasibility was assessed using the following cut-off values which were established a priori as clinically relevant based on previous studies (recruitment rate ≥25% [START_REF] Jesus | Feasibility of an exercise intervention for fatigued breast cancer patients at a community-based cardiac rehabilitation program[END_REF] ; retention rate ≥75% 41 ; and adherence ≥75%) [START_REF] Newton | Safety, feasibility and effects of an individualised walking intervention for women undergoing chemotherapy for ovarian cancer: a pilot study[END_REF] . For subgroup analyses, a difference of >10% in recruitment, retention and adherence rates between subgroups (exercise mode; intervention supervision; intervention duration; surgery; chemotherapy status; cancer subtype; disease stage; and trial quality) was a priori considered clinically relevant.

Meta-analysis of health outcomes: Health-related outcomes were analysed as continuous outcomes by comparing post-intervention means and standard deviations (SDs) for the exercise and usual care groups. To allow comparison of data from different scales, the standardised mean differences (SMDs) were used as the effect measures, calculated using RevMan software (version 5.3). R statistical software (version 3.6.2) was used to create forest plots for each meta-analysis. If means and SDs were not reported in a paper (n=2 trials), the authors were contacted (n=1 responded), or recommended formulas were used to calculate the means and/or SDs using reported data (e.g., using median, range and sample size) [START_REF] Higgins | Cochrane Handbook for Systematic Reviews of Interventions[END_REF] . If a trial involved two or more instruments for assessing an outcome, the instrument defined as being the gold standard or with demonstrated validity and reliability was used (n=6).

For each meta-analysis, data were combined at the trial level. Funnel plots were created to evaluate publication bias by plotting RDs or SMDs and standard errors and assessing the presence of asymmetries or missing sections [START_REF] Egger | Bias in meta-analysis detected by a simple, graphical test[END_REF] . The following cut-offs were used to describe the magnitude of effect: less than 0.20 representing a small effect; 0.20-0.50 representing a medium effect; and greater than 0.50 representing a large effect [START_REF]Statistical Power Analysis for the Behavioral Sciences[END_REF] . A p-value of less than 0.05 was considered statistically significant. Cochran's Q test was used to assess for statistical heterogeneity and the proportion of the overall outcome attributed to variability was investigated using the I 2 statistic [START_REF] Deeks | Analysing Data and Undertaking Meta-Analyses[END_REF][START_REF] Thompson | How should meta-regression analyses be undertaken and interpreted?[END_REF] using the following values: I 2 =0-29%, no heterogeneity; I 2 =30-49%, moderate heterogeneity; I 2 =50-74%, substantial heterogeneity; and I 2 =75-100%, considerable heterogeneity [START_REF] Deeks | Analysing Data and Undertaking Meta-Analyses[END_REF] . Planned subgroup analyses were performed to 1 assess the effects of: 1) exercise mode (aerobic, resistance, combined and other exercise); 2) intervention supervision (supervised, defined as over half of the exercise sessions involving face-to-face supervision, versus unsupervised, defined as less than half of the exercise sessions involving face-to-face supervision); 3) intervention duration (<12 weeks or >12 weeks); 4) timing of the intervention with respect to surgery (pre-surgery or post-surgery); 5) timing of the intervention with respect to chemotherapy (during or following chemotherapy); 6) cancer subtype (NSCLC, SCLC or mixed [studies involving a mix of participants with different diagnoses]); 7) disease stage (stage I-II, III-IV and mixed [studies involving a mix of participants with different stages]); and 8) trial quality (high-versus low quality) on adverse events, recruitment, withdrawal and adherence rates, and health outcomes.

Results

Literature search: A total of 2503 articles were identified after a search of databases (see Supplementary content 2 for PRISMA flow diagram). Following removal of duplicates, titles and abstracts were screened and 185 full-text publications were retrieved for review.

One-hundred and fifty-three (n=153) were subsequently deemed ineligible (see Supplementary content 2 for reasons for exclusion), leaving 32 trials for inclusion. Trials were rated as being of low (n=9, 28%) or high quality (n=23, 72%) (see Supplementary content 3 for trial quality ratings).

Trial and participant characteristics: Sample sizes ranged between 14 [START_REF] Karvinen | Effect of an exercise training intervention with resistance bands on blood cell counts during chemotherapy for lung cancer: a pilot randomized controlled trial[END_REF] and 235 47 ( median=57), and mean age of participants across all trials was 64 years (SD=3). Most trials specifically involved participants with NSCLC (n=21, 66%) , while eleven trials (n=11, 34%) involved participants with NSCLC and SCLC [START_REF] Karvinen | Effect of an exercise training intervention with resistance bands on blood cell counts during chemotherapy for lung cancer: a pilot randomized controlled trial[END_REF][START_REF] Benzo | Preoperative pulmonary rehabilitation before lung cancer resection: results from two randomized studies[END_REF][START_REF] Quist | Effects of an exercise intervention for patients with advanced inoperable lung cancer undergoing chemotherapy: A randomized clinical trial[END_REF][START_REF] Brocki | Short and long-term effects of supervised versus unsupervised exercise training on health-related quality of life and functional outcomes following lung cancer surgery -a randomized controlled trial[END_REF][START_REF] Chen | Randomised controlled trial on the effectiveness of home-based walking exercise on anxiety, depression and cancerrelated symptoms in patients with lung cancer[END_REF][START_REF] Dhillon | Impact of physical activity on fatigue and quality of life in people with advanced lung cancer: a randomized controlled trial[END_REF][START_REF] Granger | Safety and feasibility of an exercise intervention for patients following lung resection: a pilot randomized controlled trial[END_REF][START_REF] Henke | Strength and endurance training in the treatment of lung cancer patients in stages IIIA/IIIB/IV. Support care cancer Off[END_REF][START_REF] Jastrzebski | Pulmonary Rehabilitation in Advanced Lung Cancer Patients During Chemotherapy[END_REF][START_REF] Salhi | Rehabilitation in patients with radically treated respiratory cancer: A randomised controlled trial comparing two training modalities[END_REF][START_REF] Zhang | Tai Chi Exercise for Cancer-Related Fatigue in Patients With Lung Cancer Undergoing Chemotherapy: A Randomized Controlled Trial[END_REF] . Three trials involved participants with stage I-II disease [START_REF] Messaggi-Sartor | Combined aerobic exercise and high-intensity respiratory muscle training in patients surgically treated for non-small cell lung cancer: a pilot randomized clinical trial[END_REF][START_REF] Pehlivan | The effects of preoperative short-term intense physical therapy in lung cancer patients: a randomized controlled trial[END_REF][START_REF] Stefanelli | High-intensity training and cardiopulmonary exercise testing in patients with chronic obstructive pulmonary disease and non-smallcell lung cancer undergoing lobectomy[END_REF] , seven involved participants with stage III-IV 1 disease [START_REF] Rutkowska | Exercise Training in Patients With Non-Small Cell Lung Cancer During In-Hospital Chemotherapy Treatment: A RANDOMIZED CONTROLLED TRIAL[END_REF][START_REF] Egegaard | Pre-radiotherapy daily exercise training in non-small cell lung cancer: A feasibility study[END_REF][START_REF] Hwang | Effects of exercise training on exercise capacity in patients with non-small cell lung cancer receiving targeted therapy. Support care cancer Off[END_REF][START_REF] Quist | Effects of an exercise intervention for patients with advanced inoperable lung cancer undergoing chemotherapy: A randomized clinical trial[END_REF][START_REF] Dhillon | Impact of physical activity on fatigue and quality of life in people with advanced lung cancer: a randomized controlled trial[END_REF][START_REF] Henke | Strength and endurance training in the treatment of lung cancer patients in stages IIIA/IIIB/IV. Support care cancer Off[END_REF][START_REF] Jastrzebski | Pulmonary Rehabilitation in Advanced Lung Cancer Patients During Chemotherapy[END_REF] , 22 trials involved a mixed sample with stage I-IV disease 24,46- 52,55,56,58,59,62,63,65,67,68,70,71,73,76,77 . Twenty trials evaluated exercise post-surgery 46-48,53,55,56,59,61- 65,70-77 and 12 trials were pre-operative [START_REF] Lai | Systematic short-term pulmonary rehabilitation before lung cancer lobectomy: a randomized trial[END_REF][START_REF] Lai | Seven-day intensive preoperative rehabilitation for elderly patients with lung cancer: a randomized controlled trial[END_REF][START_REF] Licker | Short-Term Preoperative High-Intensity Interval Training in Patients Awaiting Lung Cancer Surgery: A Randomized Controlled Trial[END_REF][START_REF] Morano | Preoperative pulmonary rehabilitation versus chest physical therapy in patients undergoing lung cancer resection: a pilot randomized controlled trial[END_REF][START_REF] Pehlivan | The effects of preoperative short-term intense physical therapy in lung cancer patients: a randomized controlled trial[END_REF][START_REF] Rutkowska | Exercise Training in Patients With Non-Small Cell Lung Cancer During In-Hospital Chemotherapy Treatment: A RANDOMIZED CONTROLLED TRIAL[END_REF][START_REF] Garcia | Preoperative exercise training prevents functional decline after lung resection surgery: a randomized, single-blind controlled trial[END_REF][START_REF] Stefanelli | High-intensity training and cardiopulmonary exercise testing in patients with chronic obstructive pulmonary disease and non-smallcell lung cancer undergoing lobectomy[END_REF][START_REF] Huang | Short-term high-intensity rehabilitation in radically treated lung cancer: a three-armed randomized controlled trial[END_REF][START_REF] Karenovics | Short-term preoperative exercise therapy does not improve long-term outcome after lung cancer surgery: a randomized controlled study[END_REF][START_REF] Benzo | Preoperative pulmonary rehabilitation before lung cancer resection: results from two randomized studies[END_REF][START_REF] Quist | Effects of an exercise intervention for patients with advanced inoperable lung cancer undergoing chemotherapy: A randomized clinical trial[END_REF] , with one trial involving inoperable cancer [START_REF] Quist | Effects of an exercise intervention for patients with advanced inoperable lung cancer undergoing chemotherapy: A randomized clinical trial[END_REF] . With respect to chemotherapy, most trials evaluated exercise post-treatment (n=17 [START_REF] Arbane | Evaluation of an early exercise intervention after thoracotomy for non-small cell lung cancer (NSCLC), effects on quality of life, muscle strength and exercise tolerance: randomised controlled trial[END_REF][START_REF] Lai | Systematic short-term pulmonary rehabilitation before lung cancer lobectomy: a randomized trial[END_REF][START_REF] Lai | Seven-day intensive preoperative rehabilitation for elderly patients with lung cancer: a randomized controlled trial[END_REF][START_REF] Morano | Preoperative pulmonary rehabilitation versus chest physical therapy in patients undergoing lung cancer resection: a pilot randomized controlled trial[END_REF][START_REF] Messaggi-Sartor | Combined aerobic exercise and high-intensity respiratory muscle training in patients surgically treated for non-small cell lung cancer: a pilot randomized clinical trial[END_REF][START_REF] Pehlivan | The effects of preoperative short-term intense physical therapy in lung cancer patients: a randomized controlled trial[END_REF][START_REF] Wang | Regular tai chi exercise decreases the percentage of type 2 cytokine-producing cells in postsurgical non-small cell lung cancer survivors[END_REF][START_REF] Garcia | Preoperative exercise training prevents functional decline after lung resection surgery: a randomized, single-blind controlled trial[END_REF][START_REF] Arbane | Effect of postoperative physical training on activity after curative surgery for non-small cell lung cancer: a multicentre randomised controlled trial[END_REF][START_REF] Stefanelli | High-intensity training and cardiopulmonary exercise testing in patients with chronic obstructive pulmonary disease and non-smallcell lung cancer undergoing lobectomy[END_REF][START_REF] Cavalheri | Exercise training for people following curative intent treatment for non-small cell lung cancer: a randomized controlled trial[END_REF][START_REF] Chang | Effects of an early postoperative walking exercise programme on health status in lung cancer patients recovering from lung lobectomy[END_REF][START_REF] Huang | Short-term high-intensity rehabilitation in radically treated lung cancer: a three-armed randomized controlled trial[END_REF][START_REF] Benzo | Preoperative pulmonary rehabilitation before lung cancer resection: results from two randomized studies[END_REF][START_REF] Chen | Randomised controlled trial on the effectiveness of home-based walking exercise on anxiety, depression and cancerrelated symptoms in patients with lung cancer[END_REF][START_REF] Dhillon | Impact of physical activity on fatigue and quality of life in people with advanced lung cancer: a randomized controlled trial[END_REF][START_REF] Salhi | Rehabilitation in patients with radically treated respiratory cancer: A randomised controlled trial comparing two training modalities[END_REF] ), eight evaluated exercise during chemotherapy [START_REF] Karvinen | Effect of an exercise training intervention with resistance bands on blood cell counts during chemotherapy for lung cancer: a pilot randomized controlled trial[END_REF][START_REF] Rutkowska | Exercise Training in Patients With Non-Small Cell Lung Cancer During In-Hospital Chemotherapy Treatment: A RANDOMIZED CONTROLLED TRIAL[END_REF][START_REF] Egegaard | Pre-radiotherapy daily exercise training in non-small cell lung cancer: A feasibility study[END_REF][START_REF] Hwang | Effects of exercise training on exercise capacity in patients with non-small cell lung cancer receiving targeted therapy. Support care cancer Off[END_REF][START_REF] Quist | Effects of an exercise intervention for patients with advanced inoperable lung cancer undergoing chemotherapy: A randomized clinical trial[END_REF][START_REF] Henke | Strength and endurance training in the treatment of lung cancer patients in stages IIIA/IIIB/IV. Support care cancer Off[END_REF][START_REF] Jastrzebski | Pulmonary Rehabilitation in Advanced Lung Cancer Patients During Chemotherapy[END_REF][START_REF] Zhang | Tai Chi Exercise for Cancer-Related Fatigue in Patients With Lung Cancer Undergoing Chemotherapy: A Randomized Controlled Trial[END_REF] and seven trials involved mixed samples of participants who were undergoing or had completed treatment [START_REF] Quist | Early initiated postoperative rehabilitation reduces fatigue in patients with operable lung cancer: A randomized trial[END_REF][START_REF] Licker | Short-Term Preoperative High-Intensity Interval Training in Patients Awaiting Lung Cancer Surgery: A Randomized Controlled Trial[END_REF][START_REF] Stigt | A randomized controlled trial of postthoracotomy pulmonary rehabilitation in patients with resectable lung cancer[END_REF][START_REF] Edvardsen | High-intensity training following lung cancer surgery: a randomised controlled trial[END_REF][START_REF] Karenovics | Short-term preoperative exercise therapy does not improve long-term outcome after lung cancer surgery: a randomized controlled study[END_REF][START_REF] Brocki | Short and long-term effects of supervised versus unsupervised exercise training on health-related quality of life and functional outcomes following lung cancer surgery -a randomized controlled trial[END_REF][START_REF] Granger | Safety and feasibility of an exercise intervention for patients following lung resection: a pilot randomized controlled trial[END_REF] .

Intervention characteristics: Interventions ranged between one [START_REF] Lai | Systematic short-term pulmonary rehabilitation before lung cancer lobectomy: a randomized trial[END_REF][START_REF] Lai | Seven-day intensive preoperative rehabilitation for elderly patients with lung cancer: a randomized controlled trial[END_REF][START_REF] Pehlivan | The effects of preoperative short-term intense physical therapy in lung cancer patients: a randomized controlled trial[END_REF] and 20 weeks [START_REF] Edvardsen | High-intensity training following lung cancer surgery: a randomised controlled trial[END_REF] .

Most trials were less than 12 weeks (n=21, 66%) [START_REF] Lai | Systematic short-term pulmonary rehabilitation before lung cancer lobectomy: a randomized trial[END_REF][START_REF] Lai | Seven-day intensive preoperative rehabilitation for elderly patients with lung cancer: a randomized controlled trial[END_REF][START_REF] Licker | Short-Term Preoperative High-Intensity Interval Training in Patients Awaiting Lung Cancer Surgery: A Randomized Controlled Trial[END_REF][START_REF] Morano | Preoperative pulmonary rehabilitation versus chest physical therapy in patients undergoing lung cancer resection: a pilot randomized controlled trial[END_REF][START_REF] Messaggi-Sartor | Combined aerobic exercise and high-intensity respiratory muscle training in patients surgically treated for non-small cell lung cancer: a pilot randomized clinical trial[END_REF][START_REF] Pehlivan | The effects of preoperative short-term intense physical therapy in lung cancer patients: a randomized controlled trial[END_REF][START_REF] Rutkowska | Exercise Training in Patients With Non-Small Cell Lung Cancer During In-Hospital Chemotherapy Treatment: A RANDOMIZED CONTROLLED TRIAL[END_REF][START_REF] Garcia | Preoperative exercise training prevents functional decline after lung resection surgery: a randomized, single-blind controlled trial[END_REF][START_REF] Arbane | Effect of postoperative physical training on activity after curative surgery for non-small cell lung cancer: a multicentre randomised controlled trial[END_REF][START_REF] Stefanelli | High-intensity training and cardiopulmonary exercise testing in patients with chronic obstructive pulmonary disease and non-smallcell lung cancer undergoing lobectomy[END_REF][START_REF] Cavalheri | Exercise training for people following curative intent treatment for non-small cell lung cancer: a randomized controlled trial[END_REF][START_REF] Egegaard | Pre-radiotherapy daily exercise training in non-small cell lung cancer: A feasibility study[END_REF][START_REF] Hwang | Effects of exercise training on exercise capacity in patients with non-small cell lung cancer receiving targeted therapy. Support care cancer Off[END_REF][START_REF] Huang | Short-term high-intensity rehabilitation in radically treated lung cancer: a three-armed randomized controlled trial[END_REF][START_REF] Karenovics | Short-term preoperative exercise therapy does not improve long-term outcome after lung cancer surgery: a randomized controlled study[END_REF][START_REF] Benzo | Preoperative pulmonary rehabilitation before lung cancer resection: results from two randomized studies[END_REF][START_REF] Brocki | Short and long-term effects of supervised versus unsupervised exercise training on health-related quality of life and functional outcomes following lung cancer surgery -a randomized controlled trial[END_REF][START_REF] Dhillon | Impact of physical activity on fatigue and quality of life in people with advanced lung cancer: a randomized controlled trial[END_REF][START_REF] Granger | Safety and feasibility of an exercise intervention for patients following lung resection: a pilot randomized controlled trial[END_REF][START_REF] Henke | Strength and endurance training in the treatment of lung cancer patients in stages IIIA/IIIB/IV. Support care cancer Off[END_REF][START_REF] Jastrzebski | Pulmonary Rehabilitation in Advanced Lung Cancer Patients During Chemotherapy[END_REF] , and 11 trials (34%)

were 12 weeks or longer [START_REF] Karvinen | Effect of an exercise training intervention with resistance bands on blood cell counts during chemotherapy for lung cancer: a pilot randomized controlled trial[END_REF][START_REF] Quist | Early initiated postoperative rehabilitation reduces fatigue in patients with operable lung cancer: A randomized trial[END_REF][START_REF] Arbane | Evaluation of an early exercise intervention after thoracotomy for non-small cell lung cancer (NSCLC), effects on quality of life, muscle strength and exercise tolerance: randomised controlled trial[END_REF][START_REF] Stigt | A randomized controlled trial of postthoracotomy pulmonary rehabilitation in patients with resectable lung cancer[END_REF][START_REF] Wang | Regular tai chi exercise decreases the percentage of type 2 cytokine-producing cells in postsurgical non-small cell lung cancer survivors[END_REF][START_REF] Chang | Effects of an early postoperative walking exercise programme on health status in lung cancer patients recovering from lung lobectomy[END_REF][START_REF] Edvardsen | High-intensity training following lung cancer surgery: a randomised controlled trial[END_REF][START_REF] Quist | Effects of an exercise intervention for patients with advanced inoperable lung cancer undergoing chemotherapy: A randomized clinical trial[END_REF][START_REF] Chen | Randomised controlled trial on the effectiveness of home-based walking exercise on anxiety, depression and cancerrelated symptoms in patients with lung cancer[END_REF][START_REF] Salhi | Rehabilitation in patients with radically treated respiratory cancer: A randomised controlled trial comparing two training modalities[END_REF][START_REF] Zhang | Tai Chi Exercise for Cancer-Related Fatigue in Patients With Lung Cancer Undergoing Chemotherapy: A Randomized Controlled Trial[END_REF] . Combined exercise (aerobic and resistance exercise) was the most common intervention mode (n=16, 50%) 47,48,52,55,57-59,61,63,68-70,73-76 , while 13 trials involved aerobic only exercise (n=13, 41%) [START_REF] Lai | Systematic short-term pulmonary rehabilitation before lung cancer lobectomy: a randomized trial[END_REF][START_REF] Lai | Seven-day intensive preoperative rehabilitation for elderly patients with lung cancer: a randomized controlled trial[END_REF][START_REF] Licker | Short-Term Preoperative High-Intensity Interval Training in Patients Awaiting Lung Cancer Surgery: A Randomized Controlled Trial[END_REF][START_REF] Messaggi-Sartor | Combined aerobic exercise and high-intensity respiratory muscle training in patients surgically treated for non-small cell lung cancer: a pilot randomized clinical trial[END_REF][START_REF] Pehlivan | The effects of preoperative short-term intense physical therapy in lung cancer patients: a randomized controlled trial[END_REF][START_REF] Stefanelli | High-intensity training and cardiopulmonary exercise testing in patients with chronic obstructive pulmonary disease and non-smallcell lung cancer undergoing lobectomy[END_REF][START_REF] Chang | Effects of an early postoperative walking exercise programme on health status in lung cancer patients recovering from lung lobectomy[END_REF][START_REF] Egegaard | Pre-radiotherapy daily exercise training in non-small cell lung cancer: A feasibility study[END_REF][START_REF] Hwang | Effects of exercise training on exercise capacity in patients with non-small cell lung cancer receiving targeted therapy. Support care cancer Off[END_REF][START_REF] Huang | Short-term high-intensity rehabilitation in radically treated lung cancer: a three-armed randomized controlled trial[END_REF][START_REF] Karenovics | Short-term preoperative exercise therapy does not improve long-term outcome after lung cancer surgery: a randomized controlled study[END_REF][START_REF] Chen | Randomised controlled trial on the effectiveness of home-based walking exercise on anxiety, depression and cancerrelated symptoms in patients with lung cancer[END_REF][START_REF] Dhillon | Impact of physical activity on fatigue and quality of life in people with advanced lung cancer: a randomized controlled trial[END_REF] , two trials evaluated other exercise (n=2, 6%) [START_REF] Wang | Regular tai chi exercise decreases the percentage of type 2 cytokine-producing cells in postsurgical non-small cell lung cancer survivors[END_REF][START_REF] Zhang | Tai Chi Exercise for Cancer-Related Fatigue in Patients With Lung Cancer Undergoing Chemotherapy: A Randomized Controlled Trial[END_REF] , and one trial (n=1, 3%) involved resistance exercise only [START_REF] Karvinen | Effect of an exercise training intervention with resistance bands on blood cell counts during chemotherapy for lung cancer: a pilot randomized controlled trial[END_REF] . Most interventions were supervised (n=27, 84%) 47,49-58,60-70,72,74-77 , and five (16%) interventions were unsupervised (i.e., less than half of the prescribed exercise was supervised face-to-face) [START_REF] Karvinen | Effect of an exercise training intervention with resistance bands on blood cell counts during chemotherapy for lung cancer: a pilot randomized controlled trial[END_REF][START_REF] Arbane | Evaluation of an early exercise intervention after thoracotomy for non-small cell lung cancer (NSCLC), effects on quality of life, muscle strength and exercise tolerance: randomised controlled trial[END_REF][START_REF] Arbane | Effect of postoperative physical training on activity after curative surgery for non-small cell lung cancer: a multicentre randomised controlled trial[END_REF][START_REF] Chen | Randomised controlled trial on the effectiveness of home-based walking exercise on anxiety, depression and cancerrelated symptoms in patients with lung cancer[END_REF][START_REF] Granger | Safety and feasibility of an exercise intervention for patients following lung resection: a pilot randomized controlled trial[END_REF] . The supervised interventions were most commonly in a hospital setting. Supervision in these trials was from a physiotherapist/physical therapist (n=17) 47,49- 51,53-55,57,58,61,63,65,67,69,70,74,75 , an exercise physiologist (n=3) [START_REF] Egegaard | Pre-radiotherapy daily exercise training in non-small cell lung cancer: A feasibility study[END_REF][START_REF] Huang | Short-term high-intensity rehabilitation in radically treated lung cancer: a three-armed randomized controlled trial[END_REF][START_REF] Dhillon | Impact of physical activity on fatigue and quality of life in people with advanced lung cancer: a randomized controlled trial[END_REF] , a Tai chi practitioner (n=2) [START_REF] Wang | Regular tai chi exercise decreases the percentage of type 2 cytokine-producing cells in postsurgical non-small cell lung cancer survivors[END_REF][START_REF] Zhang | Tai Chi Exercise for Cancer-Related Fatigue in Patients With Lung Cancer Undergoing Chemotherapy: A Randomized Controlled Trial[END_REF] , an intensive care unit researcher (n=1) [START_REF] Chang | Effects of an early postoperative walking exercise programme on health status in lung cancer patients recovering from lung lobectomy[END_REF] , or was not specified (n=4) [START_REF] Morano | Preoperative pulmonary rehabilitation versus chest physical therapy in patients undergoing lung cancer resection: a pilot randomized controlled trial[END_REF][START_REF] Stefanelli | High-intensity training and cardiopulmonary exercise testing in patients with chronic obstructive pulmonary disease and non-smallcell lung cancer undergoing lobectomy[END_REF][START_REF] Benzo | Preoperative pulmonary rehabilitation before lung cancer resection: results from two randomized studies[END_REF][START_REF] Salhi | Rehabilitation in patients with radically treated respiratory cancer: A randomised controlled trial comparing two training modalities[END_REF] . Four of the interventions categorised as unsupervised involved low-levels of supervision from a physiotherapist (n=2) [START_REF] Arbane | Evaluation of an early exercise intervention after thoracotomy for non-small cell lung cancer (NSCLC), effects on quality of life, muscle strength and exercise tolerance: randomised controlled trial[END_REF][START_REF] Arbane | Effect of postoperative physical training on activity after curative surgery for non-small cell lung cancer: a multicentre randomised controlled trial[END_REF] or exercise physiologist (n=2) [START_REF] Karvinen | Effect of an exercise training intervention with resistance bands on blood cell counts during chemotherapy for lung cancer: a pilot randomized controlled trial[END_REF][START_REF] Granger | Safety and feasibility of an exercise intervention for patients following lung resection: a pilot randomized controlled trial[END_REF] .

Safety -overview of adverse events

1 There were no comments about adverse events in nine (28%) trials, while ten (31%) trials explicitly reported that no adverse events had occurred during the trial, and 13 (41%) trials reported the occurrence of adverse events.

Adverse events among exercise participants: Ninety adverse events occurred among participants allocated to exercise (grade 1: n=16 events; grade 2: n=10 events; grade 3: n=27 events; grade 4: n=20 events; grade 5: n=17 events, Table 1). The most common adverse events among exercise participants were death (n=17 events, grade 5), disease progression (n=12 events, Grade 4) and non-specified respiratory events (n=10 events, grade 2). Of the 90 events, 88 events (98%) were considered unrelated to exercise and 2 events (2%) were reported as exercise-related. Exercise-related adverse events were musculoskeletal soreness/pain (n=1 event, grade 1) [START_REF] Dhillon | Impact of physical activity on fatigue and quality of life in people with advanced lung cancer: a randomized controlled trial[END_REF] and a hip fracture during balance training (n=1 event, grade 4) [START_REF] Edvardsen | High-intensity training following lung cancer surgery: a randomised controlled trial[END_REF] . Of note, one study [START_REF] Quist | Effects of an exercise intervention for patients with advanced inoperable lung cancer undergoing chemotherapy: A randomized clinical trial[END_REF] reported that during the pre-screening before each supervised exercise session, five participants were excluded from 1-2 exercise sessions due to adverse events (fever, dizziness, pain, and bodily discomfort). These were not considered as exerciserelated adverse events, however they resulted in missed exercise sessions.

Adverse events among usual care participants: For participants allocated to usual care, there were 73 adverse events (grade 1: n=6 events; grade 2: n=6 events; grade 3: n=21 events; grade 4: n=22 events; grade 5: n=18 events, Table 1). The most common adverse events were death (n=18 events, grade 5), disease progression (n=13 events, grade 4) and pneumonia (n=10 events, grade 3).

Meta-analysis of adverse events: Meta-analysis of 32 RCTs involving 2109 participants (exercise: n= 1067; usual care: n= 1042) showed no difference in the risk of a grade 3-5 adverse event between exercise and usual care (n=125 adverse events [exercise: n=64 events; usual care: n=61 events], RD= -0.01 [91% CI=-0.02, 0.01]; p=0.31; I 2 =11%, Figure 1).

Subgroup analyses showed that adverse event risk was similar irrespective of exercise mode Feasibility outcomes: Recruitment, retention and adherence rates are shown in Table 2.

Recruitment rates: Overall recruitment rate met the pre-defined criterion of >25%, with a median rate of 59% (range: 9-97%, n=25 trials, Table 2). Lower recruitment rates (defined as a difference >10%) were observed for trials that were supervised compared to unsupervised (58% versus 79% respectively), <12 weeks compared to >12 weeks (54% versus 74%) and high-quality compared to low-quality trials (58% versus 79% respectively).

There were no differences in recruitment rates based on exercise mode, timing of intervention with respect to surgery or chemotherapy, lung cancer subtype, disease stage or trial quality.

Retention: Median retention rate for the exercise groups was 86% (range: 50-100%, n=32 trials), and therefore met the predefined feasibility criteria of ≥75%. Retention rate for the usual care groups was 88% (range: 33-100%), with higher (greater than 10% absolute differences) retention rates observed in interventions conducted during chemotherapy compared with post-chemotherapy (88% versus 77%). There were a total of 218 withdrawals (out of 1067 participants) from the exercise groups (n=65, 30% due to health-related reasons; n=153, 70% due to non-health-related reasons) and 228 (out of 1042 participants) withdrawals from usual care groups (n=54, 24% due to health-related reasons; n=174, 76% due to non-health-related reasons). Unspecified non-health reasons (i.e., lost to follow-up with no specified reason) were the most common reason for withdrawal in both groups (exercise groups: n=111 withdrawals; usual care: n=125 withdrawals; see Table 3 for all reasons for withdrawals).

Exercise adherence: Adherence to the scheduled number of exercise sessions met the pre-defined criterion of ≥75%, with a median rate of 80% (range: 44-100%, n=13 trials).

Compared with interventions that were conducted during chemotherapy (69%), higher exercise adherence rates were observed in trials that were post-chemotherapy (79%) or conducted during and post-chemotherapy (87%).

Health Outcomes: An overview of all instruments used to assess quality of life, aerobic

Discussion

Findings from this review support the safety and feasibility of exercise for individuals with lung cancer (NSCLC and SCLC). Exercise was safe and feasible, with similar findings 1 observed irrespective of exercise mode, degree of intervention supervision, intervention length, diagnosis, and whether exercise was performed pre-or post-surgery, or during or following chemotherapy. Benefits through exercise were observed for a range of physical and psychosocial outcomes including quality of life, aerobic fitness, upper-body strength, lowerbody strength, anxiety, depression, FEV1 and sleep.

There was no difference in adverse event risk between exercise and usual care, and the proportion of adverse events related to exercise was extremely low (n=2, 3% of all adverse events reported) and comparable to rates previously observed in studies involving other cancer types (e.g., 5% of adverse events reported in trials involving women with stage II+ breast cancer were exercise-related adverse events) [START_REF] Singh | A Systematic Review and Meta-Analysis of the Safety, Feasibility, and Effect of Exercise in Women With Stage II+ Breast Cancer[END_REF] . However, the rates of total adverse events observed here (7.7%, 163 events in 2109 participants), as well as the proportion of grade 3 or higher adverse events (76% of all adverse events, with death accounting for 25% of these) is more than double that reported in a review of exercise and breast cancer trials (3%, 156 events in 5200 participants) [START_REF] Singh | A Systematic Review and Meta-Analysis of the Safety, Feasibility, and Effect of Exercise in Women With Stage II+ Breast Cancer[END_REF] . These figures are reflective of the known higher morbidity and mortality associated with lung cancer, compared with other common cancers.

However, they also underscore the complexities of intervening with exercise in this cohort, and the importance of exercise professionals (such as Exercise Physiologists or Physiotherapists) working with lung cancer patients to have a deep understanding of the pathophysiology of the disease and treatment-related side effects. For example, all of the grade 2 adverse events reported were non-specified respiratory events, and although clearly associated with the disease and its treatment, require consideration and accommodation in any exercise prescription. Further, given the high rate of disease progression and death, there is a clear need to ensure exercise prescription is based on patient-directed goals, with reducing disease-related morbidity and maintaining independence likely to be common shortterm goals.

Despite dealing with a cancer type with poorer prognosis than other common cancers, average recruitment (59%), retention (86%) and exercise adherence rates (80%) were similar to those previously found in breast [START_REF] Singh | A Systematic Review and Meta-Analysis of the Safety, Feasibility, and Effect of Exercise in Women With Stage II+ Breast Cancer[END_REF] , prostate [START_REF] Gardner | Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: a systematic review[END_REF] and colorectal [START_REF] Boereboom | Systematic review of pre-operative exercise in colorectal cancer patients[END_REF] This review identified that only 40% of trials reported on adherence (participant attendance to exercise sessions) and no trial reported on exercise compliance. The lack of adherence and compliance data makes it difficult to determine realistic exercise prescription guidelines (including session frequency, mode, intensity and duration) with confidence and prevents a clear understanding of the relationship between exercise dose (prescribed and completed) and safety and response. These feasibility data highlighted the importance of a referral to an exercise professional who are trained to work with patients on an individualised basis to maximise gains while reducing risk of adverse events, and the subsequent positive efficacy findings of this review suggest it's important to do so.

Our efficacy findings, which showed improvements (of medium to high effect) in quality of life, aerobic fitness, upper-body strength, lower-body strength, anxiety, depression, FEV1 and sleep (p<0.05), confirm and strengthen findings from previous meta-analyses which showed improved measures of aerobic fitness [START_REF] Cavalheri | Exercise training undertaken by people within 12 months of lung resection for non-small cell lung cancer[END_REF][START_REF] Cavalheri | Exercise training for people following curative intent treatment for non-small cell lung cancer: a randomized controlled trial[END_REF][START_REF] Cavalheri | Exercise training undertaken by people within 12 months of lung resection for non-small cell lung cancer[END_REF] , quality of life [START_REF] Cavalheri | Exercise training undertaken by people within 12 months of lung resection for non-small cell lung cancer[END_REF] and lower-body strength. However, in contrast to findings reported in previous reviews of lung cancer and exercise studies we did not show beneficial effects of exercise on FVC and dyspnoea [START_REF] Cavalheri | Exercise training undertaken by people within 12 months of lung resection for non-small cell lung cancer[END_REF] .

However, differences in the inclusion criteria between the reviews (in particular patient characteristics with previous reviews conducted on studies that only involved NSCLC) may explain the differences in these findings. Further, while we did not show a benefit in these outcomes, exercise was not associated with detriment, indicating that exercise may prevent worsening in these outcomes typically observed overtime.

Findings from the subgroup analyses conducted as part of this review suggested that the effect of exercise may differ for some outcomes based on specific intervention Further, most outcomes improved with exercise, irrespective of exercise mode, degree of supervision, intervention duration, timing of intervention with respect to timing of surgery or chemotherapy, stage of disease at diagnosis, lung cancer type or study quality. When effect sizes were negligible (that is, <0.2) and/or results were not supported statistically or confidence intervals were wide, this was most likely due to having only between 2-5 studies, with small sample size overall, contributing to these results. Nonetheless, the key implication of these findings to date is that when prescribing exercise for patients with lung cancer, exercise professionals should pay close attention to patient exercise preferences.

There were several limitations to the findings of this review that need to be considered.

Overall, reporting of safety and feasibility findings in exercise trials involving lung cancer patients needs improving. Most trials in this review did not describe adverse event monitoring

Figure 1 .

 1 Figure1. Meta-analysis results of all grade 3 to 5 adverse events in exercise compared to usual care presented as overall with subgroup analyses for i) exercise mode, ii) supervision, iii) intervention length, iv) surgery, v) treatment status, vi) diagnosis, vii) stage, and vii) trial quality (n=22 trials, n=24 exercise intervention arms). Negative Risk Difference (RD) value favours exercise.

Figure 2 .

 2 Figure 2. Meta-analysis results of all health outcomes presented as overall effects.

  SMD=0.41) and other exercise (SMD=0.62) compared with aerobic exercise (SMD=-0.11; χ 2 =14.61, p<0.001). Supervision: Supervised interventions had a larger effect on quality of life (SMD=0.36) compared with unsupervised interventions (SMD=-0.02;

	χ 2 =4.73, p=0.03). Greater effects were observed for sleep following unsupervised
	interventions (SMD=0.64) compared with supervised interventions (SMD=0.14; χ 2 =5.05,
	p=0.02). Intervention length: Interventions that were 12 weeks or longer showed a larger
	effect on fatigue (SMD=0.44) compared with shorter interventions (SMD=0.01; χ 2 =6.63,
	p=0.01). Treatment: With respect to treatment, interventions that were conducted during
	treatment (SMD=0.69) had greater effects on dyspnoea compared with post-treatment
	(SMD=-0.12) or combined exercise trials (SMD=0.06; χ 2 =8.30, p=0.02). Disease stage:
	Trials involving participants with stage 1-4 (SMD=0.11) showed a small effect on FVC,
	[95% CI=0.20, 0.42]), aerobic fitness (SMD=0.54 [95% CI=0.32, 0.76]), upper-body strength
	(SMD=0.59 [95% CI=0.30, 0.88]), lower-body strength (SMD=0.38 [95% CI=0.16, 0.61]), effect on sleep (χ 2 =4.94, p=0.03), with trials involving participants with NSCLC showing no
	anxiety (SMD=0.26 [95% CI=0.11, 0.42]), depression (SMD=0.49 [95% CI=0.27, 0.72]), effect (SMD=0.04) and trials involving mixed samples (NSCLC and SCLS) showing a
	FEV1 (SMD=0.28 [95% CI=0.02, 0.54]) and sleep (SMD=0.31 [95% CI=0.01, 0.61]) (Figure moderate effect (SMD=0.46). Trial quality: Trial quality had an effect on upper-body
	2 and Supplementary material 5-11). No overall effects (p>0.05) of exercise were observed strength (χ 2 = 6.25, p=0.01); low quality studies showed a large effect (SMD=1.64) and high-
	for fatigue, length of hospital stay, FVC, dyspnoea, and pain (Figure 2 and Supplementary quality studies showed a moderate effect (SMD=0.47).
	material 12-16).
	Subgroup analyses: An overview of all subgroup effects is shown in Supplementary
	material 17. Mode: Combined exercise (SMD=0.69) had a larger effect on upper-body
	strength than aerobic exercise (SMD=0.14; χ 2 =4.66, p=0.03). Combined exercise

fitness, fatigue, upper-body strength, lower-body strength, sleep, anxiety, depression, dyspnoea, pain, FEV 1 and FVC are shown in Supplementary content 4.

Meta-analyses results: exercise versus usual care: Compared with usual care, there were small to large effects (all p<0.05) in favour of exercise for quality of life (SMD=0.31 (SMD=0.41) also showed a larger benefit on length of hospital stay compared with aerobic exercise (SMD=-0.33; χ 2 =5.44, p=0.02). For fatigue, larger effects were observed for 1 combined (while moderate and large effects were observed in trials involving participants with stage 1-2 (SMD=1.21) and stage 3-4 (SMD=0.65; χ 2 =11.72, p=0.003) disease, respectively. Timing of surgery: No subgroup effects were observed for surgery. Diagnosis: Cancer subtype had an

  the mean age of participants in included studies was 64 years compared with the mean age at lung cancer diagnosis being 70 years[START_REF] Noone | SEER Cancer Statistics Review, 1975-2015[END_REF] , it is plausible that these rates overestimate exercise feasibility for the wider lung cancer population. Further, more work is required to better understand the ability for those with lung cancer to adhere to exercise prescription.

	cancer cohorts. However,
	since 34% (n=11) of trials excluded participants with comorbidities, 31% (n=10) excluded
	participants with advanced stage cancer, no trials specifically involved individuals with
	SCLC, and

Table 3 .

 3 Overview of withdrawals reported separately based on intervention length and health-or non-health-related.

		Withdrawals from exercise groups	Withdrawals from usual care groups
		218 withdrawals out of total 1067 participants	228 withdrawals out of 1042 participants
		<12-week interventions,	>12-week interventions,	<12-week interventions, n=94	>12-week interventions, n=134
		n=104	n=114
	Reason for	Health-related reasons, n=38	Health-related reasons, n=27	Health-related reasons, n=30	Health-related reasons, n=24
	withdrawals	Death, n=12	Disease progression, n=13	Death, n=9	Disease progression, n=12
		Change of cancer treatment, n=5	Death, n=5	Change of cancer treatment, n=5	Death, n=9
		Non-malignant disease, n=4	Chemotherapy-related side effects,	Too unwell, n=4	ITU admission, n=1
		Too unwell, n=3 Knee pain, n=3 Required further treatment, n=3 Hospitalisation, n=1 Acute COPD exacerbation, n=1 Anaemia, n=1 Myalgia, n=1 Asthernia, n=1 Pneumonia, n=1 Neoadjuvant therapy, n=1 Non-resectable tumour, n=1	n=2 Bone pain, n=2 Referred to palliative care, n=1 Cancelled surgery, n=1 Brain metastasis, n=1 Hip fracture, n=1 Ankle injury, n=1 Non-health-related reasons or other, n=87 Lost to follow-up or reason not	Inoperable cancer, n=3 Anemia, n=2 Received chemotherapy, n=2 Disease progression, n=2 Further surgery required, n=1 Post-surgery complications, n=1 Leucopenia, n=1 Non-health-related reasons or other, n=64 Lost to follow-up or reason not	Required palliative care, n=1 Change of cancer treatment, n=1 Non-health-related reasons or other, n=110 Lost to follow-up or reason not reported, n=84 Refused to continue, n=11 Loss of interest or motivation n=10
			reported n=63	reported, n=41	Too busy, n=2
		Non-health-related reasons or other,	Refused to continue, n=14	Did not receive allocated usual	Change in study eligibility
		n=66	Loss of interest or motivation, n=7	care, n=18	status, n=2
		Lost to follow-up or reason not	Travelling, n=1		Transportation difficulties n=1
		reported, n=48 Did not receive intervention, n=11 Refused to continue, n=3	Caring for family, n=1 Moved away, n=1	Personal reason, n=2 Not NCLS, n=2 Transferred out of area, n=1
		Personal reason, n=1
		Transferred out of area, n=1
		Perceived a lack of benefit, n=1
		Lack of motivation, n=1

procedures and for about one-third (29%, n=9) there was no mention of whether adverse events occurred or not. Further, it is also plausible that consenting participants were likely to have higher function and less morbidity compared with the wider lung cancer population. Consequently, while results suggest exercise is safe and feasible for patients with lung cancer, caution needs to be applied to these findings and future research can aid practice through more comprehensive reporting of safety and feasibility (including exercise compliance) outcomes. There remains a scope for more translational exercise intervention research that seeks to transition patients from shorter-term highly supervised exercise to longer-term exercises in unsupervised conditions. This type of research will determine whether exercise is safe, feasible and effective for subgroups who may find it more difficult to access supervised exercise services, either due to place of residence (e.g., live in more rural/regional areas), disease-or treatment-related factors, patient preferences (e.g., prefer home-based interventions) or due to other factors (e.g., lack of carer support). Nonetheless, findings from this review suggest that exercise is beneficial for improving health outcomes among those diagnosed with lung cancer at any stage. These are important findings as they highlight that despite lung cancer being associated with poorer prognosis compared with other common cancers, promotion of physical activity guidelines and referral to exercise services remains relevant for this specific cancer group.

Funding:

The authors received no specific funding for this work.

Disclosure:

The authors declare no conflicts of interest. Grade 5 adverse events: 0/17 Grade 5 adverse events: 18 Death: 0/17 Death: 18 AE: adverse events. [START_REF] Bray | Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[END_REF] Adverse events were classified using the Common Terminology Criteria as; grade 1: asymptomatic or mild symptoms; grade 2: moderate, minimal, local or non-invasive intervention indicated and limiting age-appropriate instrumental activities of daily living; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life-threatening consequences and urgent intervention indicated, or; grade 5: death. [START_REF] Bray | Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[END_REF] Includes all adverse events (both exercise-and non-exercise related).

2

Adverse events in which the severity was not reported were considered Grade 3 or higher if the event led to trial withdrawal.