lable at ScienceDirect

Surgical Oncology 23 (2014) 17e30

Contents lists avai

Surgical Oncology

journal homepage: www.elsevier .com/locate/suronc

Review

Exercise intervention for patients surgically treated for Non-Small CellLung Cancer (NSCLC): A systematic review

Katy Crandall a,*, Roma Maguire b, Anna Campbell c, Nora Kearney a

aUniversity of Dundee, School of Nursing and Midwifery, 11 Airlie Place, Dundee DD1 4HJ, Scotland, UKbUniversity of Surrey, School of Health and Social Care, Faculty of Health and Medical Sciences, Duke of Kent Building, Guildford GU2 7TE, Surrey, UKcUniversity of Dundee, Institute of Sport and Exercise, Dundee DD1 4HN, Scotland, UK

a r t i c l e i n f o

Article history:Accepted 12 January 2014

Keywords:Systematic reviewLung cancerOncologySurgicalExercisePulmonary rehabilitation

* Corresponding author. Tel./fax: þ44 (0) 1382 388E-mail addresses: k.crandall@surrey.ac.uk, katycra

0960-7404/$ e see front matter � 2014 Elsevier Ltd.http://dx.doi.org/10.1016/j.suronc.2014.01.001

a b s t r a c t

Background: Surgery remains the best curative option for appropriately selected patients with lungcancer. Evidence suggests that improving cardiovascular fitness and functional capacity can acceleratepost-surgery recovery and reduce mortality. However, the effect of exercise intervention for patientssurgically treated for Non-Small Cell Lung Cancer [NCSLC] has not been fully examined.Purpose: This review examines the literature regarding exercise intervention for patients who are sur-gically treated for NSCLC focussing on three key areas: methodological quality, intervention design (e.g.duration, frequency, type) and outcomes measured.Methods: A search of Medline, EMBASE, CINAHL and PsychINFO was undertaken. Randomised ControlledTrials [RCTs] and non-RCTs including exercise training pre or post lung cancer resection were included.Descriptive characteristics were extracted and methodological quality assessed using Downs and Blackappraisal checklist.Results: Twenty studies (eight RCT’s) were included: nine pre-surgical, nine post-surgical and two pre topost-surgical. The quality of evidence is questionable with many limitations (e.g. small samples, inad-equate allocation concealment and a lack of clear reporting on timing, adverse events and follow-up).Regarding design of exercise intervention and outcomes measured, there was much variation betweenstudies producing a disparate set of data. An optimal programme is still to be determined; however,suggestions are made relating to type of exercise (i.e. mixing aerobic, resistance and breathing exercises).Preliminary work from this review suggests that exercise intervention compared with usual care bothpre and post-surgery is associated with improved cardiopulmonary exercise capacity, increased musclestrength and reduced fatigue, post-operative complications and hospital length of stay. Results con-cerning pulmonary function, quality of life, and blood gas analysis were variable and inconsistent.Conclusion: In order to implement exercise intervention appropriate for patients surgically treated forNCSLC, more high quality randomised controlled trials are required and more work concerning feasi-bility, acceptability and effectiveness of specific interventions on outcomes is warranted.

� 2014 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19Research questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19

Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Inclusion/exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Study design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

533.ndall@hotmail.com (K. Crandall).

All rights reserved.

K. Crandall et al. / Surgical Oncology 23 (2014) 17e3018

Outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Assessment of methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Synthesis of results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Database search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Excluded articles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Stage of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Length of intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Type of exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Frequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Intensity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Duration of session . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Supervision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Group/individual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Inpatient/outpatient/home-based . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Inclusion of control group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Other components to the rehabilitation programme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Outcomes measured . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Exercise capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Pulmonary function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Quality Of Life (QOL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Safety/adverse events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Feasibility/acceptability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Length of hospital stay and post-operative complications (POCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Fatigue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Muscle strength . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Blood gas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Authorship statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Introduction

Lung cancer is the second most common cancer in the UK andthe leading cause of cancer death worldwide [1,2]. It is frequentlydiagnosed at a late stage due to its initial asymptomatic courseoften leading to a poor prognosis. Lung cancer is histologicallydefined into two groups, Non-Small Cell Lung Cancer (NSCLC) andSmall Cell Lung Cancer (SCLC). For patients diagnosed with NSCLC(approximately 85% of those diagnosed with lung cancer) survivalrates remain much higher than for those diagnosed with SCLC [3],in particular for those deemed eligible for tumour resection [4].Surgical removal remains the best curative option for patients withearly stage (stages I and II) NSCLC and for appropriately selectedpatients with locally advanced disease (stage IIIA) [5].

At present approximately 11% of patients diagnosed with lungcancer are eligible for resection [6], owing to the stage of disease,limited functional capacity and/or associated comorbidities [7].However, with a government focus on the early detection ofcancer and lung cancer screening programmes being trialledacross the country, this may result in an increase in the number ofpatients with early stage disease, thus increasing the number ofcurative treatments being performed [8]. Despite the possibility ofa cure, surgical resection is associated with significant morbidity,functional limitations and decreased Quality Of Life (QOL) post-surgery [9,10].

Cancer care is being directed toward developing interventionsthat improve overall functioning as well as longevity [11]. There hasbeen a growing interest in the use of non-pharmacological in-terventions, such as exercise, both during and after cancer treat-ment. Exercise has been identified as a successful intervention toimprove physical and psychological health in some cancer pop-ulations (mainly breast cancer) [11]. Furthermore, cardiopulmo-nary rehabilitation has been a key component in other pulmonarydiseases such as Chronic Obstructive Pulmonary Disorder (COPD)and has been shown to be effective in reducing symptoms andminimising the exacerbation of disease [12,13].

The strongest evidence concerning exercise intervention forpatients undergoing lung resection surgery is for patients withCOPD. In this population exercise training has been shown toimprove exercise capacity and Health Related Quality Of Life(HRQOL) and reduce symptoms such as dyspnoea, fatigue anddepression [14,15]. Cavalheri et al. [16] suggest however thatalthough many patients with lung cancer will also have co-existingCOPD the above effects of exercise training may not be applicablefor two main reasons; firstly, patients with lung cancer that areeligible for surgery often have less severe COPD than those withCOPD alone; and secondly, adjuvant treatment for lung cancer mayaffect the capability of patients to complete an exercise programme.

Of significance is that few exercise interventions have beendeveloped specifically for people with lung cancer. In light of the

Figure 1. Search string in Ovid MEDLINE.

K. Crandall et al. / Surgical Oncology 23 (2014) 17e30 19

anticipated changing landscape of lung cancer care, with the like-lihood of an increase in the diagnosis of people with cancer at anearly stage, exercise intervention for this population needs to beexplored. This is of particular relevance to people undergoing sur-gical resection, who have potentially curative disease, yet currentlyexperience significant symptom burden, decreased functioning andquality of life post-surgery [9,10]. To enable exercise interventionfor this population to be integrated into clinical practice, it isimportant to review the evidence and determine the optimaldesign of exercise intervention that will be feasible, acceptable andpositively affect outcomes in a health care setting. To the authorsknowledge there are currently no systematic reviews focussing onpre and post-operative exercise intervention for patient’s treatedsurgically for lung cancer.

Objectives

The objective of this review is to identify and examine theliterature on exercise intervention for patients who are surgicallytreated for lung cancer in order to inform the design of future in-terventions. More specifically it aims to evaluate the quality of theevidence available, determine the most optimal design (type, fre-quency, intensity, duration and setting) of exercise intervention andexamine the outcomes that have been measured.

Research questions

1. What is the methodological quality of the studies to date thatinclude exercise intervention for the surgically treated patientwith lung cancer?

2. What designs of exercise intervention have been trialled andwhat aspects have been reported to be effective?

3. What outcomes have been measured and have they beenaffected by exercise intervention compared with patientsreceiving usual care?

Methods

This review has been carried out systematically and has beenconducted in linewith the Preferred Reporting Items for SystematicReviews and Meta-Analysis (PRISMA) statement guidelines [17]which aim at optimising the reporting of systematic reviews. Areview protocol was developed prior to starting the review andfollowed vigilantly.

Search strategy

A comprehensive systematic search of the following electronicdatabases; Medline, EMBASE, CINAHL and PsychINFO, was under-taken. An outline of the search conducted on Ovid MEDLINE� isgiven in Fig. 1 [note that the suffix exp ¼ exploded term, / ¼ MeSHand mp. ¼ title, abstract, original title, name of substance word,subject heading word, keyword heading word, protocol supple-mentary concept, rare disease supplementary concept, uniqueidentifier (free text term)].

Reference lists of included studies were manually reviewed foradditional relevant references and journal alerts were subscribedto.

Inclusion/exclusion criteria

Study designDue to the nature of this area of research, in that it is a newly

emerging field, both randomised and non-randomised studies

were considered to acquire a complete understanding of the topicarea. The key inclusion criterion was that all studies, regardless ofdesign, had to include some form of physical exercise training forpatients surgically treated for NSCLC. This review intended toinclude quantitative, qualitative and mixed method study designs.All poster abstracts and non-English full-text articles wereexcluded.

ParticipantsStudies that included participants that were diagnosed with

resectable NSCLC were included in this review. Studies with <65%of the patient population were excluded to ensure a consistentsample.

InterventionExercise intervention was defined as supervised or unsuper-

vised inpatient, outpatient, community or home-based interven-tion including any type of exercise training applied to patientssurgically treated for NSCLC.

Outcome measuresAll outcomes measured were recorded in this review.

Assessment of methodological quality

Two reviewers independently assessed the methodologicalquality of each study according to the Downs and Black qualityappraisal checklist [18]. This checklist consists of 27 questions to

K. Crandall et al. / Surgical Oncology 23 (2014) 17e3020

evaluate both randomised and non-randomised studies, evaluatingstudy reporting and internal and external validity.

The evaluations were cross-checked between two reviewersand the availability to go to a third reviewer was optional to resolveany disagreements. Studies were not excluded on the basis ofmethodological quality as it was the aim of this review to learnfrom the previous work in the field in order to inform future designof exercise intervention.

Data extraction

Studies that met the inclusion criteria were independentlyassessed and data regarding participants, intervention and allmeasured outcomes were extracted.

Synthesis of results

Due to the heterogeneity of exercise interventions, outcomesmeasured, tools used and the lack of robust RCT’s, a systematicnarrative review was conducted, opposed to a meta-analysis.

Results

Database search

The initial search returned 1920 journal articles after duplicateshad been removed. Three articles came from other sources (journalalerts) and were included in this review. After preliminaryscreening of titles 1850 articles were deemed to be irrelevant andwere excluded leaving 68 studies to be retrieved. After reviewingretrieved abstracts, 32 articles were excluded (16 were reviews and16 were non-English). Finally 36 full-text articles were reviewedand 25 fulfilled the inclusion criteria for this review of which 19were original studies (one article reported two studies). Eachreference list was screened for relevant studies however no newstudies were included from this step. The search is current up toMay 2013.

Excluded articlesOf the 36 full-text articles that were reviewed reasons for

exclusion included; i) not a published study (e.g. abstract fromconference or study protocol (n ¼ 8)) ii) the intervention did notinclude exercise training (n ¼ 1) and iii) the study included <65%patient of the patient population (n ¼ 2).

Study characteristics

Study characteristics are presented in Table 1. Of the 20 studiesincluded in this review eight are RCTS’s [19e25] with participantsrandomised to either an exercise intervention or control group.Benzo et al. [20] report on two RCT’s which have been included astwo separate studies; however one of these studies (study 1) wasstopped early due to poor recruitment. Two studies [26,27] reporton non-randomised controlled trials and both used historicalcontrols. The remaining ten studies were considered as SingleGroup Trials (SGT’s), these studies observed a single cohort over theperiod of an intervention without including a control group. Hoff-man et al. [28,29] report on one study that consisted of two phases.

Nine of the 20 studies included exercise intervention in thepreoperative period [20,22,24,30e34] and nine in the post-opera-tive period [19,21,24,26,28,35e38], the remaining two studies[23,27] included exercise intervention from the preoperativeperiod continuing over into the post-operative period and havebeen termed preepost-operative studies in this review.

All 20 studies used quantitative designs and no qualitative workwas found in the area. The views of patients and health pro-fessionals were not evident in the literature. Only three studies[28,32,36] measured subjective variables (using a survey) lookingat participants evaluation of the intervention.

Participants

In total, the 20 articles consisted of 575 participants, notincluding the 246 historical controls, making the average study size28.75 participants (range¼ 7e104). Themean cohort agewas 64.07years across 17 of the studies, three studies [20] (study 1) [26,31]did not report age. All studies that reported gender recruited bothmale and female participants and the average male percentage ofrecruitment was 57.29% (range 29%e95.5%). Five studies [20] (study1) [23,26,31,37] did not report on gender.

Stage of cancer

The majority of studies [22,23,25,28,34e38] included patientswith stage I to IIIA or IIIB disease. Four studies [19,21,27,32]included patients with up to stage IV disease, two studies [30,31]included patients with stage IeII disease and Divisi et al. [33]included patients with stage I disease only, however patients alsohad to have confirmed COPD. Four studies [20] (study 1 and 2)[24,26], did not report stage of disease however two of thesestudies [24,26] were post-operative studies and therefore patientswould be considered operable stage disease.

Methodological quality

Using the Downs and Black [18] quality assessment tool,consensus was reached for each article by two reviewers. Re-viewers were not blinded to authors, institution or journal ofpublication. The overall methodological quality of studies was lowmainly due to the small number of RCT’s included. For studies thatlacked a control group the main limitations (apart from lack ofcontrol, randomisation and blinding) included a lack of clearreporting on inclusion and exclusion criteria [30,31,33,38] andadverse events [27,30,31,33,37,38].

The results of the assessment of RCT’s revealed that none of thestudieswere free from risk of bias. All eight studieswere described asRCTs, but allocation concealment was only adequate in five studies[19,21,22,24,25]. Other forms of risk of bias included; an uncertaintyabout the blinding of outcome assessors [19,22e25] and the timingof the outcome assessment after the intervention [20] (study 2);small sample sizes (n < 20) [20] (study 1 and 2) [21] with only two[23,25] reporting a power calculation; and three studies did notadequately report on losses to follow-up [20] (study 1) [21,23]. Also,only three RCT’s reported on adverse events [20] (study 1 and2) [21].

Intervention

Intervention designs are summarised in Table 2.

Length of interventionThe majority (six out of nine) of pre-surgical studies focused on

four weeks exercise intervention. Divisi et al. [33] started with afour week intervention but extended it by two weeks for nine pa-tients who required further improvement before surgical resection.

Study 1 in Benzo et al. [20] found that four weeks of pre-surgicalintervention was not feasible due to patients and health pro-fessionals’ unwillingness to delay surgery. Benzo et al. [20] there-fore carried out a second study which included a ten sessionexercise intervention to be completed over one week (twice daily).

Table 1Study characteristics.

Reference (country) Preoperative/post-operative

Study design Population and treatment Gender and age

Arbane et al. 2010 (UK) POST RCT 53 (control 26, Intervention 27), NSCLC, stage IeIV, 100% post-surgical (open thoracotomy orVATs)

28 male, mean age 64

Benzo et al. 2011 Study1 (USA)

PRE RCT 9 (control 4, Intervention 5), lung cancerresection by open thoracotmoy or VATs andmoderate-severe COPD

NR

Benzo et al. 2011 study2 (USA)

PRE RCT 19 (control 9, Intervention 10), lung cancerresection by open thoracotmoy or VATs andmoderate-severe COPD

9 male, mean age control ¼ 72.0,intervention ¼ 70.2

Bobbio et al. 2007(Italy)

PRE SGT 12, NCSLC stage I or II, VO2max�15 ml/kg/min,Surgery e lobectomy

10 male, mean age 71

Cesario et al. 2007a(Italy)

POST CT 25 (þ186 control) NSCLC, Surgical (lateralmusce sparing thoracotomy)

NR

Cesario et al. 2007b(Italy)

PRE SGT 8, denied surgery on basis of poor pulmonaryfunction but had favourable clinical staging (8ended up having lobectomies) stage I-Iib

NR

Coats et al. 2013(Quebec)

PRE SGT 16 (only 13 analysed), under investigation forNSCLC (stage IeIV) awaiting surgical resection(n ¼ 10)

5 male, 8 female, mean age 59 � 9

Divisi et al. 2012 (Italy) PRE SGT 27, NSCLC stage I þ COPD, not fit for surgery atbaseline (functionally inoperable) but all hadlobectomy post intervention

20 men, mean age 55

Granger et al. 2012(Australia)

POST RCT 15 (control 8, Intervention7), suspected lungcancer (those confirmed n ¼ 10 (67%)), stage I-IV, Surgery all patients

53% male, mean age 65.5

Hoffman et al. 2013(USA)

POST SGT 7, post-surgical NSCLC stage I-IIIa 5 female, 2 male, mean age 64.6

Jones et al. 2007(Canada)

PRE SGT 25, suspected surgical lung cancer (NSCLC 65%)stage I-IIIA

70% female, mean age 65 � 10

Jones et al. 2008 (USA) POST SGT 20, NSCLC stage IeIIIB, 80% surgery 53% male, mean age 62Morano et al. 2012

(Brazil)PRE RCT 24 (12-PR, 12 CPT), NCSLC stage IeIIIA with

pulmonary disease and impaired spirometry,surgical resection by thoracotomy or VATS(n ¼ 21)

5male in CPT and 4male in PR, mean age 68.8 inCPT and 64.8 in PR

Peddle-McIntyre et al.2011 (Canada)

POST SGT 17, 94% NSCLC stage I-IIIB and limited stageSCLC, on average 3 and a half years post-surgical(82% surgical)

7 male, mean age 67

Pehlivan et al. 2011(Turkey)

PRE -POST RCT 60 (30 control, 30 intervention), NSCLC stage IA-IIIB, surgery (lobectomy/pneumonectomy)

NR, mean age Intervention group e 54.1,control group e 54.7

Reisenberg and Lubbe2010 (Germany)

POST SGT 45, NSCLC stage I-IIIB þ SCLC (2 limited an 1extensive), undergone treatment (88% surgical)time since last treatment no more than 14 days

gender NR, mean age 60.2

Sekine et al. 2005(Japan)

PRE-POST CT 22 þ 60 historical control, NSCLC stage IeIVwith COPD, thoracotomy

22 male in rehab (95.5%) and 55 male in control(91.7%), age (rehab e 70.4 � 4.6, control e69.0 � 5.5)

Spruit et al. 2006(Netherlands)

POST SGT 10, NSCLC (n ¼ 9), SCLC (n ¼ 1) þ impairedpulmonary function and exercise intolerance, 3months following treatment, stage IeIIIB

8 male, mean age 65.5

Stigt et al. 2013(Netherlands)

POST RCT 57 (control ¼ 26, intervention ¼ 23), NSCLCresectable, thoracotomy 4 weeks post-discharge

91% male active group and 73% male controlgroup, mean age active group e 63.6 � 10.2,control e 63.2 � 10.3

Wall 2000 (USA) PRE RCT 104, NSCLC I-IIIA surgery only (no chemo/radiotherapy)

53.8% male, mean age 65

K. Crandall et al. / Surgical Oncology 23 (2014) 17e30 21

Studies conducted in the post-operative time period were mostlylonger due to the time period available (ranged from four to sixteenweeks).

Type of exerciseAll studies included aerobic activity (mainly walking and

cycling) as part of the exercise intervention apart from one [36]which focused entirely on resistance exercise. Nine studiesincluded breathing exercises [20] (study 2) [22,25e27,30,31,33,36]most commonly consisting of Inspiratory Muscle Training [IMT]and abdominal exercises.

FrequencyFrequency of sessions ranged from two times per week to two

sessions per day. Studies that included daily exercise sessions were

mainly those where participants were inpatients [19,23,27,38].Most often the studies that included breathing exercises completedsessions numerous times a day [19,20] (study 2) [25,27].

Studies that included post-operative outpatient sessions deliv-ered sessions mainly twice weekly and some advised further ses-sions unsupervised at home [19,21]. The majority of home-basedstudies prescribed frequency in line with the current physical ac-tivity guidelines for adults (5 times per week) [39].

IntensityCardiovascular intensity ranged from 50 to 100% of varied

measures of intensity (e.g. max work load, max heart rate, VO2Peak) limiting the process of comparison. The majority of studiesconsidered their programme to be of moderate intensity[19,21,24,26,30,31,33e38].

Table 2Summary of interventions.

Reference Length ofintervention

Duration of sessions Exercise type Intensity Frequency Supervised/unsupervised

Inpatient/outpatient

Group/individual

Education/smokingcessation

Arbane et al.2011

12 weeks (þ5 days) Aerobic 5e10 mins1

for each componentResistance (weights) þ aerobic(walking, marching and recumbentbike)

60e80% MHR2 2�/day Both Both Individual NR3

Benzo et al.2011 Study 1

4 weeks NR e “used currentguidelines for exerciseprescription”

NR NR NR NR NR NR NR

Benzo et al.2011 study 2

1 week 20 min lowerextremity þ upperextremity þ strengthexercises þ breathing20 mins þ education

Aerobic (treadmill, step and armergometer) þ resistance þ breathing

Intensity that they felt“very confident” theycould sustain

2�/day over 5days

Supervised NR Individual Education

Bobbio et al.2008

4 weeks 1 1/2 h Aerobic(cycling) þ stretching þ breathing(incentive spirometry) þ resistance(weights)

5 min at 30% MWR4

followed by 30 min at50% increased to 80%,weights NR

5�/week for 4weeks

Supervised Outpatient Individual Smoking

cessation þ optimisation of drugs Cesario et al. 2007a 20 sessions 3 h Aerobic(cycling,

walking) þ resistance þ breathing Aerobic 70e80% MWL5,resistance NR

5�/week Supervised Inpatient NR Education

Cesario et al.2007b

4 weeks 3 h Aerobic (cycling,walking) þ breathing

Aerobic 80% MWL 5�/week Supervised Inpatient NR Education þsmoking cessation

Coats et al.2013

4 weeks Aerobic30mins þ musclestrength exercises

Aerobic (walking andcycling) þ resistance

60e80% PL6 3e5�/week Both Home-based Individual Weekly telephonecalls

Divisi et al.2012

4e6 weeks 1 1/2 h Aerobic(cycling þ walking) þ breathing

70% MWR 6�/week Supervised NR Individual Diet advice,optimisation ofdrugs þ smokingcessation

Granger et al.2013

Post-surgery todischarge þ 8weeks outpatient

1 h Aerobic(walking þ cycling) þ resistance(upper and lower) þ stretching

HR7 85% maximumpredicted

2�/day untildischarge thentwice weekly

Both Both Individual Telephone calls

Hoffman et al.2013

6 weeks (phase2 þ 10 weeks)

5 min per dayprogressing to 30 min

Aerobic þ balance Up to 60% HRR8 5�/week Unsupervised Home-based Individual Telephone calls

Jones et al.2007

Until surgicalresection, mean of30 sessions

20e30 min þ 5 minwarm up and 5 mincool down

Aerobic (cycling) 60e100% baseline VO2peak

5�/week onconsecutive days

Supervised Outpatient Individual NR

Jones et al.2008

14 weeks 15e45 min increasingover 14 weeks

Aerobic (cycling) 60e100% PL 3�/week non-consecutive days

Supervised Outpatient Individual NR

Morano et al.2012

4 weeks 10 min increasing to30 min þ resistancetraining þ10e30 min of IMT9

Strength andendurance þ breathing þ flexibility

80% max load and 20e60% IMT

5�/week NR NR NR Education

Peddle-McIntyreet al. 2012

10 weeks (28sessions)

NR Resistance þ breathing þ stretching 60% 1RM10 to progressto 85% 1RM

3�/week non-consecutive days

supervised Outpatient Individual NR

Pehlivan et al.2011

1 week pre-op untildischarge

According to patientstolerance

Aerobic (walking ontreadmill þ wandering around thecentre) þ breathing

“Patients tolerance” 3�/daywalking þ 2�/day chestphysiotherapy

Supervised Inpatient NR NR

Reisenberg andLubbe 2010

28 days 30 min per dayinterval training (3e5 min)

Aerobic (cycling) Sub-maximal Daily Supervised Inpatient NR NR

NR Both Inpatient NR Smoking cessation

K.Crandall

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K. Crandall et al. / Surgical Oncology 23 (2014) 17e30 23

One study focused on light intensity exercise [28,29] andmentioned this to be highly feasible and acceptable. A further twostudies did not report an exact intensity of exercise but insteadasked patients to exercise at a pace they felt confident [20] (study 2)or according to the patients tolerance [23].

Studies [20] (study 2) [22,24,25,36,38]including strengthtraining generally reported an intensity of between 60 and 80% ofone repetition maximum (1 Rep max) or at a level participants feltconfident [20].

Duration of sessionThe duration of each exercise session was not always easily

determined due to the type of exercise performed. For examplesessions that included resistance exercise focused more on rep-etitions rather than the time it took to perform the exercise.Although many studies [19,20] (study 2) [28,32,34,35,37] re-ported accumulating 10e45 min of aerobic exercise throughouteach session, other studies [21,22,24e27,30,31,33,38] reportedlonger sessions (e.g. 3 h) without a breakdown of minutes ofexercise/rest.

SupervisionThe majority of studies (n ¼ 17) reported supervised exercise

sessions. However, six of these studies [20] (study 2) [22,31e33,37]did not report who supervised the sessions. Supervisionwasmainlycarried out by a physiotherapist, however, three studies [26,27,30]were conducted by a rehabilitation team; two [34,35] by an exer-cise specialist; and one [32] by an exercise physiologist.

Group/individualOne study [38] reported using group exercise intervention

where participants were entered into an inpatient rehabilitationgroup for patients with severe COPD.

Inpatient/outpatient/home-basedFive studies included participants as outpatients [24,30,34e36],

three exclusively provided a home-based programme [25,28,32]and six [23,26,27,31,37,38] reported participants to be inpatients.Four studies [20] (study 1 and 2) [22,33] did not report whether theparticipants were inpatients or outpatients. Two post-surgicalstudies [19,21] started exercise intervention in an inpatientsetting and post-discharge prescribed home-based sessions.

Inclusion of control groupTen studies [19,20] (Study 1 and 2) [21e27] included control

groups, with eight [19,20] (study 1 and 2) [21e25] classified asRCT’s and two [26,27] as controlled trials. In the majority of RCT’sthe control group received usual care and therefore receivedexactly the same treatment without the exercise intervention.Some studies included other intervention variables for the controlgroup such as telephone intervention [19], chest physiotherapy[22,27] and education [22], thus reducing the ability to solelyexamine the effect of exercise intervention.

Other components to the rehabilitation programmeAlthough the main focus of studies was exercise intervention,

some studies also involved other components to the rehabilitationprogramme. Four studies [20] (study 2) [22,26,31] included edu-cation sessions on topics such as patients role in recovery, dietaryadvice, pulmonary pathophysiology, breathing techniques andrelaxation/stress management. A further four studies [27,30,31,33]reported including smoking cessation. Finally, three studies[21,29,32] used telephone calls to encourage adherence andobserve patients’ perceptions (barriers etc.) and progress.

Table 3Outcomes measured and summary of results.

Reference Measurement (tool) Time measured Results

Arbane et al. 2011 Quadriceps strength (magneticstimulation), exercise tolerance(6MWD1), QOL2 (EORTC-QLQ-LC133),hospital stay and POC4

Pre-op, 5 days and 12 weeks post-op Quadriceps strength e significant fall in controlgroup and non-significant improvement inintervention group at 5 days post-op, nosignificant difference at 12 weeks. Exercisetolerance e decreased in both groups at 5 days,returned to preoperative values in both groupsat 12 weeks. QOL e no significant differencewithin subjects or between groups. Length ofhospital stay e (mean 8.9 active and 11.0control) and POC (2 in active and 3 in control)no significant differences between groups.

Benzo et al. 2011 Study 1 Hospital stay and POC NR5 No differences were found in any outcomebetween groups e Study stopped prematurely(9 patients in 18 months)

Benzo et al. 2011 study 2 Hospital stay and POC Post-op time NR Patients in the PR6 arm had fewer days inhospital (p ¼ 0.058), had fewer days needing achest tube and lower incidence of prolongedchest tube.

Bobbio et al. 2008 Exercise tolerance (VO2max7, CPET8),hospital stay, POC, lung function

Baseline, last day of PR and postintervention

Exercise tolerance e VO2 max meanimprovement 2.8 ml/kg/min (p ¼ <0.01). VO2max at AT9, work load capacity and oxygenpulse all significantly improved (p ¼ <0.016,<0.001 and <0.007 respectively) at end of PR.11 underwent surgery e median hospital stay17.5� 14.8 days, 8 patients had POC. Pulmonaryfunction e non-significant.

Cesario et al. 2007a Exercise capacity (6MWD), pulmonaryfunction (spirometry), blood gasanalysis (radial artery)

Baseline, 1 month after discharge(intervention group at end ofintervention)

Exercise capacity e Intervention groupsignificantly increased 6MWD and Borg scale atrest and exertion improved. Blood gas e PHlevels and Hb saturation during 6MWDincreased. Pulmonary function e did notsignificantly change. Control group e

spirometry values and 6MD decreased.Cesario et al. 2007b Exercise capacity (6MWD), pulmonary

function (spirometry), POCBefore and after PR Exercise capacity e 6MWD improved by 47.4%.

Patients starting with the worst initialconditions received most benefit. Pulmonaryfunction e FVC10 significantly increased, non-significant improvements for FEV111. Allpatients re-entered functional and clinicalcriteria for surgery and were operated on.Morbidity was 25% (2/8 e 1 post-ophaemorrhage and 1 AF12).

Coats et al. 2013 Pulmonary function (spirometry),exercise capacity and oxygenconsumption (incremental cyclingexercise test, constant work rate cycleexercise, 6MWD), muscle strength (maxvoluntary contraction), QOL (sf-3613,EORTC-QLQ-30 þ QLQ-LC13 andHADS14), feasibility and acceptability(recruitment rate, adherence, adverseevents, subjective perception ofobstacles)

Baseline and post intervention Pulmonary function e no significant change.Exercise capacity e VO2 peak no significantchange, constant work rate cycle durationsignificantly improved by 60%, 6MWDimproved by 28� 29m (p< 0.05). Isotime, VO2,carbon dioxide output, ventilation andrespiratory exchange ratio were reduced postintervention. Muscle strength e strength ofdeltoid, triceps and hamstrings increasedsignificantly (p ¼ <0.05). Hand grip, biceps andquadriceps strength were not statisticallysignificant. QOL e No significant improvementsin QOL apart from depression. Feasibility andacceptability e completion rate 81%, no adverseevents, mean adherence 125% and 83% foraerobic and strength respectively.

Divisi et al. 2012 Blood gas, exercise capacity (VO2 max,6MWD, CPET), lung function(spirometry), post-op morbidity

Baseline and post intervention Blood gas e significant increase in PaO2.Exercise capacity e VO2 max significantlyincreased (p ¼ 0.00001) Pulmonary function e

FEV1 significantly improved (p ¼ 0.02). Post-opmorbidity of 15%.

Granger et al. 2013 POC, hospital stay, safety (adverseevents), feasibility (attendance),functional capacity (6MWT), functionalmobility (TUG15) and HRQOL16 (SF-36,EORTC-QLQ-C30-L13)

Preoperative and 2 and 12 weeks post-op

POC and hospital stay e Patients in the PR armhad fewer days chest tube and lower incidenceof prolonged chest tube, also PR arm had fewerdays in hospital (close to being significant(p ¼ 0.058). Safety e no adverse events.Feasibility e 71% delivered sessions. Functionalcapacity e intervention group improved 6MWTto a greater extent however TUG improvedmore in control group. HRQOL- non-significant.

Hoffman et al. 2013 Feasibility (recruitment rate e % eligibleof those who were recruited who

Pre-surgery, post-surgery baseline andweekly

Feasibility e 80% approached consented, 100%retention, adherence rate 96.6%, no adverse

K. Crandall et al. / Surgical Oncology 23 (2014) 17e3024

Table 3 (continued )

Reference Measurement (tool) Time measured Results

consented), adherence (% participatingthat adhered), safety (adverse events)acceptability (designed aquestionnaire), Cancer Related Fatigue(BFI17 measure), perceived self-efficacy(questionnaire)

events. Acceptability e highly acceptable.Fatigue e decreased from baseline (post-surgery to week 4) and increased when patientsstarted chemotherapy. Perceived self-efficacy e

decreased from pre-surgery to post-surgery,gradually increased during the intervention forboth walking and balance, perceived self-efficacy for managing fatigue decreased post-surgery but increased above pre-surgicalbaseline measurements at week 6. Phase 2 e

100% recruitment and retention, adherencedeclined from 96.6% in phase I to 87.6% at theend of phase II.

Jones et al. 2007 Exercise capacity (6MWT, CPET),pulmonary function (Spirometry), POC,adverse events, adherence

Baseline to pre-surgery Exercise capacity e mean VO2 peak increasedby 2.3 ml/kg/min (p ¼ 0.002), 6MWD increasedby 40 m (p ¼ 0.003), for participants whoattended >80% of prescribed classes VO2 peakand 6MWD increased by 3.3 ml/kg/min and49 m respectively. Pre-surgical exercisecapacity decreased post-surgery but not beyondbaseline levels. Pulmonary function e non-significant results. POCe 35%. Adverse events e2 reported. Adherence rate e 72%.

Jones et al. 2008 VO2 peak (CPET), QOL (FACT-L17, FACT-G18, TOI19), exerciseadherence(attended/prescribed)

Baseline and post intervention VO2 peak e no significant increase. QOL-significant favourable changes found forfunctional-wellbeing (p ¼ 0.007) and fatigue(p ¼ 0.03), TOI increased by 9 points (p ¼ 0.03)others did not reach significance. Adherence e

85%.Morano et al. 2012 Functional parameters (Spirometry,

6MWT, blood gas), hospital stay andPOC

Assessed before and after intervention Functional parameters e (baseline to 1 month)improved significantly in FVC (p ¼ 0.02) andpercentage predicted (p ¼ 0.00), 6MWD wasimproved (p¼ 0.00), blood gas- non-significant.Patients in intervention group had fewer days inhospital (p ¼ 0.04), needing a chest tube (0.03),lower incidence of POC (p ¼ 0.01) and less POC.

Peddle-McIntyre et al. 2012 Feasibility (adherence, eligibility,recruitment rate), physical functioning(muscle strength [1RM20] andendurance [number of reps toexhaustion], get up and go test, sit tostand test, 6MWT), PRO’s (QOL [Sf-36,FACT-L], fatigue [FACT-fatigue], sleepquality [PSQI21], dyspnoea [MRCdyspnoea scale], anxiety [Speilbergerstate anxiety scale] and depression[CES-D1022])

Baseline and post training Feasibility e adherence 87%, 3 adverse events(2� shoulder pain and 1� back pain). Physicalfunctioning e muscular strength significantlyimproved, 52% (leg press) and 42% (chest press),muscular endurance improved significantly forchest press (p ¼ 0.001) and leg press(p ¼ <0.001). Peak inspiratory muscle pressureincreased (p< 0.001). Significant improvementsin 6MWD (p ¼ <0.001), number of chair stands,arm curls and up-and-go time (p < 0.001,<0.001 and 0.015 respectively). PRO’s/QOL-borderline significant improvements for rolephysical (p¼ 0.072), bodily pain (p¼ 0.101) andphysical health component (p ¼ 0.92).

Pehlivan et al. 2011 Pulmonary function (spirometry), bloodgas, exercise capacity (maximumwalking distance), ventilationperfusion, hospital stay and POC

Baseline, post intervention (beforesurgery)

Pulmonary function did not differ betweengroups after IPT23 (before surgery) howeversignificant improvements in FVC, FEV andDLCO24 (p ¼ 0.003, 0.01 and p < 0.001respectively) were found within theintervention group. Blood gas e increased PaO2and decreased PaCO2 (p < 0.001), peripheraloxygen saturation was higher in theintervention group (p ¼ 0.008). Exercisecapacity e increased significantly inintervention group. Hospital length of stay was5.4 and 9.66 in the intervention group andcontrol group respectively (p < 0.001). POC e 5in control, 1 in intervention group.

Reisenberg and Lubbe 2010 Exercise capacity (6MWT, bicycleergometery test, heart rate variability),pulmonary function (bodyplethysmography), QOL (EORTC QLQ-C30, QLQ-LC13 and SF36) and fatigue(MFI-2027)

Baseline and end of intervention Exercise capacity e significant increase in6MWT (322 � 11 to 385 � 13 m, p < 0.001),cycling work load performance (68 � 3 to86 � 4, p < 0.001), HRR28 was reduced. HR29

variability significantly increased (9.7 � 1 to12.9 � 1, p < 0.002). Pulmonary function e

significantly increased. QOL e significantlyimproved (48 � 3 to 62 � 2, p < 0.001) andreduced fatigue (66 � 3 to 41 � 4, p < 0.001).

Sekine et al. 2005 POC, blood gas and pulmonary function(spirometry)

Before and one month after operation No significant differences between groups ofPOC or blood gases, however prolonged 02

(continued on next page)

K. Crandall et al. / Surgical Oncology 23 (2014) 17e30 25

Table 3 (continued )

Reference Measurement (tool) Time measured Results

therapy and tracheostomy more frequent in thecontrol group. Post-operative hospital stay wassignificantly longer in control group (0.0003).Pulmonary function e FEV1 less diminished inintervention group (p ¼ 0.023) however FVCremained similar between groups.

Spruit et al. 2006 Pulmonary function (spirometry),exercise capacity (6MWD and peakcycling load)

Baseline and 8 weeks Pulmonary function e no change. Exercisecapacity e 6 MWD significantly improved(median 145 m e 43.2% of baseline values,p ¼ 0.002) e without significant changes inBorg symptom scales for dyspnoea and fatigue.Peak cycling load increased (median 26 W,34.4% from baseline, p ¼ 0.0078).

Stigt et al. 2013 QOL (SGRQ30, SF-36), pain (MPQ-DLV31), exercise capacity (6MWD),pulmonary function and feasibility ofcombining rehab with adjuvantchemotherapy (attendance rates)

Baseline, 1, 3, 6 months and 1 yearfollow-up e QOL and pain. Beforesurgery and 3 months after discharge e

pulmonary function and exercisecapacity

No significant differences in QOL, control groupreported less limitations at 3 months comparedto the intervention group (p ¼ .03) e differencedisappeared at 12 months. Pain e Interventiongroup reported significantly more pain after 3and 6 months (p ¼ 0.042 and p ¼ 0.010respectively). The use of analgesics at 3 monthswas higher in the intervention group comparedwith controls (p ¼ 0.048), Exercise capacity e

6MWDwas improved in the intervention groupat 3 months compared with the control group(p ¼ 0.024). Pulmonary function did notsignificantly differ between groups. Feasibilitye dropout rates were quite high and even morefor those who received adjuvant chemotherapy.

Wall 2000 Hope (HHI32) and power (PKPCT. VII33) 7e10 days pre-surgery, day beforesurgery, 4e6 days post-surgery (prior topatients receiving information abouttheir final surgical pathology)

Power increased in intervention group whilethe non-exercise group decreased. Hope e nodifferences.

Abbreviations: 1six minute walk distance, 2Quality Of Life, 3European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, 4post-operativecomplication, 5not reported, 6pulmonary rehabilitation, 7maximum oxygen consumption, 8Cardio Pulmonary Exercise Test, 9anabolic threshold, 10forced vital capacity,11forced expiratory volume in one second, 12atrial fibrillation, 13Short Form e 36 assessment,14Hospital Anxiety and Depression Scale, 15Timmed Up and GO test, 16HealthRelated Quality Of Life, 17Functional Assessment of Cancer Therapy scale Lung, 18Functional Assessment of Cancer Therapy scale General, 19Total Outcome Index, 20oneRepetition Maximum, 21Pittsburgh Sleep Quality Index, 22Center for Epidemiologic Studies Depression Scale e 10, 23intensive physical therapy, 24diffusion lung capacity forcarbon monoxide, 25partial pressure of oxygen, 26partial pressure of carbon dioxide, 27multi-dimensional fatigue inventory, 28heart rate reserve, 29heart rate, 30St GeorgeRespiratory Questionnaire, 31McGill Pain Questionnaire, 32Herth Hope Index, 33power as knowing participation in change test.

K. Crandall et al. / Surgical Oncology 23 (2014) 17e3026

The potential effect of each component (exercise, physiotherapy,diet advice, etc.) should be considered when interpreting resultsfrom these studies.

Outcomes measured

Outcomes measured are presented in Table 3.

Exercise capacityExercise capacity was the most commonly measured outcome,

measured in thirteen studies [19,21,23,24,26,30e35,37,38]. Thiswas measured using the six Minute Walk Distance test (6MWD)and/or a Cardio Pulmonary Exercise Test (CPET) test to measureVO2 max or VO2 peak. A further two studies [37,38] used a peakcycling load test to measure bicycle ergometer performance(measured in Watts).

Of the studies that used the 6MWD test, all but one [19] reporteda significant increase in distance measured from baseline to postintervention (increase of 28me377m [range]). However, this study[19] focused on muscle strength. They found a deterioration inwalking distance immediately post-surgery (which is consistentwith other studies) [21] however did not find an improvement indistance from baseline to twelve weeks. This may be due to theintervention focus on strength training. However, adherence toexercise was not monitored at home making this result difficult tointerpret.

Those using CPET reported exercise capacity (VO2 max andVO2 peak) to increase significantly in three out of five studies

[30,33,34], with VO2 max improving between 2.8 and 6.3 ml/kg/min and VO2 peak improving by 1.7 ml/kg/min. Also, peakcycling load was shown to increase significantly in both studies[37,38] by 27% and 34.4% respectively. The study [38] thatshowed the highest percentage of improvement was twice aslong in the duration of intervention (eight weeks compared tofour weeks, both inpatient, post-surgical studies). Studies whichrecruited patients who had impaired exercise capacity at baseline(VO2 max <15 ml/kg/mi) [30e33] showed the most improve-ment post exercise intervention.

Of the four RCT’s [19,21,23,24] that measured exercise capacity,two [21,24] reported significant increase in 6MWD in the inter-vention group.

Pulmonary functionPulmonary function (FEV1 and FVC) was measured in ten

studies [23,26,27,30e34,37,38], most commonly tested usingspirometry with two studies also using body plethysmography[30,37]. Diffusion Capacity (DLCO) was measured in four studies[23,30,33,34]. The majority of studies indicated non-significantresults for all pulmonary function measures [26,27,30,32,34,38]however, four studies [23,31,33,37] reported improved pulmonaryfunction. Furthermore, although Sekine et al. [27] did not findsignificant improvements, they reported less diminished FEV1post-surgery in the intervention group compared with the controlgroup and would suggest that prophylactic pulmonary rehabilita-tion may prevent some of the decline seen in pulmonary functionpost-surgery.

K. Crandall et al. / Surgical Oncology 23 (2014) 17e30 27

Quality Of Life (QOL)Out of the eight studies [19,21,24,32,35e37,40] that measured

QOL there were conflicting results, with some studies reportingimprovements [35,37] but the majority reporting no change[19,21,24,32,36,40]. Generic QOL measures that often lack sensi-tivity to disease specific symptoms were used in the majority ofstudies. For example, the SF-36 health survey, not yet validated inthe lung cancer population, was the most commonly used tool tomeasure QOL, used in five of the seven studies [21,24,32,36,37].

Riesenberg and Lübbe’s [37] 28 day post-operative inpatientstudy was the only study to report consistent significant findingsacross the QOL variables (physical, role, emotional, cognitive andsocial functioning and decreased symptoms). Jones et al. [35] re-ported improvements in QOL but only for patients who did notreceive adjuvant chemotherapy. Furthermore, Coats, Maltais,Simard et al. [32] considered depression under QOL. They foundthat although there were no significant changes in QOL measures,depression scores measured by the HADS were significantlydecreased (p ¼ <0.05).

Safety/adverse eventsOnly nine studies [20,21,26,28,32,34e36] reported recording

adverse events. One study [34] reported two patients experiencingan abnormal decline in systolic blood pressure (<20 mmHg) andanother study [36] reported three events; one patient experiencedlower back pain, another patient experienced exacerbation ofshoulder arthritis and another experienced shoulder pain post-testing. The other seven studies reported no adverse events.

Feasibility/acceptabilityFeasibility was measured in seven studies [21,24,28,32,34,36,41]

monitoring; eligibility, recruitment rate, completion/retention rate,consent rate, delivered sessions and attendance/adherence rate.

Eligibility rate, measured in two studies [34,36], ranged from10% to 81%. Recruitment rate was measured in all seven studies andranged from 43% to 80% (mean¼ 60.6%). Completion/retention ratewas reported in two studies [28,32] as 81% and 100% respectively.Adherence/attendance rate was measured in all seven studies andranged from 72% to 125% (some reporting more sessions attendedthan prescribed). Stigt et al. [24] found that the attendance rateamongst patients being treated with adjuvant chemotherapy waslower, 43% (mean).

Of significance is that only three studies [28,32,36] exploredpatients’ perceptions regarding acceptability, each using a ques-tionnaire developed by the research team. Perceived benefits werereported as: helped to start performing physical activities,improved dyspnoea, improved strength and having more energy[32]. Themain obstacles reported were lack of time and difficulty ofintegrating the intervention into an already busy schedule ofseveral medical appointments.

The only study to report major complications with feasibilityand acceptability was Benzo et al. [20] (study 1) in which patientsand health professionals were reluctant to delay surgery for fourweeks; thus their subsequent study was designed as a one weekpre-surgical intervention.

Length of hospital stay and post-operative complications (POCs)Four out of five studies that included a control group and

compared length of hospital stay showed significantly fewer days(on average 5 days less) in hospital for patients in the exerciseintervention arm [20] (study 2) [22,23,27]. The study [19] that didnot show significant difference between groups was one thatfocused on improving muscle strength.

Furthermore, out of the four studies [19,22,23,27] to report onpost-operative complications (POCs), two [22,23] reported less

POCs (such as atelectasis, dyspnoea and pneumonia) in the exercisegroup comparedwith the control groupwhile the other two studiesdid not result in significant changes [19,27].

FatigueFatigue was measured in five studies [28,29,35e37,40] by a

range of different tools including; the Brief Fatigue Inventory (BFI);Perceived Self-Efficacy for Fatigue Self-Management (PSEFSM);FACT-an; FACT-fatigue; and the multi-dimensional fatigueinventory-20 (MFI-20) questionnaire.

Studies that measured pre to post-surgical data found that fa-tigue increased significantly between the pre-surgery to immedi-ately post-surgery time point; however, significant reductions infatigue were found from baseline to post-intervention in three[28,35,37] out of five studies.

In comparison, two studies [36,40] did not find significant re-ductions in fatigue severity from baseline to post-intervention.However, one [36] focused entirely on resistance exercise trainingand the other [40] was a preoperative intervention, suggesting thatparticipants may have not been experiencing high fatigue levelspre-treatment.

In relation to patients receiving adjuvant treatment,Hoffman et al. [29] found that the two participants who did notreceive adjuvant treatment after surgery experienced lower levelsof fatigue than those who were receiving adjuvant chemotherapy.

Muscle strengthThree studies [19,32,36] measured muscle strength. From the

studies reviewed it can be suggested that muscle strengthimproved for patients who participated in resistance exercise. Theonly study that did not show a significant improvement reported anon-significant increase in the intervention group which was sta-tistically significantly different to the significant decrease in musclestrength in the control group [19]. It would seem that in this studyexercise intervention had a prophylactic effect, preventing thedecline in muscle strength seen in the control group.

Blood gasOf the four studies that measured blood gas analysis

[23,26,27,33] the majority reported non-significant findings. Onlyone study showed significant increase in both PaCO2 and PaO2 [33]also showing improved SaO2. This again was the study thatrecruited participants with poor pulmonary function furtheremphasising the possible amplified effect of exercise interventionin this particular population. Cesario et al. [26] was the only otherstudy to show significant findings for increased PaO2.

OtherFurther outcomes from three original studies [34e36] were

reported in subsequent articles [40e43]. These outcomes include;inflammatory markers [40], correlates of adherence [42], motiva-tional outcomes [43] and oxidative status [41].

Jones et al. [40] reported the effects of pre-surgical exercisetraining on systemic inflammatorymarkers. Findings indicated thatexercise training resulted in a significant reduction in ICAM-1however other markers did not significantly change.

Peddle et al. [42] report on correlates of adherence to supervisedpre-surgical exercise training using the theory of planned behav-iour. Results indicated that significant correlates of adherence toexercise were perceived behavioural control (p ¼ 0.004) and sub-jective norm (p ¼ 0.014).

Peddle-McIntyre et al. [43] reported on changes in motivationaloutcomes in a resistance based exercise intervention. After theintervention, significant increases in self-efficacy and perceivedbehavioural control were found. Intention was significantly lower

K. Crandall et al. / Surgical Oncology 23 (2014) 17e3028

post-intervention and significantly correlated to instrumentalattitude, self-efficacy, perceived behavioural control and affectiveattitude. Post-intervention self-efficacy was significantly correlatedwith planning.

Finally, Jones et al. [41] examined the effects of aerobic trainingon oxidative status post-surgery. Concerning individual isomers,only two increased significantly (iPF (2-alpha)-III and iPF (2alpha)-VI.

Discussion

This systematic review aimed to synthesise all available evi-dence with regard to exercise intervention for patients who aresurgically treated for NSCLC. The results illustrate the infancy of thefield under study, with only twenty studies across the spectrumbeing considered eligible for this review, of which the majority ofstudies includedwere observational SGT’s. Studies included variousforms of exercise intervention and investigated a wide range ofoutcomes (using various measures) that produced a disparate set ofdata. This in itself is an important finding as it indicates a lack ofconsensus around the design of exercise intervention, the mostdesired outcomes to be measured and the appropriate outcomemeasures to be used.

The quality of studies included was variable and the findingsare tempered by this fact. Quality assessment revealed an overallweak methodological quality of study design in the area. This ismainly due to the number of studies not including a controlgroup; however this review has also revealed limitations in theavailable RCT evidence, most notably the small numbers, poor/limited reporting of methodology and outcome assessment.Future trials should focus on including a control group, adequaterandomisation, significant numbers powered for the primaryoutcome, validated and appropriate assessment tools andblinding of outcome assessors throughout the study. Also clearreporting of age, gender and treatment of patients should bereported and the documentation of adverse events mandatory instudies in order for the context, safety and transferability of in-terventions to be assessed.

The heterogeneity of exercise intervention programmesreviewed made comparisons difficult and from the studies above itis not evident as towhat the optimal exercise programme should befor this population. In particular a pre-surgical and post-surgicalintervention should be considered separately mainly due to thetime period available and the physical status of the patient in eachsetting.

Due to the relatively small time period from diagnosis to sur-gery, pre-surgical studies were generally shorter in duration andmore frequent in prescribed sessions per week to enable maximumbenefit. However one pre-surgical study [40] mentioned that theirexercise programmemay have worsened fatigue due to the intenseand demanding nature of the intervention in a population that wasdeconditioned and suffered significant comorbidity. So far themajority of studies utilise the current physical activity guidelinesfor adults (5 times per week) [39], however this may be adaptedwhen more research is completed concerning patients undergoingspecific cancer treatments.

It is evident that exercise intervention is influenced greatly bythe setting of intervention. For example, inpatient studies includedmore frequent supervised sessions. It remains questionable if thiswould be feasible and acceptable in an outpatient setting as travelhas been reported as one of the main barriers regarding cardiacrehabilitation [44]. Realistically due to financial circumstancesoutpatient or home-based studies may be more financiallymanageable in the longer term. A review by Dalal et al. [45] thatlooked at home-based versus centre based cardiac rehabilitation

found that adherence to the programme was superior for thosewho received a home-based programme; they also conclude thatthis may be more cost effective.

In relation to delivery (supervised/unsupervised), structure(group/individual sessions), duration, intensity of sessions andlength of intervention, it is not clear which may be most beneficial.However based on the evidence [46] from the area of cardiacrehabilitation, depending both on the stage of treatment and theindividual’s ability and willingness to participate in exercise, whatcan be suggested is that this should be considered on an individ-ualised level, relating to particular patient desires and needs.

With regards to type of exercise, aerobic exercise in comparisonto other forms of exercise, for example resistance exercise alone,would seem superior for improving outcomes such as exercisecapacity (VO2max); however with only one small single group trial[SGT] [36] focussing on resistance exercise, it is impossible to maketrue comparisons. As one would expect, the study [36] that focusedon resistance exercises alone showed a significant improvement inmuscle strength. Thus, the combination of resistance and aerobicexercise training may provide the optimal training programme forthis population.

Although exercise intervention has been included as a corecomponent in cardiac rehabilitation, participation rates remainlow. Three main barriers have been identified in the literatureregarding participation; service and system level barriers (e.g.physician recommendation and misconceptions about cardiacrehabilitation) practical barriers (e.g. transport and parking); andthirdly, personal barriers (e.g. perceptions of the ability to controlthe disease) [44]. Research into the development of similar in-terventions should consider these barriers from the offset whichmay help design more acceptable interventions.

Preliminary findings from this review would suggest that ex-ercise intervention compared with usual care both pre and post-surgery is safe, feasible and acceptable and associated withincreased exercise capacity, reduced POC and hospital stay,increased muscle strength and reduced fatigue. However the re-sults concerning pulmonary function, QOL, and blood gas analysisare variable and inconsistent.

The increase in exercise capacity post intervention is notparticularly surprizing, it is a well-established finding in patientswith COPD [12] and reviews including other cancer populations[11,47]. However what was recognised in this review was thatstudies which recruited patients who had impaired exercise ca-pacity at baseline (VO2 max <15 ml/kg/mi) [30e33] were thosereceiving the most benefit from exercise intervention.

Exercise capacity is an important consideration in the decision-making process regarding the feasibility of surgical resection. VO2peak is reported as one of the strongest independent predictors ofsurgical complications [48] and poor exercise capacity has beenshown to be a major determinant of post-operative morbidity andmortality following lung resection surgery [49,50]. Therefore in-terventions aimed at improving exercise capacity may, in turn,lower the risks associated with poor cardiopulmonary function.Interestingly reduced POC and length of hospital stay were found inthe majority of pre-surgical intervention studies that measuredthese outcomes, affirming that they may be linked to increasedexercise capacity.

Increased muscle strength and reduced fatigue are also prom-ising findings. Muscle strengthwas improved particularly in studiesthat included resistance exercise, highlighting the need for a variedintervention. Regarding fatigue, results from this review and from areview by Cramp and Byron-Daniel [51], looking at exercise inter-vention for the management of CRF, suggest that physical exercisecan help to reduce fatigue both during and after treatment forcancer. However, the evidence is not sufficient to demonstrate the

K. Crandall et al. / Surgical Oncology 23 (2014) 17e30 29

best type or intensity of exercise for reducing the symptom offatigue.

Improvements in outcomes, in particular exercise capacity,together with no change in pulmonary function may be an unex-pected finding at first sight, however this coincides with previousresearch in patients with other pulmonary diseases, for example,COPD [52,53] and restrictive disorders [54]. Overall the evidence isunclear as to how exercise may or may not improve pulmonaryfunction in this population.

Regarding QOL, although the majority of results were non-significant, a few explanations were evident. Studies conducted inthe preoperative period [32,40] may have found no change in QOLdue to a possible ceiling effect. Of the three RCT’s [19,21,24] thatmeasured QOL, all were post-operative interventions and found nosignificant differences in QOL between groups, however certainlimitations must be emphasised in relation to this result. Arbaneet al. [19] lacked reporting adherence to home-based exerciseleaving the result open to scrutiny of how much exercise was un-dertaken, in Granger et al.’s [21] study the intervention group wassignificantly fitter at baseline, and finally, Stigt et al. [24] did not usea disease specific tool to measure QOL but instead used onedesigned for patients with COPD. Differences in tools (generic/specific), design of intervention and extent of surgery made com-parisons and conclusions concerning QOL difficult. To clarify thismatter, it is desirable that future studies use equal measurementinstruments for which reliability and validity has been establishedin the relevant patient population.

From thewider literature it is clear that further outcomes shouldbe explored that have not been included in the reviewed papers,such as; pain, breathlessness and fear of recurrence which havebeen reported to be some of the main outcomes that concern pa-tients [55,56]. Finally, missing from the literature was both thestudy of patient experience/beliefs and of long term follow-up onoutcomes and recurrence. Therefore questions remain about thesustainability and long term effectiveness of exercise intervention.

The lack of qualitative evidence is a finding worth commentingand suggests that the present studies are ‘researcher led’ and theopinions of patients and health professionals have not been fullyexplored in the development stage of study design. The MedicalResearch Council (MRC) framework [57] for developing complexinterventions suggests that in the development stage of an inter-vention it might be necessary to do some new primary research, forexample interview key ‘stakeholders’, to ensure the intervention isappropriate for those involved. This reveals an areaworth exploringto enhance and evaluate the design of exercise intervention; ensureit reflects the needs of those receiving the intervention; and so itcan be implemented in clinical care.

Conclusion

This review has revealed that currently there is insufficient ev-idence to conclude what is the best design of exercise interventionfor patients surgically treated for lung cancer. Further methodo-logically sound studies are urgently required to determine theoptimal exercise intervention for this particular patient group. Tofacilitate comparison between studies and allow replication, it isessential that future studies clearly describe the content of theexercise intervention, adherence rates to the intervention and anypossible adverse events, thus giving insight into the exercise dosereceived and safety of the intervention.

Authorship statement

Study conception and design: Crandall.Acquisition of data: Crandall.

Analysis and interpretation of data: Crandall, Maguire,Campbell.

Drafting of manuscript: Crandall.Critical revision: Kearney, Maguire, Campbell.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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