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Feature and review paper

Exercise for the management of cancer-related fatigue in lung cancer: a systematic review V.S. PARAMANANDAM, B.P.T., MSC IN PSYCHOLOGY, MSC IN CANCER CARE, SCIENTIFIC ASSISTANT D (PHYSIOTHERAPIST), Tata Memorial Hospital, Dr. E. Borges Marg, Parel, Mumbai, India, & V. DUNN, SENIOR LECTURER (PALLIATIVE CARE), Faculty of Health and Social Care, Oxford Brookes University, Oxford, Oxfordshire, UK PARAMANANDAM V.S. & DUNN V. (2014) European Journal of Cancer Care Exercise for the management of cancer-related fatigue in lung cancer: a systematic review Cancer-related fatigue is a common, persistent and disabling side-effect of the cancer and its treatments. Exercise, once was contraindicated, is now the key non-pharmacological management for cancer-related fatigue. However, the role of exercise in lung cancer cohort is not clear. A computerised database search was undertaken using keyword search in the CENTRAL, PubMed, EMBASE, CINAHL, SPORTDiscus, AMED and Web of Science. Ten relevant articles were reviewed; the evidence on this cohort was found to be limited, warrants further research. However, the available evidence from other than lung cancer groups shows significant beneficial effects of exercises on cancer-related fatigue. Hence, exercises could possibly be used in the management of cancer-related fatigue in this cohort with due caution until more robust evidences are available.

Keywords: cancer-related fatigue, lung cancer, exercise, symptom management.

INTRODUCTION Lung cancer is the most frequently diagnosed cancer among men and a leading cause of cancer deaths worldwide (Jemal et al. 2011). Additionally, lung cancer is the second leading cause of cancer deaths in women. According to Jemal et al. (2011), in 2008, lung cancer accounted for 13% of overall cancer cases and 18% of overall cancer deaths. Although there was significant variation noted among different geographical areas, smoking was predicted as the leading cause of lung cancer in 80% of cases in men and 50% of cases in women (Ezzati & Lopez 2003; Ezzati et al. 2005). Although majority of lung cancer patients diagnosed in advanced stage with poor prognosis, the survival rate have steadily improved in those treated early in their disease process because of the improvements

Correspondence address: Vincent Singh Paramanandam, Tata Memorial Hospital, Dr. E. Borges Marg, Parel, Mumbai 400012, India (e-mail: [email protected]).

Accepted 11 March 2014 DOI: 10.1111/ecc.12198 European Journal of Cancer Care, 2014

© 2014 John Wiley & Sons Ltd

in screening, surgical techniques and adjuvant chemotherapy and radiotherapy techniques (Jones et al. 2010). Disease and the treatment-related symptoms, however, pose many challenges for the survivors (Granger et al. 2011; Peddle-McIntyre et al. 2012). Patients with lung cancer experience complex plethora of symptoms that negatively influence their physical function and impair activities of daily living. In addition to that they report higher psychological suffering and lower quality of life than other cancer patients (Schag et al. 1994; Sugimura & Yang 2006; Dagnelie et al. 2007). Not only the disease but also the treatment effects lead to many physical and psychological dysfunctions in these patients (Montazeri et al. 2003; Carlsen et al. 2005). Moreover, higher symptom burden in lung cancer patients often reported to be associated with lower survival period. Therefore, clinicians and researchers are increasingly focused in symptom management to improve overall quality of life in patients with lung cancer (Granger et al. 2011). Cancer-related fatigue is a disabling and distressing symptom present throughout the cancer trajectory from the time of diagnosis until the end of life. Depending upon the measurement methods, cancer-related fatigue is

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reported to be affecting 25% to 99% of the cancer population during their lifetime (Servaes et al. 2002). Despite of the higher incidence, it is often under reported, under diagnosed and neglected symptom (Mitchell 2010; NCCN 2011). In addition to that cancer-related fatigue affects the normal functioning and interferes with the activities of daily living (Dimeo et al. 2004; de Jong et al. 2006) and the quality of life (Schmidt et al. 2012). Often, cancer-related fatigue is reported, by patients with cancer, as one of the most distressing complications of cancer and its therapy, more distressing than pain or nausea, which are commonly controlled effectively by pharmacotherapy (Servaes et al. 2002, 2003). Historically, cancer patients are advised to limit their physical activities and take rest; however, growing evidences show that both exercise and physical activity could be safe and beneficial to the people with cancer (Schmitz et al. 2010). Although, in clinical settings and literature, exercise and physical activity both these terms are often used interchangeably, they are different. Exercise is a well-planned physical activity with an objective to improve physical fitness; whereas, physical activity refers to any bodily movement produced by skeletal muscles that results in energy expenditure (American College of Sports Medicine 2009; Garber et al. 2011). Exercise not only prevents and controls cancer but also it helps in improving physical function, cardio respiratory fitness, quality of life and reduces cancer-related fatigue (Courneya et al. 2004; World Cancer Research Fund & American Institute for Cancer Research 2007; Rajarajeswaran & Vishnupriya 2009; Schmitz et al. 2010; Fong et al. 2012; Mishra et al. 2012). Specific exercise programming, such as aerobic, resistance, endurance or flexibility exercises could be used to achieve desired outcomes and often certain adaptations may be required according to the disease status. Currently, the American College Sports Medicine (ACSM) position stand (Garber et al. 2011) and ACSM roundtable on exercise guidelines for cancer survivors (Schmitz et al. 2010) provides guidance in exercise testing and prescription for cancer survivors. According to the National Comprehensive Cancer Network (NCCN) guidelines on cancer-related fatigue, activity enhancement is one of the important nonpharmacological management (NCCN 2011). There are strong evidences to show that exercise and physical activity reduces cancer-related fatigue and improves physical function, quality of life and treatment related side-effects during and post cancer treatment. A meta-analysis by Duijts et al. (2010) concluded that the physical exercises produced significant improvements in fatigue [effect size (ES) −0.315; 95% confidence interval (CI) −0.532 to −0.098, 2

P = 0.004], depression (ES −0.262; 95% CI −0.476 to −0.049, P = 0.016), body-image (ES 0.280; 95% CI 0.077 to 0.482, P = 0.007) and health-related quality of life (ES 0.298; 95% CI 0.117 to 0.479, P = 0.001). Other recent past systematic reviews (Cramp & Daniel 2008; Kangas et al. 2008) and comprehensive overviews reported similar results (McNeely & Courneya 2010; Mitchell 2010). Although these results are convincing, they are predominantly from the studies conducted on breast cancer population; hence, there is urgent need for reviews on specific cancer population, such as patients with lung cancer (Cramp & Daniel 2008). Though there is a recent systematic review by Granger et al. (2011) to study the effect of exercise intervention on exercise capacity and health-related quality of life for patients with non-small cell lung cancer, it was not focusing primarily on cancer-related fatigue outcome. Therefore, in view of lack of reviews on this cohort, this systematic review was conducted to study the effect of exercise intervention on cancer-related fatigue in lung cancer population. METHODS Search strategy The review objective was deconstructed into the PICOS format to ensure the systematic search of the available literature (Doig & Simpson 2003; Centre for Reviews and Dissemination 2009; Jesson et al. 2011). In addition, the inclusion exclusion criteria were developed based on the PICOS format (O’Connor et al. 2011). PICOS format stance for Population (P), Intervention (I), Comparison (C), Outcome (O) and Study design (S). Table 1 shows the PICOS format of the current review objective. Three key terms were used to build the search strategy; ‘exercise’, ‘cancer-related fatigue’ and ‘lung cancer’. These key terms were used to create exhaustive list of keywords, later, the Boolean operators ‘AND’, ‘OR’ were used effectively to focus or broaden the query in electronic search strategy (Centre for Reviews and Dissemination 2009; Machi 2009; Jesson et al. 2011; Lefebvre et al. 2011). On the contrary, another Boolean operator ‘NOT’ was deliberately avoided to prevent accidental exclusion of relevant literature (Machi 2009; Khan et al. 2010). Additionally, appropriate truncations were utilised to build search strategy. Information source Computer database search was performed during the period 1 January 2001 to 13 April 2012 using search strategy developed for this review. This time period was selected in © 2014 John Wiley & Sons Ltd

Cancer-related fatigue in lung cancer

Table 1. PICOS format Population (P)

Intervention (I)

Comparison (C) Outcomes (O) Study design (S)

Studies that evaluated the effect of exercise on cancer-related fatigue in adults of any age with lung cancer, regardless of gender, tumour stage and type of cancer treatment. Participants may have been actively receiving treatment, be in long-term follow-up, or receiving palliative care. Studies that reported the effect of physical exercise on cancer-related fatigue. The intervention could take place in any setting and be delivered to a group or individual participant. All types of physical exercise were considered for inclusion, including, aerobic exercise, strength training and flexibility exercises. The studies that compared exercise with no exercise, a usual care group (i.e. no specific exercise programme prescribed) or an alternative treatment for fatigue associated with cancer. Cancer-related fatigue measured by patient-reported assessment tools. All study designs except cross-sectional study and survey.

view of the fact that the exercises intervention in this population is new and it would be highly unlikely to have studies before this period. The following databases were searched electronically: the CENTRAL, PubMed, EMBASE, CINAHL, Web of Science, ScienceDirect and SPORTDiscus. After the initial search, date restriction, language limit and peer review were applied to the results as available to the databases and their hosts. Additionally, reference list of the identified journals and previous reviews were searched for any potential articles. Weekly automated search alerts were created for databases that provided the service. All the search results were stored in the Zotero, a free, open source research management software version 3.0.6.

Selection of studies Each studies obtained through the database search was checked for eligibility against the predefined inclusion criteria by reviewer (VP) and supervised by another reviewer (VD). It was conducted in three stages (Centre for Reviews and Dissemination 2009; Machi 2009). In the first stage, all the duplicate entries were removed using Zotero de-duplication facility. In the next stage, titles and abstracts of the articles were checked for eligibility for selection. In the final stage, articles which did not have abstracts and whose eligibility could not be decided by screening the title and abstract alone were obtained in full text for screening. Those articles met all the inclusion criteria were considered for the data extraction process.

Definition of cancer-related fatigue For this review, the definition of NCCN guidelines for cancer-related fatigue was adopted. According to NCCN, ‘Cancer-related fatigue is a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning’ (NCCN 2011: FT–1). Moreover, it is most often presents with other symptoms, such as pain, dyspnoea and breathlessness as symptom clusters and diagnosis is made always through self-reported measures.

Types of participants In this review, studies which included adults with lung cancer regardless of their gender and with or at risk of developing cancer-related fatigue were included. Participants from the entire spectrum of cancer treatment were considered for this review.

Types of Interventions Trials studying the effects of exercises or physical activity on lung cancer-related fatigue were considered for this review. Exercise intervention could be of any one type, for example aerobic exercise, or mixed type, to illustrate, resistance and flexibility exercise. Considering the paucity of the literature in this field, it was decided to include studies with exercise as part of other treatment programme, such as pulmonary rehabilitation.

Eligibility criteria The PICOS format was used, as already explained, in developing the eligibility criteria for the studies to be included in this review. Hence, the review results may guide the clinical decision-making process (Doig & Simpson 2003; Centre for Reviews and Dissemination 2009; Jesson et al. 2011). © 2014 John Wiley & Sons Ltd

Types of comparison Comparisons, if available, of the above mentioned intervention against any of the following were considered for this review; no exercise, any other form of pharmacological or non-pharmacological treatments for cancer-related fatigue. 3

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of studies in this cohort it was decided to include studies with levels 1–5 for this current review.

Outcome measures Cancer-related fatigue measured by patient-reported assessment tools, even if it is reported as subscale, for example fatigue score from European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ) scale, was considered as primary outcome.

Methodological evaluation Methodological quality of the selected studies were evaluated using the generic quantitative appraisal tool developed by Law et al. and modified by Machotka et al. (2009) (permission has been taken from the corresponding author). Studies with different study designs were included for this review; hence, this generic critical appraisal tool for quantitative studies was selected to appraise the studies. This modified tool contains 12 criteria representing key elements to evaluate the methodological quality of the studies. Each affirmative answers were scored as one and overall score was calculated by simple summation of the scores and converted into percentages for ease of interpretation. Scoring was performed by a single reviewer (VP) and supervised by other reviewer (VD). Methodological evaluation results are presented in the Table 3.

Types of study Studies that evaluated the effect of any form of exercise with quantitative research designs, such as randomised controlled trial (RCT), pseudo-RCT as well as case series and case studies, were considered as eligible for inclusion. Studies published in English and in peer reviewed journals were considered for this review. Abstracts and unpublished data were not included; the last search was conducted on 13 April 2012.

Hierarchy of evidence Levels of Evidence developed by The Oxford Centre for Evidence Based Medicine (Table 2) was used to evaluate the selected studies. In view of the fact that this review was about the effectiveness of the exercise intervention only quantitative studies were included. Due to the lack

Data extraction Data from the selected studies was extracted using the pre-designed data extraction forms regarding the characteristics of studies, exercise delivery, the nature of exercise

Table 2. Hierarchy of evidence (OCEBM Levels of Evidence Working Group 2011) Question

(Level 1*)

(Level 2*)

(Level 3*)

(Level 4*)

(Level 5)

Does this intervention help?

Systematic review of randomised trials or n-of-1 trials

Randomised trial or observational study with dramatic effect

Non-randomised controlled cohort/ follow-up study

Case-series, case–control studies, or historically controlled studies

Mechanismbased reasoning

*Level may be graded down on the basis of study quality, imprecision, indirectness [study Population, Intervention, Comparison and Outcome (PICO) does not match questions PICO], because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size.

Table 3. Methodological quality of studies Criteria Study

1

2

3

4

5

6

7

8

9

10

11

12

Score

%

Peddle-McIntyre et al. (2012) Quist et al. (2012) Litterini and Jette (2011) Andersen et al. (2011) Riesenberg and Lübbe (2010) Ozalevli et al. (2010) Temel et al. (2009) Peddle et al. (2009) Jones et al. (2008) Spruit et al. (2006)

Y Y Y Y Y Y Y Y Y Y

Y Y Y Y Y Y Y Y Y Y

Y Y Y Y Y Y Y Y Y Y

N N N/A N N N N N ND N/A

ND Y ND ND ND ND ND Y Y Y

Y Y Y Y N Y Y Y Y Y

ND ND ND ND ND N N ND Y N

Y Y N/A Y&N Y Y Y Y Y Y

Y Y Y Y Y Y Y Y Y Y

ND Y ND ND ND ND ND N ND Y

Y Y N Y N Y Y Y Y N

Y Y Y Y Y Y Y Y Y Y

8/12 10/12 6/12 7.5/12 6/12 8/12 8/12 9/12 10/12 9/12

66.66 83.33 50 62.5 50 66.66 66.66 75 83.33 75

1 = Study purpose reported; 2 = Relevant background literature; 3 = Sample description; 4 = Sample size justification; 5 = Reliable & valid outcomes measures; 6 = Intervention description; 7 = Contamination & co-intervention; 8 = Statistical significance; 9 = Appropriate analysis method(s); 10 = Clinical importance; 11 = Drop outs; 12 = Appropriate conclusions. N, no; N/A, not applicable; ND, not reported; Y, yes.

4

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Cancer-related fatigue in lung cancer

and the fatigue outcome. Data extraction was performed and rechecked by one reviewer (VP) and supervised by other reviewer (VD). Table 4 summarises the study characteristics, such as, study aim, design, participants, interventions and outcomes. Intervention settings, repeatability, type, mode, intensity along with duration, frequency and total length of the exercise intervention are presented in Table 5. Extracted data of fatigue outcome along with level of evidence are tabulated in Table 6. Additionally, in this table, information regarding feasibility of the exercise intervention in lung cancer population is also presented. Extracted data were stored in Microsoft office word document 2007.

Data analysis In view of clinical heterogeneity among the included studies and methodological limitations, it was decided that summary statistic calculation would be inappropriate. Hence, study results were presented as reported in the included trials (Table 6).

Quality of life is the most common outcome measures among the included studies (80%), other commonly reported outcomes are pulmonary function, physical function and muscle strength. The details of the studies and other characteristics are summarised in the Table 4.

Methodological quality of included studies Table 3 depicts the summary of the methodological quality of the studies selected for this review. From this table it is clear that the reviewed studies’ quality ranged from 50% (Riesenberg & Lübbe 2010; Litterini & Jette 2011) to 83.33% (Jones et al. 2008; Quist et al. 2012). Most of these studies did not provide explicit justification for the sample size; this could be due to that these studies were conducted to explore the feasibility of the exercise intervention. Only 40% of the included studies addressed about the reliability and validity of the chosen outcome measures (Spruit et al. 2006; Jones et al. 2008; Peddle et al. 2009; Quist et al. 2012). Only two included studies (Spruit et al. 2006; Quist et al. 2012) discussed about the clinical relevance of their results.

RESULTS Study selection

Exercise delivery

The initial search yielded 453 studies and the reference list search identified another 40 potential studies. After the removal of duplicates and the irrelevant studies 331 studies were included for further screening. Screening of the title and the abstract for exercise intervention on lung cancer excluded 284 studies from the review. The remaining 47 articles were considered for full text review; however, full text for 13 studies could not be retrieved (11 – abstracts and 2 – not available through Oxford and Oxford Brookes University Library) another 24 studies were excluded because they were not meeting the inclusion criteria. Consequently, 10 studies with available full text were included for this current review (Jones et al. 2008; Peddle et al. 2009; Temel et al. 2009; Ozalevli et al. 2010; Riesenberg & Lübbe 2010; Andersen et al. 2011; Litterini & Jette 2011; Peddle-McIntyre et al. 2012; Quist et al. 2012). Figure 1 depicts the flow of search.

All of the included studies provided exercise intervention under supervision, six of them under the supervision of physiotherapists (Spruit et al. 2006; Temel et al. 2009; Ozalevli et al. 2010; Andersen et al. 2011; Litterini & Jette 2011; Quist et al. 2012), two of them under exercise physiologists and one under ACSM certified exercise physiologist (Jones et al. 2008). Riesenberg and Lübbe (2010), however, did not report the detail of the supervisor. Two studies delivered the intervention in groups (Spruit et al. 2006; Temel et al. 2009), three studies in individual basis (Jones et al. 2008; Peddle et al. 2009; Litterini & Jette 2011) and other two had group- and individual-based approach (Andersen et al. 2011; Quist et al. 2012). All the included studies were based on institution, two studies (Andersen et al. 2011; Quist et al. 2012) had also included a home programme; however, the exercise was taught in institution under supervision before practised at home. There were few studies that had reported co-interventions. Table 5 illustrates the details of exercise intervention.

Study characteristics Except one case study by Litterini and Jette (2011), all other studies were prospective single group intervention studies. One hundred and ninety-two participants with lung cancer participated in these studies. In general, these studies were conducted to evaluate the feasibility of exercise intervention in lung cancer with diverse outcome measures. © 2014 John Wiley & Sons Ltd

Type and mode of exercises Most of the reviewed studies included aerobic exercise and interval training (Jones et al. 2008; Peddle et al. 2009; Ozalevli et al. 2010; Riesenberg & Lübbe 2010; Andersen et al. 2011). Stationary bikes and treadmill both were 5

6

Feasibility and preliminary efficacy of a PRET intervention in post-treatment lung cancer survivors

Safety and feasibility of a 6-week supervised structured exercise and relaxation training programme on estimated peak oxygen consumption, muscle strength and health-related QOL In a 65-year-old woman following lobectomy, chemotherapy and radiation for lung cancer, will an exercise regimen be beneficial for reducing fatigue? Feasibility and effect of a COPD-rehabilitation exercise programme on lung cancer

To assess changes in exercise capacity and QOL before and after pulmonary rehabilitation in lung patients Effect of inpatient chest physiotherapy programme in stage 3 and 4 lung cancer patients

To evaluate the feasibility of a hospital-based exercise programme for patients with advanced non-small cell lung cancer To explore the effects of pre-surgical exercise training on QOL in patients with malignant lung lesions The effects of supervised aerobic exercise on non-small cell lung cancer following surgery Effect of exercise intervention in lung cancer cohort as part of a rehabilitation programme

Peddle-McIntyre et al. (2012)

Quist et al. (2012)

Riesenberg and Lübbe (2010)

Temel et al. (2009)

PSGIS

PSGIS

PSGIS

PSGIS

PSGIS

PSGIS

PSGIS

Case study

PSGIS

PSGIS

Design

Aerobic exercise

N = 20 (16 women) with advanced NSCLC N = 9 (6 women) N = 19 (10 men) with NSCLC N = 10 (8 men) 9 = NSCLC 1 = SCLC

Aerobic and resistance exercises. Gymnastics

Aerobic and resistance exercises Aerobic exercise

N = 18 (15 men) stage 3 and 4 LC

45 person with LC

Aerobic and resistance exercises COPD exercise protocol & walking In patient pulmonary rehabilitation In patient chest physiotherapy

Aerobic and resistance exercises

N = 29 (16 women) all were 3rd and 4th stage LC A 65-year-old woman with SCLC 24 patients with LC (14 men)

PRET

Interventions

17 (10 women)

Participants

Cardiopulmonary testing, QOL and exercise adherence Pulmonary function test, Six-minute walk test, Fatigue, Dyspnoea, Peak cycling load

Respiratory symptoms, functional capacity, pulmonary function, pain and QOL Exercise response, functional exercise capacity, muscle strength, QOL and symptom assessment Exercise testing, QOL and fatigue

Physical exercise capacity, pulmonary function, QOL and fatigue

VO2 max, walking time at 85% VO2 max. Pulmonary function and QOL

Fatigue – visual analogue scale

Feasibility, Eligibility, Recruitment rate, Exercise adherence, Muscular strength, Body composition, Physical functioning, QOL, Fatigue, Dyspnoea and patient-rated function Safety and adherence, QOL and Physical and functional capacity

Outcomes

PRET, progressive resistance exercise training; PSGIS, Prospective Single Group Intervention Study; LC, lung cancer; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; QOL, quality of life; COPD, chronic obstructive pulmonary disease.

Spruit et al. (2006)

Jones et al. (2008)

Peddle et al. (2009)

Ozalevli et al. (2010)

Andersen et al. (2011)

Litterini and Jette (2011)

Aim

Citation

Table 4. Study characteristics

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© 2014 John Wiley & Sons Ltd

Physiotherapist/ Institution based/NR Physiotherapist/ Institution based/ Group Exercise Physiologist/ Institution based/ Individual

ACSM certified exercise specialists/ Institution based/ Individual

Y

Y

Y

N

Y

Y

Y

Y

Y

Quist et al. (2012)

Litterini and Jette (2011)

© 2014 John Wiley & Sons Ltd

Andersen et al. (2011)

(Riesenberg & Lübbe 2010)

Ozalevli et al. (2010)

Temel et al. (2009)

Peddle et al. (2009)

Jones et al. (2008)

Spruit et al 2006

Interval training using bicycle ergo meter at submaximal heart rate (maximum HR of 180/ min individual age of each patient, furthermore, minus 10 beats if patients were using beta-blockers or other HR-lowering preparations) for 30 min with 3–5 min interval. Breathing control, breathing exs., relaxation exs., upper and lower extremity exs. and mobilisation based on the individual needs. Each exs. was repeated 10 times and adjusted according to the individual’s tolerance. WU: 10 min, AEs using treadmill and bicycle for 30 min with 70–85% of their maximum HR or perceived exertion of 13 in modified Borg scale. RE at 60% of 1RPM to start and over the end of 16th session to be progressed to 80%. 10 repetitions of three sets. AE using cycle ergo meter: Week 1; Duration and intensity from 20 min at 60% of VO2 peak to 30 min at 65% of VO2 peak. Weeks 2–3; 4 ss of 25–30 min at 60–65% of VO2 peak and 1 session of 20 min at ventilatory threshold. After that, 3 ss of 60–65% of VO2peak for 30–35 min, 1 threshold workout and 1 interval workout per week. Interval workouts for 30 s at peak VO2 followed by 60 s of active recovery for 10–15 intervals. AE using cycle ergo meter: Week 1; exs. intensity was initially set at 60% of baseline peak workload for 15–20 min. Weeks 2–4; up to 30 min at 65% peak workload. Weeks 5–6; 60–65% of peak workload for 30–45 min for 2 ss. In the remaining sessions patients cycled for 20–25 min at ventilatory threshold. Weeks 7–9; 2 ss at 60–70% peak workload with 1 threshold workout for 20–30 min. Weeks 10–14 for 2 ss at 60–70% peak workload with 1 interval session. Interval workouts consisted of 30 s at peak workload followed by 60 s of active recovery for 10–15 intervals. WU & cool down 5 min each. AE using cycle ergo meter and treadmill for 20 min non-stop at 60% of baseline peak cycling load; treadmill walking – for 20 min non-stop at 80% of baseline mean walking speed; Resistance training for all major muscle groups – for 3 × 15 repetitions at 60% 0f 1RM; 30 min of gymnastics.

PRET: Leg press and chest press, 60% of 1RM. Other exercises: ss 1–9; 10–12 repetitions and 2 to 3 sets. ss 10–16; 6–8 repetition and 2–3 sets. ss 19–25; 4–6 repetitions and 2–4 sets. ss 26 to 28; progressive tapering prior to follow-up testing. Chest wall strengthening using chest PowerLung® training apparatus. WU for 10 min in stationary bike at 60–90% of patients’ maximum HR. Strength training with Technogym machines was aimed at completing 3 series of 5–8 sets, with 70–90% of 1RM. Circuit training with bike at 85–95% of maximum HR for 10–15 min. Passive stretching for 10 min. Progressive relaxation for 10–20 min. Home-based walking programme is progressed starting from 20 min week 1–2, 30 min week 3–4, and end with 40 min week 5–6. WU: 5–10 min in stationary bike or treadmill with an intensity of 10–12 on the 6–20 Borg RPE scale, while maintaining O2 saturation > 90%. RE were initiated with 1 set of 8–15 repetitions and progressed to a maximum of 3 sets of 15 repetitions. WU: sitting in a chair arm and leg exs. low to moderate intensity. Walking in a correct speed to achieve calculated 85% VO2MAX. Dyspnoea coping using stationary bike, steps (step training) and chair (chair to stand).

Summary (type, mode and intensity)

70 1/day 8 wks

45 3/wk 14 wks

WU = 5–10 RE = NR 2/wk 90 SE = 2/wk HE = 3/wk 7 wks 30 1/day 28 ss 20–30 2/day NR 90–120 2/wk 16 ss 20–35 5/wk 9 wks

SE = 90 HE = 40–60 SE = 2/wk HE = 3/wk 6 wks

NR 3/wk 28 ss

Duration (min) F/wk Length

ACSM, American College of Sports Medicine; AE, aerobic exercise; F, frequency; HE, home exercises; HR, heart rate; L, length; min, minutes; N, no; NR, not reported; PRET, Progressive Resisted Exercise training; RE, resistance exercise; RM, repeated maximum; ss, sessions; wk, week; wks, weeks; WU, warm up; Y, yes.

Physiotherapist/ Institution based/ Group

Physiotherapist/ Institution based/ Individual Physiotherapist/ Institution & Home/Group & individual NR/Institution based/NR

Qualified exercise physiologist/ Institution based/NR Physiotherapist/ Institution and Home based/Group & individual

Y

Peddle-McIntyre et al. (2012)

Supervision/setting/ group

Repeatability

Study

Table 5. Exercise summary

Cancer-related fatigue in lung cancer

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Table 6. Fatigue outcome Study

Level of evidence*

Peddle-McIntyre et al. (2012) Quist et al. (2012)

4 4

Litterini and Jette (2011) Andersen et al. (2011)

5 4

(Riesenberg & Lübbe 2010)

4

Ozalevli et al. (2010)

4

Temel et al. (2009)

4

Peddle et al. (2009) Jones et al. (2008)

4 4

Spruit et al. (2006)

4

Feasibility demonstrated

Fatigue – outcome results Mean change = 0.5, 95% CI = −3.5 to 2.5 and P = 0.715 FACT fatigue scale: Base mean (SD) = 73.4 (14.2); Follow-up mean (SD) = 74.2 (12.4); Change (95% CI) = 0.8 (4.7 to 6.1) P = 0.780 38 points reduction in the 100 points visual analogue scale Median scores of Fatigue subscale of EORTC-QLQ-C30 Baseline = 22, Post intervention = 33 Multidimensional Fatigue Inventory (MFI) P < 0.001 Study reported statistically significant improvement in all five dimensions Before inpatient chest physiotherapy = 94.4 and after inpatient chest physiotherapy = 50.0; P = 0.01 FACT-fatigue scale, Base mean = 35.35, Post mean = 38.77, 95% CI = −11.17 to 4.32 Friedman, P = 284 Fatigue was assessed by the 13-item Fatigue Scale, Base line mean = 19 ± 8, Post intervention = 12 ± 8. The mean difference = −7 (CI = −1 to −17, P = 0.03 Median change: −0.3 points (interquartile range: −3.4 to 1.5), P = 0.4922

Y Y

N/A N Y

Y Y N Y

Y

*OCEBM Levels of Evidence Working Group 2011. CI, confidence interval; FACT, Functional Assessment of Cancer Therapy; N, no; N/A, not applicable; EORTC-QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; Y, yes.

Intensity, frequency and duration Although 90% of included studies showed repeatability, they varied greatly in the intensity, frequency, duration and length of the exercise programme. Table 5 outlines the details of the variation in the exercise protocol between selected studies.

Effect of exercise on cancer-related fatigue

Figure 1. Search results. N/A, not applicable.

commonly used as mode of exercise, except Andersen et al. which was using only walking as an exercise mode. Four trials included both aerobic and resistance as the intervention (Spruit et al. 2006; Temel et al. 2009; Litterini & Jette 2011; Quist et al. 2012). A study by Peddle-McIntyre et al. (2012) used progressive resistance exercises and chest wall strengthening with PowerLung training apparatus. Quist et al. (2012) used Technogym apparatus for strengthening exercises. 8

All studies, except Litterini and Jette (2011), were level 4 evidences and study by Litterini and Jette is of level 5 evidence. In order to study the effect of exercise on cancerrelated fatigue, fatigue outcome results were extracted and summarised in Table 6. Seven out of 10 studies reported the results in statistical significance, out of these seven studies, three showed significant reduction in fatigue (Jones et al. 2008; Ozalevli et al. 2010; Riesenberg & Lübbe 2010). Although all other studies showed some improvement, they were not statistically significant (Table 6). Studies with significant results, however, were not similar in their exercise intervention; for example, Riesenberg and Lübbe used cycle ergometer whereas Ozalevli et al. used breathing exercise, relaxation and aerobics. Additionally, study by Jones et al. 2008 included only participants with non-small cell lung cancer while other two studies had both small cell and non-small cell carcinoma. © 2014 John Wiley & Sons Ltd

Cancer-related fatigue in lung cancer

DISCUSSION Despite the scarcity of evidence present in this topic area, the available evidence, though low level, supports the exercise intervention in the management of cancer-related fatigue in lung cancer. None of the included studies, except a study by Peddle et al. (2009), reported decline in the outcomes. Peddle et al. (2009), although, showed improvement before surgery, reported decline immediate post surgery. However, the increased fatigue score could be related to the effect of acute surgical injury. Although statistically significant results shown by some of these studies (Jones et al. 2008; Ozalevli et al. 2010; Riesenberg & Lübbe 2010), lack of control group and small sample size in these trials severely undermine the outcome. Additionally, variation in the participants and exercise intervention undermined the chance of extrapolating the results to the clinical practice. Nevertheless, a well-conducted systematic review by Cramp and Daniel (2008) reported significant improvement in cancer-related fatigue in other cancer population. This finding was confirmed by other two systematic reviews by Kangas et al. (2008) and Duijts et al. (2010). Another important finding from this review is that seven out of 10 studies showed that the exercise intervention is safe and feasible despite of the fact that lung cancer is associated with plethora of difficult symptoms and restricted physical capacity. Similar results were reported by a systematic review by Granger et al. (2011). Although the results are encouraging, all the studies included in this review were case series or case study, thus, it should be interpreted with caution until large, well conducted studies with control groups are available. Until then, it is advisable to follow the NCCN guidelines for the management of cancer-related fatigue. The NCCN guidelines for cancer-related fatigue suggest for regular screening for cancer-related fatigue in all cancer patients including lung cancer and treat any underlying cause, for example anaemia, pain. In absence of any underlying cause or co-morbidities, the NCCN guidelines strongly advice for physical activity or exercises enhancement programme along with psychosocial intervention for cancer-related fatigue (NCCN 2011). Exercise delivery In view of the fact that the complex symptoms associated with the lung cancer it would be safe to provide exercises under supervision. Moreover, it will help in learning the exercise in an appropriate biomechanical way and to prevent injury. The ACSM roundtable on exercise guidelines for cancer survivors recommends individualised © 2014 John Wiley & Sons Ltd

exercise prescription and supervision by qualified professionals (Schmitz et al. 2010).

Type and mode of exercises There are no advantage reported for a particular type or mode of exercise over the other, however, to gain the benefits of different types of exercises, it is advisable to do aerobic and resistance exercise along with flexibility exercises. For example, aerobic exercises are preferred to improve the cardio-respiratory fitness body composition, whereas, resistance training is to improve the muscle strength, endurance and body composition. Additionally, it is advisable to add some flexibility training to improve and maintain range of motion. Mode of exercises could be decided by available modes, safety and comfort of the patients.

Intensity, frequency and duration The studies reviewed were not conforming to any particular intensity, frequency and duration, thus, it is advisable to follow the ACSM guidelines for quality and quantity of exercises document and exercise guidelines for cancer survivors document (American College of Sports Medicine 2009; Schmitz et al. 2010; Garber et al. 2011).

LIMITATIONS Although this review was conducted by a student researcher (VP) under a meticulous supervision by author VD, it limited the scope of using second reviewer to minimise the subjective bias in study selection and data extraction process. However, a systematic, replicable methodology was used in this review to limit the subjective bias. Conducting a systematic review with more than one author, especially for the study selection, data extraction and methodological quality evaluation, would be more objective. However, it may not be beneficial at present due to the fact that there are limited numbers of quality studies available in this area. Studies published in English language only considered for this review, there are chances that in other languages some well conducted research articles might have been published. Considering the limitation in the resources, it was difficult to do an exhaustive search of literature within the time limit.

CONCLUSION This current review shows that the exercise is beneficial and safe in lung cancer-related fatigue; however, the studies are small, without any control group lacks clinically 9

PARAMANANDAM & DUNN

significant effect. Thus, exercises could be used in the management of cancer-related fatigue in lung cancer, in view of the available evidence in other cancer cohorts with due caution. There is an urgent need of further research with adequate sample size, preferably, randomised control trials to evaluate the effect of exercise in this cancer cohort.

PRACTICE IMPLICATIONS All lung cancer survivors need to be screened for cancerrelated fatigue in every visit and if they are inpatients

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