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Lung Cancer 75 (2012) 203– 208

Contents lists available at ScienceDirect

Lung Cancer

j our na l ho me p age: www.elsev ier .com/ locate / lungcan

afety and feasibility of a combined exercise intervention for inoperable lungancer patients undergoing chemotherapy: A pilot study

orten Quista,∗, Mikael Rørthb, Seppo Langerb, Lee W. Jonesc, Jørgen H. Laursend, Helle Pappotb,arl Bang Christensene, Lis Adamsenf

The University Hospitals Centre for Nursing and Care Research (UCSF) Department 7331, University Hospital Copenhagen, DenmarkDept. of Oncology 5073, Copenhagen University Hospital, Rigshospitalet, DenmarkDuke University Medical Centre, Durham, USADept. of Oncology 5111, Copenhagen University Hospital, DenmarkDepartment of Biostatistics, University of Copenhagen, DenmarkInstitute of Public Health, University of Copenhagen (UCSF), Denmark

r t i c l e i n f o

rticle history:eceived 11 April 2011eceived in revised form 22 June 2011ccepted 11 July 2011

eywords:dvanced lung cancererobic exerciseunctional capacityuality of lifehemotherapy

a b s t r a c t

Aim: To investigate the safety and feasibility of a six-week supervised structured exercise and relaxationtraining programme on estimated peak oxygen consumption, muscle strength and health related qualityof life (HRHRQOL) in patients with inoperable lung cancer, undergoing chemotherapy.Methods: A prospective, single-arm intervention study of supervised, hospital based muscle and cardio-vascular group training and individual home-based training. Peak oxygen consumption (VO2peak) wasassessed using an incremental exercise test. Muscle strength was measured with one repetition maxi-mum test (1RM). HRQOL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L)scale.Results: Twenty-five patients with non-small cell cancer (NSCLC) stage III–IV and four patients with exten-sive disease small cell lung cancer (SCLC-ED) were recruited. Six patients (20.7%) dropped out leaving23 patients for analysis. Exercise adherence in the group training was 73.0% and 8.7% in the home-based

training. There were improvements in estimated VO2peak and six-minute walk distance (6 MWD) aswell as increased muscle strength measurements (p < 0.05). There was significant improvement in the“emotional well-being” parameter (FACT-L) while there were no significant changes in HRQOL.Conclusion: Exercise training produces significant improvements in physiological indices and emotionalHRQOL and is safe and feasible in patients with advanced stage lung cancer, undergoing chemotherapy.

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. Introduction

Physical exercise in selected groups of cancer patients canelieve the burden of disease symptoms and side effects from anti-ancer treatment, e.g. poor exercise tolerance, fatigue, depressionnd anxiety [1–4]. The benefits of physical exercise for canceratients are described in a series of studies [5–11], most of which

ncluded patients with breast cancer and haematological neo-lasias. The studies measured HRQOL and functional capacity and

ncluded patients groups with early stage disease. Only two exer-ise intervention studies have included patients with lung cancerho were undergoing chemotherapy [12,13] and only one study,

∗ Corresponding author at: The University Hospital’s Centre for Nursing and Careesearch (UCSF) Department 7331, University Hospital Copenhagen, Denmark.el.: +45 35457335.

E-mail address: m.quist@rh.regionh.dk (M. Quist).

169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.lungcan.2011.07.006

ining was done because of low adherence.© 2011 Elsevier Ireland Ltd. All rights reserved.

Temel et al. [12] investigated the effect of physical training inadvanced lung cancer (NSCLC III–IV) and found no significantimprovement or decline in HRQOL, anxiety, depression, and phys-ical function (assessed by six minutes walking distance (6 MWD)).However, significant improvement was demonstrated in strengthin a single muscle group. Other studies have shown significantimprovements following exercise intervention in quality of life andphysical function (6 MWD) as well as physical capacity (VO2peak and1RM) in patients with lung cancer who were at an earlier stage ofdisease (NSCLC I–III, SCLC LD) [13–17].

Moreover, it has been shown that physical activity and relax-ation training can relieve side-effects and symptoms in cancerpatients with advanced disease who are undergoing chemother-apy [18–20]. It is not known whether these benefits of physical

activity can be achieved in patients with advanced NSCLC andSCLC during chemotherapy. We investigated the impact on aer-obic capacity (VO2peak), muscle strength (1RM), and quality oflife (HRQOL) in patients with lung cancer (NSCLC stage III–IV

204 M. Quist et al. / Lung Cancer 75 (2012) 203– 208

Table 1Weekly schedule.

Monday Tuesday Wednesday Thursday Friday

Home training Physical training Home training Physical training Home trainingin

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30 min 90 min 30 mRelaxation Relaxation Rela30 min 30 min 30 m

nd SCLC-ED) undergoing a six-week hospital based, supervisednd structured, muscle-cardiovascular-relaxation training pro-ram and home based exercise program while they receivedhemotherapy. We hypothesized that the intervention couldncrease physical capacity (fitness and strength) and functionalapacity (6 MWD) as well as improve HRQOL.

. Patients and methods

Patients >18 years with a WHO performance status 0–2ith stage III–IV NSCLC and SCLC-ED who were undergoing

hemotherapy were referred from the Dept. of Oncology at theopenhagen University Hospital, Rigshospitalet. Exclusion criteria:rain or bone metastases; prolonged bone marrow suppression;nti-coagulant treatment; symptomatic heart disease, includingongestive heart failure, arrhythmia or myocardial infarction diag-osed within the last three months; inability to provide informedonsent.

The study was approved by the Data Inspectorate (File No. 2008-1-2279) and by the Regional Ethics Committee for the Capitalegion under Case No. HA-2008-06. All included patients providedigned informed consent.

Patients were screened by a clinical nurse specialist (JL) prioro participating in each physical training session and before thehysiological tests [21]. If one of the following criteria were met,he patient was prohibited from exercising/being tested on thatay: diastolic blood pressure <45 or >95, heart rate (HR) at rest115/min, temperature >38 ◦C, respiratory rate at rest >30/min,nfection requiring treatment, fresh bleeding, total leucocyte count1.0 × 109/L or platelets <50 × 109/L. Physical tests and HRQOLvaluation were performed at baseline and after six weeks of train-ng.

Aerobic capacity (VO2peak) was measured by using a stationaryrgo meter (MONARK Ergomedic 839ETM) Watt (W) max test. Theest started with a burden of 47 W, after which it was increasedith 10 W. The test was complete when the patient could no longeraintain a momentum of RPM or if the patient developed sudden

aleness, dizziness, changes in heart rhythm or developed a coldweat. The burden achieved (maximum power output (MPO)) wassed to calculate the estimated VO2peak = 0.16 + (0.00117 × MPO)nd was expressed in L/min [22]. This test has been used in otherstudies with cancer patients undergoing chemotherapy preformedy this group [23,38]. Adamsen et al. [23] compared the esti-ated VO2peak with the VO2peak and found no significant difference

etween the two tests.Muscle strength was measured by the one repetition maximum

1RM) [24] tests using a TechnogymTM that included leg presslower extremity), chest press (pectoral muscles), lateral machinelatissimus dorsi), leg extension (quadriceps femoris), abdominalrunch (rectus abdominis) and lower back press (erector spinae).he 1RM test is the golden standard and has been found to be a reli-ble assessment to measure upper and lower extremity strength25].

Functional capacity was measured by a 6 MWD test. The test wasarried out over a pre-measured distance of 28 m in complianceith the American Thoracic Society (ATS) statement [26]. The 6WD test has demonstrated good reliability and validity in COPD

90 min 30 min Relaxation Relaxation

30 min 30 min

patients [27] who are similar to patients with lung cancer in diseasepathophysiology and symptomology.

Lung capacity forced expiratory volume in 1 s (FEV1) was mea-sured using a Piko-meter (piko-6, Ferraris RespiratoryTM). The useof the piko-6 instrument to measure FEV1 has demonstrated goodreliability and validity in COPD patients [28].

Demographic data was collected from questionnaires andtraining diaries. In order to evaluate HRQOL and cancer relatedsymptoms, the FACT instrument comprising two parts, i.e. the gen-eral part (FACT-G) and the lung specific part (FACT-L) was used.The reliability and validity of the FACT-L has been documented inpatients with lung cancer [29] and has been extensively used.

The intervention consisted of supervised group training (physi-cal training and relaxation) as well as home training (walking andrelaxation). The supervised training was carried out in groups of10–12 patients and each session was a duration of 1.5 h, adminis-tered twice weekly (see Table 1) and was supervised by a researchphysiotherapist (MQ). The training comprised warm up exercises,strength- and fitness-training as well as stretching. Warm up exer-cises consisted of 10 min of light, stationery cycling, adjusted to60–90% of the patient’s maximum HR. Strength training was carriedout using 6 machines (Technogym: leg press, chest press, lateralmachine, leg extension, abdominal crunch, and lower back). Thepractical aim of strength training was to complete 3 series of 5–8sets, with 70–90% of 1RM. The exercises were specifically selectedto involve the largest possible number of muscle groups in the leastnumber of exercises. To ensure progression in strength training,each patient was instructed in carrying out the 1RM test using eachof the above-mentioned strength training machines once everysecond week, after which their program would be adjusted. Cardio-vascular training was carried out as interval training on stationerybikes. Intensity was equivalent to 85–95% of each patient’s max-imum HR and lasted approximately 10–15 min. After the trainingsession, 5–10 min were dedicated to stretching the large musclegroups in order to increase agility.

Following each training session, progressive relaxation of15–20 min was performed.

The home training component comprised walking and relax-ation and was prescribed for a 6-week period. Walking wasestablished as a progressive exercise, requiring 20–40 min of activ-ity (20 min week 1–2, 30 min week 3–4, 40 min week 5–6), 3times weekly. Relaxation training took a progressive approach over15–20 min. In order to increase adherence, patients completed atraining diary and were asked to record every activity they per-formed within the (home training) program. Training diaries werereturned weekly to the research physiotherapist (MQ) who con-ducted the hospital-based supervised training program.

2.1. Statistical analysis

Descriptive statistics and paired t-tests were calculated withSPSSTM 17.0. Paired t-tests were used to compare scores for physical

capacity (VO2peak, 1RM), functional capacity (6 MWD) and FACT-Lat baseline and after the intervention.

Statistical significance was set at p < 0.05. The values areexpressed as mean ± standard deviation (SD).

M. Quist et al. / Lung Cance

Table 2Baseline demographic characteristics of the population (n = 29).

Age, mean (range) 63 (45–80)Men, n (%) 13 (44.8%)Participation percentage, mean (range) 73 (45–100)Occupation

Unemployed, n (%) 2 (6.9%)Employed, full-time, n (%) 6 (20.7%)Employed, part-time, n (%) 5 (17.2%)Retired, n (%) 16 (55.2%)

Marital statusLiving with a partner, n (%) 3 (10.4%)Married, n (%) 13 (44.8%)Living alone, n (%) 9 (31%)Widow (man/woman), n (%) 3 (10.4%)Separated/divorced, n (%) 1 (3.4%)

SmokingSmoker, n (%) 5 (17.3%)Ex smoker, n (%) 23 (79.3%)Non-smoker, n (%) 1 (3.4%)Years of smoking, mean (range) 48 (10–75)

Physical activity prior to illnessSedentary, n (%) 2 (6.9%)Under 3 h weekly, n (%) 14 (48.3%)

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At least 3 h weekly, n (%) 12 (41.4%)Over 4 h weekly, n (%) 1 (3.4%)

. Results

From October 2008 to December 2009, 258 patients with inop-rable NSCLC were screened for eligibility (Fig. 1). Twenty-nineatients were included (16 females, 13 males; median age 63 years)Table 2). All 29 completed baseline testing, however six patients20.6%) did not perform the 6-week test point due to loss of moti-ation (n = 3) or decrease in performance status (n = 3). Hence, 23atients undergoing concurrent systemic treatment were eligibleor analysis (Table 3).

.1. Supervised group training implementation, safety anddherence

There was no difference in the 6 patients who dropped out ofrom the study with respect to their stage of disease or demographicata compared to the patients completing the intervention. Thedherence rate for the remaining 23 patients who participated inhe supervised group training was 73.3%. During the pre-screeningrocess before the supervised training, 2 patients were excludedrom the physical training component (i.e. one exercise session outf twelve) due to fever (38.3 ◦C) and dizziness (haemoglobin on.20 × 109/L and had a blood transfusion in the ward). No patientshowed spontaneous or unexpected reactions (e.g. heart or respira-ory stop, hypotension, etc.) during the supervised training or anydverse events.

.2. Home training: implementation, safety and adherence

Two of the patients completed the training diaries used to mon-tor home training. Twenty-one patients did not perform the homeraining program, leading to a participation rate of 8.7%

able 3oncurrent systemic antineoplastic treatment in patients with inoperable lung can-er (23).

Diagnosis Treatment Number

NSCLC 1st line carboplatin + vinorelbine 16NSCLC 2nd and 3rd line erlotinib 2NSCLC 2nd line pemetrexed 1SCLC 1st line cisplatin + etoposide + thoracic radiotherapy 2SCLC 1st line carboplatin + etoposide 2

r 75 (2012) 203– 208 205

3.3. Physical capacity and functional capacity

Table 4 shows the results of physical capacity (VO2peak, 1RM)and functional capacity after the 6-week program. There wasa significant increase in aerobic capacity – VO2peak (p = 0.014)and functional capacity – 6 MWD (p = 0.006). There was signifi-cant improvement in strength: leg press (p < 0.001), chest press(p < 0.001), lat. machine (p = 0.049), abdominal crunch (p < 0.001),lower back (p < 0.001), and leg extension (p < 0.001).

3.4. Quality of life

The HRQOL results are shown in Table 5. There was a signifi-cant change in the parameter for ‘emotional wellbeing’ (p = 0.025)a moderate effect size of 0.38 when comparing baseline to thesix-week evaluation. However, there were no significant improve-ments in general HRQOL, fatigue, or FACT-L sub-scales (i.e., physicalwellbeing, functional wellbeing, social/family wellbeing and lung-cancer subscale).

4. Discussion

The current study is one of the first to test whether a supervised,group based physical intervention is beneficial and safe for patientswith advanced stage lung cancer while they undergo chemother-apy. According to two recently published reviews by Grangeret al. [30] and Jones et al. [31] no studies including patients withadvanced stage lung cancer have shown significant improvementsin aerobic capacity. The current study showed significant improve-ments in aerobic capacity, muscle strength, functional capacity andemotional wellbeing. There was no significant improvement in gen-eral quality of life or in lung capacity.

Twenty-three patients with lung cancer (completionrate = 79.3%) out of the 29 patients had an adherence rate of73.3% (100% = 12 training sessions) in the planned training ses-sions. In a comparable study by Temel et al. [12] a completionrate at 44% and an adherence rate of 100% were reported. Incontrast, Jones et al. [13] achieved a completion rate of 95% and anadherence rate of 85%. Our study included inoperable patients withlung cancer all of whom were undergoing chemotherapy, hence,the burden of disease was larger in our population compared withother studies [13–17]. The present exercise intervention seemsfeasible for patients with advanced stage lung cancer. None of thestudies [12–17] that tested physical training in patients with lungcancer reported adverse reactions, which is in accordance with thefindings of our study.

We demonstrated a statistically significant improvement(p = 0.024) in VO2peak and functional capacity (p = 0.006) after 6weeks of training. The clinical relevance of this finding is not yetknown. A prospective study by Kasymjanova et al. [32] showedthat patients with lung cancer with advanced disease significantlylowered their functional capacity (6 MWD) after two series ofchemotherapy (p = 0.01). Moreover, patients with low functionalcapacity before starting chemotherapy had a significantly higherdisease progression (p = 0.02) and significantly shorter lifespancompared with those with a higher functional capacity. The resultsof the two studies could indicate that improvement in functionalcapacity could be of clinical importance but randomized controlledstudies are needed to define the clinical importance of improvedVO2peak and functional capacity.

The patients in the present study achieved a significant increase

in strength of the trained muscle groups measured at 1RM anda cumulative improvement of 17% in strength after 6 weeks ofthe training program. These results are in accordance with thoseof Temel et al. [12] in which patients experienced a significant

206 M. Quist et al. / Lung Cancer 75 (2012) 203– 208

Fig. 1. Flow chart over eligible patients with advanced stage lung cancer.

Table 4Physical capacity (VO2peak, 1RM) and functional capacity (6 MWD) before and after the 6 week intervention (n = 23).

Variable (n = 23) Base mean (SD) Post mean (SD) Change (95% CI) p value

BMI 25.1 (5.0) 25.3 (4.8) 0.2 (−0.3 to 0.5) 0.076Lung capacity

FEV1 1.76 (0.70) 1.96 (0.63) 0.20 (−0.01 to 0.41) 0.061Aerobic capacity

VO2peak (L/min) 1.48 (0.41) 1.57 (0,41) 0.09 (0.02 to 0.16) 0.014Functional capacity

6 MWD (m) 524.7 (88.5) 564.0 (88.6) 39.3 (12.5 to 66.1) 0.006Muscle strength

Leg press (kg) 70.4 (26.9) 86.9 (28.8) 16.5 (11.5 to 21.7) 0.000Chest press (kg) 30.8 (13.2) 40.3 (16.3) 9.5 (6.4 to 12.7) 0.000Lat machine (kg) 35.8 (13.8) 39.2 (17.6) 3.4 (0.0 to 6.7) 0.049Abdominal crunch (kg) 24.9 (10.7) 29.5 (11.3) 4.6 (3.2 to 6.0) 0.000Lower back (kg) 35.3 (14.1) 43.1 (16.2) 7.8 (4.8 to 10.8) 0.000Leg extension (kg) 38.6 (15.5) 45.1 (18.9) 6.5 (4.1 to 8.9) 0.000

Table 5Functional Assessment of Cancer Therapy (FACT-L) before and after the 6-week intervention (n = 23).

Variable (n = 23) Baseline mean (SD) Follow-up mean (SD) Change (95% CI) p value

FACT-L total score 91.7 (16.7) 94.3 (14.2) 2.6 (−4.2 to 9.4) 0.452Physical well-being 20.3 (5.0) 20.3 (4,0) 0.0 (−2.1 to 2.2) 0.973Social well-being 22.9 (3.6) 21.8 (5.4) −1.1 (−2.8 to 0.6) 0.182Functional well-being 15.9 (6.5) 16.0 (5.1) 0.1 (−2.3 to 2.4) 0.940Emotional well-being 14.3 (4.7) 16.1 (4.3) 1.8 (0.3 to 3.4) 0.025Lung cancer subscale 18.3 (4.6) 20.1 (2.9) 1.8 (0.4 to 4.0) 0.099Trial outcome index 54.5 (11.8) 56.4 (9.8) 1.9 (−3.2 to 7.0) 0.442FACT fatigue scale 73.4 (14.2) 74.2 (12.4) 0.8 (4.7 to 6.1) 0.780

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M. Quist et al. / Lung

mprovement (p < 0.03) in strength in a single (elbow muscle)ut of 6 muscle groups. In contrast to these results, Spruit et al.15] found no significant advancement in muscle strength. Theignificant improvement in the current study can most likelye explained by the higher training intensity (70–90% of 1RM)nd the progressive strength training. The results are accordanceith the RCT study carried out in our group with cancer patientsith mixed diagnoses and who were undergoing chemotherapy

18].There was significant improvement in emotional well-being

ith a moderate effect size of 0.38 while there was no signifi-ant improvement in general HRQOL. In contrast, the study byemel et al. [12] found significant improvement in the lung specificACT-L (p < 0.05). Jones et al. [13] found significant improvementn “fatigue” (p = 0.03) and “functional wellbeing” (p = 0.007) andRQOL (p = 0.03). A possible explanation for the improvement inmotional well-being could be the inclusion in our study of relax-tion training which, beyond the effect of general HRQOL, mightnfluence the patients as seen in a review study [33]. This minimallymportant difference in emotional well-being is 2–3 points [34], ahange of 1.8 points in this study, shows a trend towards clinicalignificance and needs to be investigated through further stud-es. It has been suggested [35] that an improved HRQOL, includingmotional well-being, is a prognostic factor for survival in patientsith advanced lung cancer although no studies have demonstrated

mprovement in general HRQOL in patients with lung cancer withdvanced disease. This indicates that these patients are in a lifeituation (a five-year overall survival rate of 9%) in which it maye unrealistic to expect that 6 weeks of physical training could

mprove their HRQOL.There are several limitations to the current study. This is a

on-randomized, phase II study of 23 patients with lung cancernd as such the results cannot be generalized for all patients withdvanced stage lung cancer. To confirm the effects, the interventionhould be investigated in a randomised controlled study. Anotherimitation of the present study is the selection bias. All of theatients who met the inclusion criteria were screened and thenffered participation in the study. It is therefore likely that the par-icipants were considerably more motivated than those who did notant to participate (n = 83). This might indicate that these patientso not have a need for rehabilitation or find the programme tooime demanding. Moreover, the patients with lung cancer withrain metastasis, bone metastasis and poor performance statusere not included.

Another weakness of the study is that the professionals whoonducted the physical training also collected the data. This couldotentially have led to bias.

Home training was not a valid option in this population sincenly 2 out of the 29 patients included in the intervention actu-lly performed the home-based training. The patients’ reasons forhis low adherence rate have been the subject in a recently pub-ish qualitative analysis [36]. Although the patients claimed thathe home-based training program was easy to understand, thereere substantial reasons why they did not manage to do it. Typ-

cally, they stated a lack of self-discipline and expressed doubtsbout yielding any benefits from it that would equal the sensationhey felt with their bodies when finishing the supervised trainingrogram (muscle-strength training and wellbeing). These factors

n combination with shortness of breath, physical annoyances, full-lown feeling of fatigue and a general “bad” mood when withoutheir exercise partners were the most important barriers from theatients’ perspectives [36].

The strength of the current study is its use of well-validatedbjective tests (estimated VO2peak, 1RM, 6 MWD); a psychometricest (FACT-L) and drop-out analyses both of the included patientsnd those who did not complete the intervention.

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r 75 (2012) 203– 208 207

Pyrol et al. [37] and Jones et al. [31] pointed to the importanceof using the right test to measure VO2peak. We used an estimatedWatt-max test that has been validated by our research group [23]in the present study.

5. Conclusion

The Study shows that patients with advanced stage lung can-cer can carry out a 6-week supervised, structured and groupbased out-patient training program and improve their physicalcapacity, functional capacity and emotional wellbeing. The studyfurthermore shows that home training used in supplement to thesupervised training in this group of patients is not a realistic optiondue to the lack of adherence. More studies are needed in this areato confirm this point.

The completion rate (79%) and adherence rate (73%) as well asthe absence of adverse reactions indicate that it is safe for patientswith advanced stage lung cancer to undertake twice weekly groupbased, supervised physical training.

Conflict of interest

The authors made no disclosures.

Acknowledgements

This research was supported by grants from The Simonsen Foun-dation, The Wedell-Wendellsborgs Foundation, The Wilma PeetzGrant, Roche A/S, The Novo Nordisk Foundation and The DanishCancer Society.

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