This study was a pilot single-blinded RCT approved by the Ethics Committees of Sir Charles Gairdner Hospital (SCGH) and Royal Perth Hospital (RPH), Perth, WA, Australia (approval numbers 2011/105 and RA-11/033) and Curtin University, Perth, WA, Australia (approval number HR178/2011). The trial was prospectively registered (15/08/2011) with the Australian New Zealand Clinical Trials Registry (ACTRN12611000864921).

Data collection was performed between February 2012 and April 2014. Measurements were collected in people 6–10 weeks after lobectomy for NSCLC (stages I–IIIA) or, for those who required post-operative chemotherapy, 4–8 weeks after their last chemotherapy cycle. Exclusion criteria comprised: presence of any co-morbid condition that could compromise safety during assessments; severe neuromusculoskeletal limitations; participation in a program of supervised exercise training in the last 3 months; and inability to understand spoken or written English. Participants were recruited from outpatient clinics and referrals to the pulmonary rehabilitation programs at two hospitals and a private thoracic surgery clinic.

After obtaining written informed consent, baseline assessments were undertaken over 2–3 days, with a minimum of 24h between each assessment day. Participants were then randomized to an exercise group (EG) or a control group (CG). The randomization sequence was generated and managed by an independent researcher using a computer and concealed using sequentially numbered opaque envelopes. The sequence was stratified according to the hospital from which the participant was recruited and for the use (or not) of adjuvant chemotherapy.

Participants were reassessed on completion of the 8-week intervention period. The primary outcome was exercise capacity. Secondary outcomes comprised physical activity and sedentary behavior, peripheral muscle force, HRQoL, fatigue, feelings of anxiety and depression, and lung function. The primary investigator, who was responsible for the baseline and post-intervention period assessments, was not aware of whether a participant had been allocated to the EG or the CG. For both baseline and post-intervention period assessments, the first and second assessment days took place at the hospital at which the participants had received their treatment.

Measurements performed on the first assessment day were:

• (i)

  6MWD (45-m straight course within an enclosed corridor. Two tests, separated by a 30-min rest period, were conducted and the best 6MWD was recorded as the test result).15,16

• (ii)

  HRQoL (Medical Outcomes Study Short-Form 36 general health survey (SF-36),17 Functional Assessment of Cancer Therapy – Lung scale (FACT-L),18 and European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire Core-30 [EORTC QLQ-C30]19).

• (iii)

  Feelings of anxiety and depression (Hospital Anxiety and Depression Scale [HADS]20).

• (iv)

  Fatigue (Functional Assessment of Chronic Illness Therapy – Fatigue subscale [FACIT-Fatigue]21).

• (v)

  Isometric handgrip force (measured using a hydraulic hand dynamometer [Jamar; JA Preston Corporation; USA]). Peak handgrip force was assessed bilaterally, with the elbow at 90° flexion and the forearm and wrist in a neutral position.22

Participants were also given two physical activity monitors (the SenseWear armband23,24 and the Stepwatch activity monitor25) to be worn over 7 consecutive days. A minimum of 4 full days of data (defined as ≥10h/day of monitoring), including one weekend day, were required for participants’ data to be included in analyses. Data on energy expenditure (i.e., metabolic equivalent units [MET]), provided by the SenseWear armband, and daily step count, provided by the Stepwatch, were averaged for analysis. Using measures of MET derived from the SenseWear armband, proportion of time spent in three domains were calculated: (i) sedentary behavior (≤1.5 MET); (ii) light intensity physical activity (>1.5 and ≤3 MET); and (iii) moderate-to-vigorous intensity physical activity (>3 MET).26

Following the completion of 7 days of activity monitoring, participants returned for the second assessment day, during which measures were made of spirometry, lung volumes, and gas transfer.27–30 The Medgraphics Elite Series DX plethysmograph (Medical Graphics Corporation, USA) was used. Thereafter, a symptom-limited ramp cycle-ergometry cardiopulmonary exercise test (CPET) was undertaken on an electronically braked bicycle ergometer (Corival; Lode, The Netherlands) in accordance with published guidelines.31 Breath-by-breath measurements were collected (Ultima™ CardiO2®; MGC-Diagnostics, USA). Blood pressure was measured every 2min by automated sphygmomanometry. Twelve-lead electrocardiography was used and arterial oxygen saturation measured via pulse oximetry (SpO2) was continuously monitored (Radical; Masimo Corporation, USA). The modified BORG scale (0–10) was used to quantify dyspnea and leg fatigue prior to starting the test, each minute during the test, and on test completion. Measures were collected of peak rate of oxygen consumption (VO2peak), VO2 at the anaerobic threshold (AT) maximum work rate (Wmax), and oxygen pulse (O2 pulse), which was calculated by dividing the VO2peak by the maximal heart rate.31 The Wmax and measures of VO2peak were expressed in absolute values and as a percentage of the predicted value in a healthy population.32

The third assessment day comprised the measurement of isometric quadriceps muscle torque.33 It was performed in the upright seated position using the HUMAC NORM isokinetic dynamometer (CSMi; Stoughton, USA). The dominant leg was chosen and participants were asked to perform five maximum contractions of the quadriceps at 60° knee flexion. Each contraction was separated by 60s. The contraction that generated the highest torque, and was within 5% of another effort, was recorded as the test result. Measures were expressed in absolute values and as a percentage of the predicted value in a healthy population.33 The measurement of isometric quadriceps muscle torque took place at the University. As the University is approximately 15km from either of the hospitals, participants were given the option to decline this assessment.

Participants in the EG underwent an 8-week exercise training program aimed at improving aerobic capacity and muscle strength. This program was embedded within the exercise training programs at SCGH and RPH. It comprised individual, supervised training three times per week delivered by senior physical therapists. Each session was 60min in duration. In the event that a participant could only attend two supervised sessions per week, they were provided with a cycle ergometer (OBK600A; Orbit fitness equipment, Perth, WA, Australia) to use at home for one training session per week. Each class comprised aerobic (walking/cycling) and resistance training (upper/lower limbs). Adherence to exercise training was defined as a completion rate of ≥60% of training sessions (i.e., ≥15 training sessions) and reported by the senior physical therapists to the investigators.

Participants walked in a 100-m long corridor or on a treadmill for 20min. For corridor walking, the initial average speed was set at 80% of the average 6MWT speed.34 For instance, for someone with a baseline 6MWD=450m, the walking goal was calculated as follows:

For treadmill walking, the initial average speed was set at 70% of the average 6MWT speed.34 Average walking speed was increased if the participant was able to walk for 20min continuously providing symptoms and SpO2 were within acceptable limits (≥88%). Cycling consisted of 10min of endurance training (initial work rate was set at 60% of the Wmax achieved during the CPET) and two periods of 2min of power training (initial work rate was set at 80% of the Wmax achieved during the CPET performed at the baseline assessment).

The resistance training comprised step-ups (undertaken within parallel bars in two sets of 10 repetitions) and exercises with hand weights for the biceps brachii muscle (elbow flexion) and deltoid muscle (short-lever shoulder abduction). Upper limb training was undertaken in three sets of 10 repetitions (initial weights: 1.5kg for women and 2kg for men).

Participants in the CG were instructed to continue to perform their usual activities during the period of the study. They received weekly phone calls from a research assistant, which consisted of general conversation as well as standardized questions about their health and well-being. These phone calls allowed the investigators to maintain contact with those in the CG and optimize their retention in the study and also served to minimize bias resulting from differences in attention provided by the investigators to the participants during the intervention period.

Statistical analyses were performed using SPSS® (Statistical Package for Social Sciences, version 22.0). As this is a pilot RCT, sample size was determined by the number of participants recruited during the period allowed for commencement and completion of the study (i.e., from February 2012 to April 2014). Analyses were undertaken according to the intention-to-treat principle. The distribution of data was analyzed via frequency histograms and the Shapiro–Wilk test. For normally distributed data, both within- and between-group differences were assessed using two-way repeated measures ANOVA. Between-group differences are reported as the mean difference and 95% confidence interval (CI) (F values are provided in the tables). Regarding non-normally distributed data, within-group differences were assessed using a Wilcoxon test whereas between-group differences were assessed using a Mann–Whitney test. For all analyses, a p value <0.05 was considered significant. Data are expressed as either mean±standard deviation or median [interquartile range].

Baseline and post-intervention period measures are presented in Table 2.

On completion of the intervention period, no between-group differences were observed in light intensity physical activity, moderate-to-vigorous intensity physical activity, sedentary behavior and daily steps (Table 3). At baseline, isometric quadriceps torque and isometric handgrip force in both groups were >90%pred (Table 3). On completion of the intervention period, no between-group differences were observed in these outcome measures (Table 3).

No between-group differences were observed in the component summary scores or individual domains of the SF-36, the scores of the FACT-L and EORTC QLQ-C30 (Table 4).

No between-group differences were observed in fatigue (FACIT-Fatigue median [interquartile range]; EG, baseline 43 [43–49], post-intervention 47 [38–52]; CG, baseline 39 [26–40], post-intervention 38 [28–42]; p=0.82 for between-group difference) or feelings of anxiety (HADS: mean±SD anxiety score; EG, baseline 3±2, post-intervention 5±4; CG, baseline 2±2, post-intervention 4±5; p=0.17 for between-group difference) and depression (HADS: mean±SD depression score; EG, baseline 2±2, post-intervention 4±5; CG, baseline 3±3, post-intervention 4±3; p=0.40 for between-group difference).

No between-group differences were observed in any measure of lung function (mean difference, 95% CI for between-group difference in change from baseline to post-intervention: FEV1 −0.09 [−0.22 to 0.03]L; FVC −0.12 [−0.43 to 0.18]L; total lung capacity −0.03 [−0.61 to 0.54]L and single breath diffusing capacity for carbon monoxide −1.4 [−3.3 to 0.6]).

On completion of the intervention period, no between-group differences were observed in any of the other measures. The lack of between-group difference in physical activity or sedentary behavior following exercise training in people following lung resection for NSCLC is in agreement with data from a previous RCT41 and is likely to be due to the minimal impairment in these measures at baseline. The baseline values of daily steps reported in the current study is also similar to the results of an earlier work that assessed people within four weeks of hospital discharge following lobectomy for NSCLC (7978±4486steps/day).42 Further, a recent study published by our group has demonstrated that people following curative intent treatment for NSCLC spend as much time in moderate-to-vigorous intensity physical activity and sedentary behavior as their healthy counterparts.43

Our study did not demonstrate any change in isometric quadriceps muscle force or handgrip force. The reasons for this may relate to: (i) insufficient training load to induce change; (ii) lack of statistical power, especially for changes in quadriceps force as only a small number of participants chose to attend the University for this assessment; and (iii) minimal impairment in these measures at baseline. The lack of improvement in muscle force demonstrated in this study is in agreement with a previous RCT,44 which investigated the effect of a 12-week training program initiated immediately following surgery for NSCLC. Similar to the current study, this earlier study was also likely to be underpowered to demonstrate a between-group difference in quadriceps force. A larger RCT (n=45) of resistance exercise training for people in stage I to III lung cancer demonstrated significant between-group differences in quadriceps torque on completion of a 12-week training program.45 Of note, this RCT only included people who presented with quadriceps muscle weakness, defined as either a quadriceps muscle force<70% of their predicted value or a decrement of 10% in quadriceps muscle force following lung cancer treatment.45 Therefore, in people with lung cancer, resistance training may be most effective in those with demonstrated muscle weakness.

Our results showing no difference in HRQoL on completion of exercise training in people following lung resection for NSCLC corroborate findings of earlier studies.14,44 We used both a generic questionnaire and two disease-specific HRQoL questionnaires, the latter of which were expected to be more responsive than the questionnaires used in an earlier work44; however, we were unable to demonstrate any effect of exercise training on HRQoL. The current study also demonstrated no differences in fatigue or feelings of anxiety and depression on completion of exercise training. Similar to measures of peripheral muscle force, it is possible that the lack of improvement in HRQoL, fatigue and feelings of anxiety and depression may be attributable to near normal baseline scores, suggesting minimal impairment in these domains. Specifically, in the EG, the physical component score (PCS) and the mental component score (PCS) of the SF-36 at baseline were similar to the mean normal scores of 50±10 (PCS) and 53±10 (MCS) reported for the Australian population.46 Likewise, at baseline, participants did not present with fatigue21 and had low scores for feelings of anxiety and depression (HADS anxiety and depression scores ≤7). This suggests that there was little scope for improvement with exercise training.