Volume 38, Issue 6 , Pages 950-956, December 2009
Randomized Controlled Pilot Study of Neuromuscular Electrical Stimulation of the Quadriceps in Patients with Non-Small Cell Lung Cancer
Article Outline
Abstract
Patients with lung cancer experience muscle wasting and weakness. Therapeutic exercise may be beneficial but is not always practical. An alternative approach may be neuromuscular electrical stimulation (NMES) of the quadriceps muscles, but this has not been formally examined in patients with cancer. Thus, we have undertaken this pilot study to assess feasibility and inform the design of future studies. Sixteen patients were randomized to receive usual care (control group) or usual care plus NMES for four weeks. NMES consisted of daily stimulation to both thighs for up to 30
minutes (frequency 50Hz, “on” cycle 11%–25%). Adherence was assessed by a self-report diary and a semistructured evaluation form. Quadriceps muscle strength, exercise endurance, and free-living physical activity were assessed using a Cybex NORM dynamometer, an endurance shuttle walk test, and an ActivPAL accelerometer (mean daily step count), respectively. Changes in outcome from baseline were compared between groups by mean differences and their 95% confidence intervals using independent t-test (P=0.05). Median (range) adherence to the program was 80% (69%–100%). All patients found the NMES device easy to use. Changes in outcome favored the NMES group, with mean differences of 9.4 Nm (21%) in quadriceps muscle strength, 768 steps (15%) in free-living activity, and 138 m (8%) in exercise endurance, but none of the differences were statistically significant. In conclusion, NMES warrants further study in patients with lung cancer.
Key Words: Cachexia, electrical stimulation, exercise, lung cancer, muscle wasting, rehabilitation
Introduction
Cachexia is common in patients with incurable non-small cell lung cancer (NSCLC), leading to muscle wasting and weakness. Together, these changes may impair physical function and quality of life.1, 2, 3 Anti-cancer treatments also may cause fatigue and lead to physical inactivity and further muscle deconditioning.4 Effective treatments are lacking and new approaches are required.
One option is therapeutic exercise.5 However, there are issues with acceptability, and only about half of patients with cancer or who have received curative treatment for cancer are willing and able to complete an exercise program.6, 7, 8 Furthermore, patients experiencing breathlessness and/or fatigue at low levels of exertion may find some forms of exercise, for example, walking or circuit training, too demanding.
One approach that avoids some of these difficulties is neuromuscular electrical stimulation (NMES) of the quadriceps muscles. NMES can be self-administered at home while seated and, being a passive intervention, demands less motivation and change in lifestyle than traditional forms of exercise. The treatment is administered by a small, battery-operated stimulator unit, which, via self-adhesive electrodes, produces controlled contraction and relaxation of the underlying muscle equivalent to 20%–50% of the patient's maximum voluntary contraction. Treatment regimens generally consist of a 30-minute period of stimulation five to seven times a week. In healthy subjects, NMES leads to similar changes in muscle biochemistry9, 10, 11 and improvements in strength as volitional training.12 NMES has increased quadriceps muscle strength by 10%–40% in patients with chronic obstructive pulmonary disease (COPD) or heart failure, with improvements in exercise capacity and health-related quality of life also seen in some studies.9, 10, 13, 14, 15, 16
NMES has not been formally examined in patients with cancer to our knowledge. Thus, the primary aim of this pilot study was to explore if it is a feasible and tolerable intervention for patients with NSCLC. Secondary aims were to examine efficacy around muscle strength, exercise endurance, and physical activity levels for the purpose of informing the design of future studies.
Methods
Subjects
Patients with NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from thoracic oncology clinics. Medication had to have been stable for at least one week. Patients were excluded if they had received radiotherapy or chemotherapy within the last four weeks, lost >10% of their premorbid body weight, had ischemic heart disease, had a cardiac pacemaker, or had any problem that might affect their ability to undertake a walking exercise test. Patients gave written informed consent, and the study was approved by the Nottingham Research Ethics Committee (ref. 05/Q2402/62) and registered with Current Controlled Trials (ISRCTN 86814835).
Measurements
AcceptabilityTreatment acceptability was assessed by patients' adherence to the recommended duration and frequency of NMES, as recorded in a self-report daily diary, and also by patients' experience of NMES, as recorded using a semistructured evaluation form on completion of the program. The form used an open question to obtain any good or bad comments about NMES, for example, any difficulties with its use, and specifically asked patients to record if they would be prepared to use it again in the future.
Quadriceps Muscle StrengthStrength was assessed with a Cybex NORM dynamometer (Cybex, Division of Lumex, Inc., New York, NY, USA; software version 2.06) using a protocol previously used in patients with NSCLC.17 Patients are seated with the padded lever arm of the dynamometer placed just above the ankle of the dominant leg, that is, the one preferred to kick a ball with, and undertake 30 maximal isokinetic contractions through a fixed range of movement from knee flexion to extension at 180°/second. The first five repetitions are for familiarization purposes; maximum strength is indicated by the peak torque (Nm) obtained in the remaining 25 repetitions.17, 18
Exercise EnduranceEndurance was assessed using the endurance shuttle walk test (ESWT; Department of Respiratory Medicine, Glenfield Hospital, Leicester, UK).19 Patients walk around two cones 10m apart at a constant pace dictated by an external audio signal from a tape cassette player. The test kit contains eight cassettes, covering a range of walking speeds from 1.78 to 6km/hour. For each patient, the walking speed is selected to be closest to a workload equivalent to 85% of the patient's predicted peak oxygen uptake. This is calculated from the maximum walking speed achieved by the patient in a prior incremental shuttle walk test (ISWT). This is carried out in an identical manner to the ESWT except that the frequency of the audio signals and walking speed progressively increases.20, 21 The ESWT is continued until the patient is unable to maintain the pace or if the maximum duration of the test is reached (20minutes). The distance walked in meters is recorded.
Physical activity was assessed as mean daily step count measured over a period of one week using an ActivPAL™ monitor (PAL Technologies Ltd., Glasgow, UK). This small, lightweight (20×30×5mm, 20g) uniaxial accelerometer is applied to the mid-thigh using adhesive pads and is worn continuously except for when showering/bathing or during NMES. It is accurate over a wide range of walking speeds22 and is not falsely triggered by travel in a motor vehicle.23
Forced expiratory volume in one second and forced vital capacity were measured, with participants seated, as the best of three recordings using a dry wedge spirometer (Vitalograph Type R Spirometer, Buckingham, UK).
Neuromuscular Stimulation
Neuromuscular stimulation was delivered by a MicroStim Exercise Stimulator MS2v2 (Odstock Medical Limited, Wiltshire, UK) using two 7cm round PALS® Platinum self-adhesive electrodes (Axelgaard Manufacturing Co. Ltd., Lystrup, Denmark) placed on the anterior thigh over the body of the quadriceps muscle. The program consisted of daily stimulation to one thigh at a time for 15minutes, increasing to 30minutes after one week. One treatment session for both thighs would, therefore, last 30–60minutes in total. Pulse waveform (symmetrical biphasic squared), frequency (50Hz), and width (350microseconds) were constant throughout the four-week period. The amplitude (device output 0–120mA, tested across 1000Ω) was initially set to elicit a visible and comfortable muscle contraction; patients were encouraged to subsequently increase the amplitude as tolerated. The proportion of the treatment duration which was active stimulation, that is, the duty cycle, increased on a weekly basis from 11% to 18% to 25%, remaining constant thereafter. The program was based on one found to be of benefit in patients with COPD.13 The stimulation parameters were selected to favor gains in strength over endurance (frequency), minimize skin irritation (pulse width), and allow for sufficient recovery of the muscles between contractions (duty cycle).24
Protocol
All assessments, except free-living physical activity, were carried out in a human performance laboratory at the same time of day (±1hour). Patients were given written instructions to avoid caffeine for one hour, large meals for two hours, and excess alcohol the night before the tests and to keep the times of any drug administration constant. Verbal encouragement was minimal and standardized. Patients were randomized 1:1 into NMES or control groups (no intervention) using randomized permuted blocks generated by an independent researcher and concealed using opaque envelopes.
Over a five-week period, all patients attended the hospital three times and received two home visits; those in the NMES group received two additional home visits. The initial home visit was to begin recording free-living physical activity. One week later, at hospital, patients undertook spirometry and two ISWT, 30minutes apart, the first for familiarization purposes. The maximal walking speed achieved in the second ISWT was used to determine the ESWT walking speed. The next day, an ESWT was undertaken, followed, after 30minutes rest, by assessment of quadriceps muscle strength. Those receiving NMES were taught how to use the stimulator and received two additional weekly home visits to facilitate optimal usage and adherence. After three weeks, all patients were visited at home to begin recording free-living physical activity. One week later, at the final hospital visit, the ESWT, quadriceps muscle strength, and spirometry were repeated and the evaluation form was completed.
Statistical Analysis
Normally distributed data were expressed as mean ± standard deviation. Age, body mass index, spirometric values, and baseline values and changes in quadriceps muscle strength, exercise endurance, and free-living physical activity were compared between the control and NMES groups using Student's t-test. Change between groups was compared by mean differences and their 95% confidence intervals. Calculations were performed using Statistical Package for the Social Sciences (SPSS) version 14.0 (SPSS Inc., Chicago, IL, USA). A P value of <0.05 was considered as statistically significant.
Results
Of 53 patients approached over a two-year period which commenced in January 2006, 16 completed the study (Fig. 1; Table 1). All patients were able to complete all assessments. In the NMES group, because of equipment failure, quadriceps muscle strength and free-living physical activity data were lost in one patient each. Three patients (two in the control group) reached the maximum duration (20minutes) of the ESWT at baseline; only one in the control group achieved this subsequently.
Fig. 1
Study flow diagram.
Table 1. Patient Detailsa
| Control (n=8) | NMES (n=8) | P-value | |
|---|---|---|---|
| Sex (male/female) | 5/3 | 4/4 | — |
| Age (years) | 64 (5) | 56 (9) | 0.65 |
| Eastern Cooperative Oncology Group performance status (0/1) | 2/6 | 2/6 | — |
| Body mass index (kg/m2) | 26.2 (1.2) | 27.2 (2.8) | 0.39 |
| Diagnosis | |||
| Adenocarcinoma | 3 | 5 | — |
| Squamous | 2 | 3 | |
| Large cell | 1 | 0 | |
| Undifferentiated | 2 | 0 | |
| Stage (III/IV) | 2/6 | 3/5 | — |
| Treatment history | |||
| Surgery | 1 | 2 | — |
| Chemotherapy | 8 | 8 | |
| Radiation therapy | 3 | 3 | |
| Medication | |||
| Nonopioid analgesic | 4 | 0 | — |
| Weak opioid analgesic | 4 | 1 | |
| Inhaled bronchodilator | 8 | 2 | |
| Inhaled corticosteroid | 1 | 1 | |
| Oral bronchodilator | 1 | 0 | |
| Hormone therapy | 1 | 2 | |
| β-blocker | 0 | 1 | |
| Other | 8 | 5 | |
| Spirometry | |||
| FEV1 (L) | 1.64 (0.78) | 1.71 (0.69) | 0.87 |
| FVC (L) | 2.56 (0.63) | 2.63 (1.01) | 0.87 |
| FEV1/FVC (%) | 59 (21) | 66 (11) | 0.72 |
| Quadriceps muscle strength (Nm) | 57 (23) | 46 (22) | 0.34 |
| Distance walked on ESWT (m) | 845 (517) | 660 (550) | 0.50 |
| Mean daily step count | 5554 (4581) | 5061 (1516) | 0.78 |
aExpressed as mean (standard deviation) unless otherwise stated. |
There were no significant differences in age, body mass index, or spirometry nor in the baseline values of quadriceps muscle strength, exercise endurance, and free-living physical activity between the control and NMES groups (Table 1). To date, 13 have died, with a median (range) survival of 40 (10–67) weeks.
Use of NMES
Patients reported undertaking NMES for a median (range) of 80% (69%–100%) of the overall recommended treatment time, often while carrying out activities such as watching television or completing a crossword. The main reason for missing a treatment session was another activity taking priority. No serious adverse events were reported. Three patients reported minor muscle discomfort after the first day of use, lasting about one hour. One patient each commented that the treatment sessions sometimes felt long or restricted other activities. At the end of the study, all patients provided positive comments about the ease of use of the device and three comments about its impact: “The stairs are easier now,” “I am better at standing up after sitting around,” and “My legs feel more solid when I am walking.” All were prepared to use NMES again.
Physical Performance
Quadriceps muscle strength and free-living physical activity levels improved by a mean of 7.4Nm (22%) and 136 steps (11%), respectively, in the NMES group, whereas exercise endurance deteriorated by a mean of 20m (4%). This compared with essentially no change −2.0Nm (0%), a mean deterioration of 633 steps (3%), and 159m (12%) in quadriceps muscle strength, free-living physical activity levels, and exercise endurance, respectively, in the control group (Table 2). The mean difference in outcomes between the two groups varied from 8% to 21% in favor of the NMES group; however, the degree of difference was not statistically significant (Table 2). On an individual patient basis, for each of the outcome measures, consistently more patients improved in the NMES group than in the control group (Table 2).
Table 2. Mean (SD) Absolute and Percentage Change in Outcome Measures and Individual Response
| Control Group | NMES Group | Difference in Change (95% CI) | P-value | |
|---|---|---|---|---|
| Quadriceps muscle strength | ||||
| Absolute (Nm) | −2.0 (9.0) | 7.4 (10.3) | 9.4 (−1.3, 20.7) | 0.08 |
| Percentage | 0 (26) | 22 (31) | 21 (−10, 53) | 0.17 |
| Improved/deteriorated (n) | 1/7 | 6/1 | ||
| Distance walked on ESWT | ||||
| Absolute (m) | −159 (222) | −20 (254) | 138 (−118, 394) | 0.27 |
| Percentage | −12 (31) | −4 (51) | 8 (−37, 54) | 0.70 |
| Improved/unchanged/deteriorated (n) | 1/1/6 | 3/0/5 | ||
| Mean step count per day | ||||
| Absolute (steps) | −633 (1335) | 136 (2660) | 768 (−1530, 3066) | 0.48 |
| Percentage | −3 (26) | 11 (52) | 15 (−35, 65) | 0.49 |
| Improved/deteriorated (n) | 2/6 | 4/3 | ||
Discussion
Our findings suggest that NMES is acceptable and tolerable to patients with NSCLC. Adherence over a longer period will need to be formally evaluated, and it may help to halve the overall treatment duration by stimulating both thighs simultaneously. We found trends, but no significant differences, between the NMES and placebo groups, and efficacy requires further exploration in adequately powered studies. Our data can be used to inform sample size calculations.
The use of therapeutic exercise to improve physical function and quality of life in patients with cancer has mostly involved those receiving curative treatment, with limited experience in patients with incurable cancer.5, 6 Nonetheless, programs utilizing traditional forms of exercises experience difficulties with recruitment and retention.6 We consider NMES a more practical approach worth exploring. NMES has been used therapeutically for at least 20 years, mainly as an adjunct in the rehabilitation of patients with neurological conditions, for example, post-stroke or spinal cord injury.25 More recently, the use of NMES has been examined in patients with COPD or heart failure.9, 10, 13, 14, 15, 16 After several weeks of use, NMES results in similar beneficial changes in muscle as with other forms of exercise, such as improved oxidative capacity resulting from changes in fiber type and levels of oxidative enzymes.9, 10, 11 High or low frequencies of stimulation may result in a preferential improvement in either muscle strength or endurance by targeting type II or type I muscle fiber types, respectively.24, 26 In patients with cancer, the literature appears limited to a case report of the beneficial effect of NMES in a patient with lung cancer and brain metastases.27
The mean improvement in quadriceps muscle strength in the NMES group was 22%. With similar magnitudes of change in quadriceps muscle strength, others also have reported improvements in exercise capacity/endurance assessed by various means, for example, 6 minute walk test.10, 13, 14 By comparison, we found that exercise endurance assessed by the ESWT deteriorated in the NMES group. Differences in the type and duration of stimulation are possible explanations. For pragmatic reasons, we used a stimulation regimen reported to be successful in patients with COPD, but the high frequency (50Hz) of stimulation may favor improvements in muscle strength rather than endurance.13, 26 We also evaluated NMES after four weeks compared with 6–10 weeks in other studies, and perhaps this was too short for changes in endurance to appear. Other possible reasons include the different pathological processes that may exist in patients with cancer and the use of different outcome measures.
Three of the 16 patients reached the maximum duration of the ESWT (20minutes) at baseline, suggesting that it is not an ideal assessment for the range of abilities found in this patient group. Furthermore, its inclusion limited the rate of recruitment, as many potential participants were excluded because of contraindications to undertaking an exercise test. Ultimately, formal exercise tests are an artificial assessment of what patients actually do on a day-to-day basis, and the assessment of free-living physical activity was included as a potentially more relevant outcome.28 The mean daily step count improved in the NMES group and decreased in the control group. We are currently developing this outcome measure by examining the acceptability and optimal duration of monitoring in a larger group of patients with lung cancer.
Undertaking controlled studies of NMES is challenging because of the difficulties of blinding a treatment that produces an obvious contraction of the muscle. We considered a no-treatment control group sufficient for this pilot study. However, it is possible that our findings reflect that those in the NMES group derived greater psychological benefit from undertaking the intervention and/or the two additional visits from the physiotherapist. This could have enhanced their motivation to be more active and to perform better in the assessments. Future studies could consider the use of an active control group, for example, one that would receive a once weekly stimulation program, unlikely to be of physiological benefit, but involving similar contact time with professionals.
In conclusion, NMES appears an acceptable and tolerable exercise intervention and one worth pursuing in patients with lung cancer. If successful, it may be best offered as a proactive supportive care intervention soon after diagnosis to preserve muscle and physical function as best as possible, rather than waiting until the cachectic process is advanced.
Acknowledgments
The authors thank Sarah Lewis for statistical advice and all the patients who took part in this study. The authors would like to pay particular tribute to Simon Mockett, who co-supervised the lead author and supported this work from its inception until his unexpected death in 2007.
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This study was made possible by funding from the Nottinghamshire, Leicestershire and Derbyshire Research Alliance.
PII: S0885-3924(09)00711-8
doi:10.1016/j.jpainsymman.2009.05.011
© 2009 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Volume 38, Issue 6 , Pages 950-956, December 2009
