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The effect of radical treatment and rehabilitation on muscle mass and strength: A randomized trial in stages I–III lung cancer patients

Lung Cancer

Abstract

Objectives

Little is known about the impact of an oncological treatment on muscle mass and strength in patients with lung cancer and the impact of a subsequent rehabilitation program. This study investigates the effect of radical treatment and post-treatment pulmonary rehabilitation on muscle mass and strength in patients with lung cancer and the relationship between muscle mass and strength.

Methods

Lung cancer patients, candidate for radical treatment, were randomly (2:1) allocated after radical treatment to either standard follow up (CON) or a 12-week rehabilitation training program (RT). Muscle mass was estimated by bioelectric impedance and CT-scan. Muscle strength was estimated by measuring quadriceps force (QF) with a hand held dynamometer. All variables were measured before (M1) and after radical treatment (M2), and at the earliest 12 weeks after randomization (M3). Data are presented as means with standard deviation.

Results

45 lung cancer patients (age: 65 years (9)) participated in the study. At M2, both muscle cross sectional area (MCSA) and QF were significantly decreased (p < 0.05). 28 patients were randomized. 13/18 RT and 9/10 CON patients ended the trial. At M3, RT-patients improved significantly their MCSA compared to CON-patients (ΔMCSA: 6 cm2 (6) (p = 0.003) vs. 1 cm2 (11) (p = 0.8)).

Conclusion

Muscle mass and strength: (1) are decreased at presentation in a substantial part of lung cancer patients; (2) are significantly negatively affected by radical treatment and (3) completely recover after a 12 week structured rehabilitation program, whereas a further decline was observed in CON-patients.

Keywords: Lung cancer, Radical treatment, Body composition, Muscle weakness.

1. Introduction

In cancer patients, muscle weakness the result of skeletal muscle wasting (loss of muscle mass) and decreased muscle strength [1] has been associated with increased morbidity [2] and [3], excessive fatigue, reduced performance status, lack of energy [4] , poor quality of life, poor treatment response and survival [5] and [6]. Muscle mass is an even more accurate predictor of survival than BMI [7], [8], and [9]. Cancer-related muscle wasting has been attributed to various mechanisms, such as the hypermetabolic status, caused by a direct effect of the tumor-induced secretion of hormones or cytokines [10] on the organism [11] and cancer-related fatigue (CRF) caused by the cancer-treatment and the reduced activity pattern [12] . However, the exact pathophysiological mechanism between muscle wasting, decreased muscle strength and CRF in cancer patients remains poorly understood [13] .

Muscle wasting and decreased muscle strength are not systematically addressed in an oncological setting. Peripheral muscle mass and strength are regularly measured in COPD patients, since they are good markers of deconditioning and have been shown to respond to exercise training [8] and [9]. Although muscle weakness is mostly observed in patients with advanced lung cancer, some degree may already be present at the time of diagnosis [14] . Little is known about the impact of an oncological treatment on muscle weakness in patients with lung cancer and the impact of a subsequent rehabilitation program. Preliminary data suggest that exercise may slow down the decline in muscle mass and physical functioning [15] .

Several methods are available to assess muscle mass: dual energy X-ray absorptiometry (DEXA), midthigh computed tomography (mCT) and bioelectric impedance (BEI). The first two methods are very accurate and yield reproducible results, but are time consuming and expensive [16] . Moreover, mCT requires considerable expertise and exposes the patient to radiation [17] and [18]. Conversely, BEI requires limited operator skills, is non-invasive and provides immediate results [16] , but is less reliable in underweight or obese patients and in those with abnormal hydration status [19] .

Current methods of strength testing include manual muscle testing, computerized dynamometry, and hand-held dynamometry. Although manual muscle testing is a practical option for strength testing, its questionable reliability and subjective nature has created an interest in alternative methods. The use of computerized dynamometry for measurement the isokinetic and isometric muscle strength has been shown to be highly reliable and is currently the gold standard for strength measures. However, their cost makes them uncommon in a clinical setting. Hand-held dynamometry is a relatively inexpensive and portable device, making it a practical alternative to computerized dynamometry. It has been shown to be reliable for evaluation of knee strength in various populations including patients with cancer [20] .

The aim of the present study was to investigate the effect of a radical oncological treatment and of a 12-week rehabilitation program on muscle mass and strength in lung cancer patients. Secondary aims were determining the relationship between muscle mass and muscle strength and between muscle mass as measured by mCT and BEI.

2. Materials and methods

This study is a pre-defined sub study of REINFORCE [21] , an open, prospective, randomized, controlled multicenter trial investigating the effects of rehabilitation in patients with either lung cancer or mesothelioma, treated with radical intent. Radical treatment was defined as either complete resection with or without a perioperative platinum-based chemo-(radio) therapy, or definitive thoracic radiotherapy with or without concurrent or sequential platinum-based induction chemotherapy. Patients had to be between 18 and 80 years, without anemia (Hb < 8 g/dl), fever, cachexia (≤35% premorbid weight) or a co-morbidity interfering with exercise training. Moreover, QF at M2 had to be <70% predicted, or have to be decreased between M1 and M2 with more than 10%. Only patients included at Ghent University Hospital participated in the present sub study. After their radical oncological treatment, patients fulfilling all in- and exclusion criteria were randomly allocated (2:1) to either standard follow up group (CON) or a rehabilitation training group (RT). Patients allocated to CON were asked not to change their activities of daily living and were discouraged to improve their exercise tolerance and muscle strength with professional help. Patients randomized to RT attended three rehabilitation sessions per week for 12 weeks. These sessions consisted of an initial warming-up of 20 min, followed by resistance training of the upper- and lower limb muscles (conventional resistance training or whole body vibration training). Participants were evaluated before (M1) and after their scheduled radical therapy (M2) as well as 12 weeks after randomization (M3). Patients had to provide written informed consent at inclusion.

Muscle cross sectional area (MCSA) was assessed on a regularly calibrated multi-detector CT-scan (Volume Zoom or Somatom Definition Flash, Siemens, Erlangen, Germany). Patients were laying in a relaxed and feet-first, supine position. The procedure was standardized to a maximal extent. First an antero-posterior scout view was obtained of both upper legs. On this view a line was drawn from the top of greater trochanter to the roof of the intercondyloid fossa. A single, 10 mm, transverse slice (120 kVp and 200–250 mA) was acquired in the middle of this line, at the femoral midpoint. Then, a circular region of interest was drawn around the right thigh on each image. Calculations of the MCSA were based on the density of the tissues in Hounsfield units (HU), where 0 HU equals the density of water and −1000 HU the density of air. Pixels with a density between 30 and 100 HU were assumed to represent muscle tissue [22] . All transverse images were analyzed by the same radiologist (WH) on the same workstation (Leonardo, Siemens, Erlangen, Germany). MCSA was expressed in cm2, with the lower limit of normal (LLN) in healthy elderly defined as 84 cm2 [18] .

Fat free mass (FFM) was assessed using a single frequency (50 kHz) bioelectrical impedance device and the results were analyzed with the standard equation of the device (Bodystat 1500 Medical, Isle of Man, LTD). The electrical current was applied to the skin through four adhesives electrodes attached to the right dorsal side of wrist and foot, with the patient laying in supine position [23] . FFM was expressed in kg and the LLN defined for FFM index (FFMI = FFM/length2) as 17.8 kg/cm2 for male and 14.6 kg/cm2 for female patients [24] .

Isometric quadriceps force (QF) was measured using an isometric handheld dynamometer (Microfet; Biometrics, Almere, the Netherlands) attached to a knee pendicular bank. Extension peak torque was evaluated at 60° of knee flexion. Patients were asked to perform a 5 s maximal isometric contraction. The best out of three attempts was retained and expressed as a percentage of the predicted value [25] . QF was expressed in N m and as percentage of the predicted values [25] . The LLN for QF was defined as 72% of the predicted value [25] .

The ratio between QF and MCSA was measured over time. A comparative decrease in both is suggestive that weakness is caused by muscle atrophy whereas a disproportionate reduction suggests that the muscle contractile apparatus and/or the neuromuscular activation are modified [18] .

2.1. Statistical assumptions and analysis

The primary endpoints of this part of the REINFORCE study were the effect of radical treatment and 12 weeks of rehabilitation on muscle mass (MCSA and FFM) and strength (QF). ΔM2 − M1 was estimated by subtracting the results obtained after radical treatment (M2) from the baseline data (M1) and ΔM3 − M2 by subtracting the data obtained after rehabilitation (M3) from the M2 ones. Changes in time within treatment arms were compared with Paired-Samples-T test and differences in between intervention arms were analyzed with the Independent-Samples-T test. Changes in LLN were analyzed with the Fisher-exact test.

Secondary endpoints in muscle mass and strength were between M1 and M3 (ΔM3 − M1) and the correlations between QF, MSCA and FFM, as defined by the Pearson correlation coefficient. ΔM2 − M1 and ΔM3 − M2 were analyzed in all patients who completed the study. Statistics were performed with the Statistical Package for the Social Sciences (SPSS 20.0, Chicago, IL), using p < 0.05 as threshold of significance. Data are presented as means with standard deviation.

3. Results

Forty-five of the 121 patients included in the REINFORCE study participated in the present sub study ( Fig. 1 ). Seventeen patients left the sub-study between inclusion (M1) and randomization (M2), because of lack of motivation (N = 6), disease progression (N = 5), comorbidities (N = 4) and ineligibility, because treatment did not induce a QF decrease of more than 10% (N = 2). Two patients did not undergo a mCT because of logistic reasons. Of the remaining 26 radically treated patients, 16 patients were allocated to RT and 10 to CON. One CON and three RT-patients were not reevaluated after 12 weeks, because of lack of motivation (N = 2), disease progression (N = 1) and comorbidity (N = 1).

gr1

Fig. 1 Diagram of patient flow in the study.

Characteristics of the included and of the randomized patients are presented in Table 1 . Of the 26 randomized patients, 23 patients were diagnosed with NSCLC and 3 with SCLC. Seven out of these had COPD. The majority of patients underwent surgery with or without chemotherapy and/or radiotherapy. The characteristics of the randomized patients were well balanced between both arms except for BMI and number of pack years. The median interval between M1 and M2 was 13 weeks (6–35), and between M2 and M3 13 weeks (5–30) and 14 weeks (7–36) weeks for CON and RT, respectively.

Table 1 Patient characteristics.

  All registered patients

N = 45
Randomized patients

N = 28
CON

N = 10
RT

N = 16
Mean age (years) 65 [9] 66 [8] 65 [7] 65 [9]
 
Gender (M/F) (N) 37/8 24/4 10/0 13/3
 
Mean pack years (N) 40 [18] 43 [16] 51 [16] * 38 [14] *
Current smoker (N) 16 10 5 4
 
Mean Charlson Comorbidity index (points) 4 [2] 34 [2] 3 [2] 4 [2]
 
COPD (N) 11 7 3 4
Diagnosis (N)
NSCLC 39 24 9 14
SCLC 6 4 1 2
 
Treatment (N)
S w/wo C and/or Ra 30 17 5 10
Ra w/wo C 15 11 5 6
 S 20 12 4 6
 Ra 4 3 1 2
 S + C 9 5 1 4
 Ra + C 11 8 4 4
 S + Ra + C 1 0 0 0
 
Mean BMI (kg/m2) 26 [5] 26 [5] 27 [4] * 24 [3] *
 
Mean FEV1 (%pred.) 86 [18] 85 [18] 88 [5] 85 [6]
 
Mean DL,CO (%pred) 74 [23] 75 [25] 67 [5] 85 [8]
 
Mean MCSA (cm2) 99 [24] 101 [23] 100 [9] 103 [8]
 
Mean FFM (kg) 52 [11] 53 [10] 50 [9] 57 [3]
 
Mean QF (N m) 119 [41] 123 [42] 119 [9] 130 [17]

* p = 0.05.

Data presented as mean with standard deviation in [ ] or in number (N); CON: control; RT: rehabilitation training COPD: chronic obstructive pulmonary disease; NSCLC: non small cell lung cancer; SCLC: small cell lung cancer; S: surgery; C; chemotherapy; Ra: radiotherapy; BMI: body mass index; FEV1: forced expiratory volume in one second; DL,CO: diffusion capacity; MCSA: muscle cross sectional area; FFM: fat free mass; QF: quadriceps force.

At M1, seven (25%) of the 28 included patients had a MCSA below the LLN, 11 (39%) had a QF below the LLN, and 9 (32%) had a FFMI below LLN.

Radical treatment did not affect FFM, but significantly decreased mean FEV1 from 2.5 L (0.8) to 2.2 L (0.8) (p = 0.002), mean MCSA from 99 cm2 (25) to 96 cm2 (24) (p = 0.003) and mean QF from 119 N m (41) to 104 N m (33) (p = 0.001) ( Table 2 ). After radical treatment, 9 (35%) of the 28 treated patients had a MCSA below the LLN, 17/28 (61%) had a QF below the LLN and 12/28 (42%) had a FFMI below the LLN.

Table 2 Effect of radical treatment (N = 30).

  M1 M2 P value
FEV1 (L) 2.5 (0.8) 2.2 (0.8) 0.002
FEV1 (%pred.) 86 (18) 75 (20) 0.003
 
BMI (kg/m2) 26 (5) 26 (4) 0.8
MCSA (cm2) 99 (25) 96 (24) 0.003
 
FFM (kg) 52 (11) 52 (10) 0.5
QF (N m) 119 (41) 104 (33) 0.001

Data presented as mean with standard deviation; M1: at inclusion; M2: after radical treatment FEV1: forced expiratory pressure; BMI: body mass index; CSA: cross sectional area; FFM: fat free mass; QF: quadriceps force.

Mean MCSA improved significantly with 6 cm2 (6) in RT (p = 0.003) at M3, whereas no such change was observed in CON ( Table 3 ). Differences between both arms did not reach statistical significance (p = 0.2). Rehabilitation did not significantly affect FFM or QF. In RT, the number of patients with value below the LLN decreased to 15% (2/13) for MCSA, 46% (6/13) for QF and 31% (4/13) for FFMI, respectively. In CON the number of patients with value below the LLN increased further to 44% (4/9) for MCSA, 89% (8/9) for QF and 44% (4/9) for FFMI, respectively.

Table 3 Effect of 12 weeks rehabilitation in complete cases (N = 22).

  CON (N = 9) RT (N = 13)
  M1 M2 M3 M1 M2 M3
MCSA (cm2) 103 (26) 96 (29) * 93 (32) 102 (24) 98 (22) * 105 (22) o
FFM (kg) 55 (9) 53 (9) 53 (8) 50 (9) 50 (9) 50 (9)
QF (N m) 124 (54) 91 (32) * 97 (36) * 123 (37) 109 (29) * 119 (40)
QF (% pred) 71 (25) 53 (12) * 56 (15) * 82 (19) 72 (12) * 78 (21)

* p < 0.05: vs. M1.

o M3 vs. M2.

Data presented as mean with standard deviation; CON: control arm; RT: rehabilitation training arm; MCSA: muscle cross sectional area; FFM: fat free mass; QF: quadriceps force; M1: at inclusion; M2: after radical treatment; M3: after intervention.

Recovery of MCSA was only seen in RT, but not in CON. ΔM3 − M1 in RT (+3 cm2) (8) and CON (−7 cm2) (14) were of borderline statistical significance (p = 0.056). QF almost completely recovered after RT, the ΔM3 − M1 deficit in QF being only −4 N m (38) (p = 0.7), whereas this deficit remained −26 N m (28) (p = 0.02) in CON. However, the difference in QF deficit between the two arms was not statistically significant (p = 0.2) ( Fig. 2 ). No significant intra- or inter arm changes in ΔM3 − M1 were observed for FFM.

gr2

Fig. 2 Changes in muscle cross sectional area (MCSA), quadriceps force (QF) and fat free mass (ffm) over time. Values at baseline (M1) were set to 100% and values after radical treatment (M2) and intervention (M3) were expressed as percentage of M1-value.

The QF/MCSA ratio remained stable throughout the study in both arms (CON: p = 0.4; RT: p = 0.1) and was affected neither by radical treatment nor by the randomized intervention ( Fig. 3 ). A statistically significant correlation was observed between MCSA and FFM (r = 0.73, p < 0.0001), QF and MCSA (r = 0. 58, p < 0.0001) and QF and FFM (r = 0.63, p < 0.0001).

gr3

Fig. 3 The ratio of QF over MCSA. The ratio between quadriceps force (QF) over muscle cross sectional area (MCSA) is shown at inclusion (M1), after radical treatment (M2) and intervention (M3). The left hand panel shows the ratio in the control arm (CON) and on the right hand panel the ratio in the rehabilitation training arm (RT). No significant differences were seen over time.

4. Discussion

The present study shows that muscle mass and muscle strength are significantly reduced in a substantial number of patients with lung cancer at presentation, and are further affected by an oncological treatment with radical intent. Moreover, the present data show that rehabilitation induces a significant recovery of quadriceps mass and strength.

It has been observed that muscle wasting is present in some patients at an early stage of cancer [26] . This study confirms this observation: baseline MCSA and QF were below the LLN in 25 and 40% of our patients, respectively. Although the mean MCSA of our patients fell below the mean reference value (110 cm2), it was still higher than those reported in COPD patients (84 cm2) [18] . However, it was unclear if the decrease is solely due to the cancer or secondary to comorbidities such as COPD.

The present data tend to support the notion that the detrimental effects of cancer and its treatments should be attributed to muscle atrophy subsequent to the expected reduction in physical activity and food intake during radical treatment [3] and [27]. Indeed, the ratio between QF and MCSA was not significantly affected by radical treatment and rehabilitation. Nevertheless, a tendency to decrease with radical treatment and to increase only with rehabilitation was noted. A more detailed analysis of the available data, however, critically questions whether muscle atrophy is the only mechanism involved. If this had been the case, the observed change in QF would have been proportionate to the decrease in MCSA. This was not observed, since the decrease in QF vastly exceeded the relatively mild, but statistically significant change in MCSA. At the end of treatment, one-third of patients showed a MCSA below the LLN, whereas two-thirds of the patients exhibited a weakness of the quadriceps muscle. The disproportion observed between the severe decrease in QF and the milder reduction in MCSA tends to support that other mechanisms such as muscle fatigue might be involved in the pathogenesis [13] .

Traditionally, skeletal muscle wasting has been identified as an important predictor of mortality and morbidity in patients with cancer-induced cachexia [28], [29], [30], and [31]. Moreover, skeletal muscle wasting contributes to excessive fatigue, weakness and lack of energy [32] leading to a vicious cycle, maintaining the patient in a condition of long-lasting disability [33] . It is tempting to hypothesize that a structured rehabilitation program could interrupt this circle. By modulating muscle metabolism, insulin sensitivity and levels of inflammation and improving exercise tolerance and quality of life [34], [35], and [36], rehabilitation represents a rational approach to reduce cancer-related cachexia and fatigue. Preliminary data indicated that rehabilitation restores muscle strength in surgically treated patients for lung cancer [34] . The present study clearly shows that 12 weeks of rehabilitation resulted in a complete recovery of MCSA, whereas no such changes were observed in the CON. Rehabilitation also restored QF to its initial value. However, that increase did not reach statistical significance, if compared to the QF obtained after radical treatment. Interestingly, QF measurements are volitional in nature [37] and are characterized by a larger variability than the highly reproducible MCSA. The present sub study was, however, not powered for that specific outcome. The increase in QF in RT reached statistical significance in the complete study (p = 0.0009), in which 70 patients were randomized [38] . The increase in QF in the present study is in line with those of a previous report, showing that a 12-week rehabilitation program significantly increased QF in lung cancer patients [34] .

The current findings indicate that cancer treatment plays a major role in the pathogenesis of cancer-related muscle fatigue and that muscle mass and strength are responsive to rehabilitation. Although cancer fatigue may be peripheral and central in origin, recent studies suggest that muscle fatigue is predominantly of central origin and characterized by a loss of voluntarily activated muscle [13] and [39]. Cancer fatigue can also be caused by abnormal muscle electrophysiology [39] and [40] and selective atrophy of type II fibers [39] .

Although FFM correlated reasonably well with MCSA, mean FFM remained stable throughout the study. This is in line with a previous observation, in which body composition is within normal limits in most patients with stages I–III lung cancer at time of diagnosis [29] .

Our finding that changes in muscle mass after radical treatment were only detectable by CT-scan and not by BEI is in line with previous observations, showing that whole body FFM did not change after chemotherapy in patients with small cell lung cancer [41] . Similarly, whole body FFM was not affected by rehabilitation. These findings allow to conclude that BEI is not sensitive enough to pick up relatively small changes induced by cancer and its treatment. One theoretical explanation for this discrepancy could be that lung cancer selectively induces muscle wasting of the lower limbs. It is, however, far more probable that confounding factors such as variations in patient fluid and electrolyte status and the selection of a predictive equation might have affected the outcome of BEI measurements to a certain extent. To date, the two equations that are currently recommended have been derived from a mixed patient population with cancer from different organs [42] and [43]. Consequently, BEI should be used with extreme caution when assessing the body composition in lung cancer populations, and assessments with DEXA or per CT remain first choice. An appropriate population, age and pathology specific equation is urgently needed to validate the measurement of FFM by BEI [44] in lung cancer patients.

5. Conclusion

The present study shows that a substantial number of lung cancer patients demonstrate a decreased muscle mass and strength at the time of diagnosis. Furthermore, it provides a scientific basis for the use of a structured rehabilitation program in radically treated patients with stages I–III lung cancer. It not only shows that radical treatment exerts negative effect on muscle mass and strength, but unequivocally demonstrates that rehabilitation has the potential to reverse these detrimental effects. The present findings invite the scientific community to design additional clinical studies in which the effects of rehabilitation on even more relevant clinical outcomes, such as survival, exercise tolerance and quality of life are investigated.

Funding

This study was supported by the Belgian Government Agency of Innovation by Science and Technology for applied Biomedical Research and by the Clinical Research Fund of Ghent University Hospital, Belgium.

Conflict of interest statement

We declare no conflict of interest for all the authors and that the grant provider had no influence on the design and outcome of the study, nor on its analysis or content of this article.

Acknowledgements

The authors thank the members of the pulmonary rehabilitation team, Gilles Thysebaert and the patients for their gracious collaboration.

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Footnotes

a Department of Respiratory Medicine, Ghent University Hospital, Belgium

b Department of Medical Imaging, Ghent University Hospital, Belgium

c Biostatistical Unit, Faculty of Medicine, Ghent University, Belgium

d Thoracic Oncology, MOCA, Antwerp University Hospital, Belgium

lowast Corresponding author at: Department of Respiratory Medicine, Ghent University Hospital, De Pintelaan 185, 7K12IE, 9000 Ghent, Belgium. Tel.: +32 9 332 5536; fax: +32 9 332 2341.

Clinical trial number: NCT00752700 .


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