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Progressive resistance training rebuilds lean body mass in head and neck cancer patients after radiotherapy – Results from the randomized DAHANCA 25B trial
Radiotherapy and Oncology, 2, 108, pages 314 - 319
The critical weight loss observed in head and neck squamous cell carcinoma (HNSCC) patients following radiotherapy is mainly due to loss of lean body mass. This is associated with decreases in muscle strength, functional performance and Quality of Life (QoL). The present study investigated the effect of progressive resistance training (PRT) on lean body mass, muscle strength and functional performance in HNSCC patients following radiotherapy.
Patients and methods
Following radiotherapy HNSCC patients were randomized into two groups: Early Exercise (EE, n
In the first 12
PRT effectively increased lean body mass and muscle strength in HNSCC patients following radiotherapy, irrespectively of early or delayed start-up.
Keywords: Head and neck cancer, Exercise, Muscle mass, Muscle function.
Head and neck squamous cell carcinoma patients (HNSCC) treated with radiotherapy typically experience a weight loss of 6–12% of pre-treatment body weight  and . The weight loss is caused by the cancer disease itself and by the side effects of radiotherapy, such as mucositis and dysphagia impeding sufficient energy intake. This weight loss is reported to persist more than two years post-treatment  and . It has been shown that weight loss negatively impacts survival, morbidity, functional performance and quality of life (QoL) in HNSCC patients  and .
More than 70% of the weight loss in HNSCC patients is reported to be lean body mass , which is associated with impaired muscle strength, a decline in physical activity, functional capacity and decreased independence in performing activities of daily living  and . Consequently, effective interventions to regain lean body mass, muscle strength and functional performance in radiotherapy treated HNSCC patients are strongly needed.
Progressive resistance training (PRT) increases muscle mass, muscle strength and functional performance in healthy individuals including elderly sarcopenic individuals  and . Randomized controlled trials on the general effects of PRT in cancer survivors are limited and predominantly involve breast- and prostate cancer survivors . Moreover, only few studies primarily in breast cancer survivors have investigated PRT-induced changes in lean body mass .
Prolonged side effects and sustained negative energy balance following radiotherapy  may inhibit the potential effect of PRT on lean body mass in HNSCC patients. Both impaired physical performance reducing sufficient training effort and chronic negative net protein balance could reduce the PRT response and allowing further recovery from radiotherapy by delaying the start-up of training may affect the effect on rebuilding lean body mass.
In radiotherapy treated HNSCC patients, only two studies have investigated the effect of PRT on lean body mass yielding diverging results. One of these studies found no changes in mean values of lean body mass, muscle strength or functional performance following a 12
However, in the DAHANCA 25A feasibility trial , we found that 12
In perpetuation of the feasibility trial we conducted the present DAHANCA 25B trial with the primary purpose to investigate the effects of PRT on lean body mass in a randomized trial in HNSCC patients following radiotherapy. The potential effect of time of initiation of PRT was also investigated. Secondly, we investigated the effect on maximal muscle strength, functional performance and quality of life. It was hypothesized, that PRT would increase lean body mass, maximal muscle strength and functional performance irrespectively of time since treatment.
Materials and methods
Settings and patients
The present study was a multi-center, randomized, stratified and parallel-grouped study. Approval was achieved from the regional Ethics Committee for the Central Denmark Region (id: 20110065), and the study was registered at clinicaltrials.gov (identifier: NCT01509430). Eligible participants fulfilled the following inclusion criteria:
(1) Histologically diagnosed with squamous cell carcinoma of the larynx (except glottic stage I
All 41 patients received accelerated radiotherapy according to DAHANCA guidelines (www.dahanca.dk) with IMRT if relevant to total tumor dose of 66–68
At the two months post treatment follow-up, patients were given oral and written information about participation before signing a written consent. Before randomization patients were stratified according to HPV/p16 status  (positive vs. negative), relative weight loss (cut-off: 8.5% of pre-treatment body weight) and presence vs. no presence of feeding tube at the two months follow-up. Patients were randomly allocated to the Early Exercise (EE) or Delayed Exercise (DE) group. During the initial 12
Progressive resistance training
At different commercial training facilities located close to the patients′ residences thirty PRT sessions were evenly dispersed over 12
Assessment of primary and secondary endpoints
All endpoints were evaluated at baseline and following 12
The study was planned to include 40 patients randomized equally into two groups. This number was based on a priori power calculation where PRT-induced lean body mass change was considered the primary endpoint. Using an expected 5% lean body mass change  (±5% standard deviation) with an anticipated drop-out rate of 20%, power was 0.8 and level of significance was 0.05.
All continuous data followed a normal distribution (tested using box plots, q–q-plots, histograms and dot-plots). Multivariate analyses of variance were used to evaluate possible time and group interactions of all endpoints. In case of detecting group-time interactions or time effects within groups, Student’s paired t-test evaluated changes over time within group and Student’s unpaired t-tests evaluated group differences. The effect of PRT on lean body mass was also presented as odds ratios of the relative odds of increasing lean body mass above the population median. Data from the EORTC QLQ-C30 questionnaires were assumed to be ordinally distributed. Thus, unpaired Wilcoxon–Mann–Whitney tests were performed to analyze group differences and the paired Wilcoxon signed rank test was used to analyze changes over time within groups. All completers were included in the statistical analyses. Thus, patients who did not undergo evaluation after baseline (n
Of 191 eligible HNSCC patients from July 2011 to July 2012, 41 were included for randomization providing a recruitment rate of 22% (Fig. 1). Twenty patients were allocated into EE and 21 patients into DE.
Patient inclusion/exclusion flow is presented in Fig. 1. Two patients were excluded from all physical tests because of knee injuries hindering maximal effort contractions at 12 and 24
|Patient characteristics||Early exercise (randomized patients)||Early exercise (non-completers)||Delayed exercise (randomized patients)||Delayed exercise (non-completers)|
|Number of patients||20||1||21||6|
|Center||Aarhus||13 (65%)||1 (100%)||13 (62%)||6 (100%)|
|Odense||7 (35%)||0 (0%)||8 (38%)||0 (0%)|
|Age in years (range)||55
|Body weight in kg at time of inclusion||71.4
|Weight loss in kg (range)||8.5
|Weight loss||>8.5%||5 (25%)||1 (100%)||8 (38%)||2 (33%)|
|<8.5%||15 (75%)||0 (0%)||13 (62%)||4 (67%)|
|Gender||Women||5 (31%)||1 (100%)||2 (14%)||1 (17%)|
|Men||11 (69%)||0 (0%)||12 (86%)||5 (83%)|
|Tumor site||Pharynx||16 (80%)||1 (100%)||14 (67%)||4 (66%)|
|Larynx||1 (5%)||0 (0%)||0 (0%)||0 (0%)|
|Oral Cavity||1 (5%)||0 (0%)||2 (10%)||1 (17%)|
|Unknown primary tumor||2 (10%)||0 (0%)||5 (23%)||1 (17%)|
|Stage||I–II||4 (20%)||0 (0%)||4 (19%)||1 (17%)|
|III–IV∗||16 (80%)||1 (100%)||17 (81%)||5 (83%)|
|Treatment||Radiation therapy alone||6 (30%)||0 (0%)||14 (67%)||3 (50%)|
|Chemoradiation therapy||14 (70%)||1 (100%)||7 (23%)||3 (50%)|
|HPV/p16 status||Positive||13 (65%)||0 (0%)||18 (86%)||5 (83%)|
|Negative||7 (35%)||1 (100%)||3 (14%)||1 (17%)|
|Feeding tube||Yes||11 (55%)||1 (100%)||10 (48%)||3 (50%)|
|No||8 (45%)||0 (0%)||11 (52%)||3 (50%)|
Lean body mass
After the first 12
In the present population the overall 12
Maximal muscle strength
After the first 12
Functional performance and quality of life
After the first 12
Overall, from baseline to week 24, the primary and secondary endpoints improved within both intervention groups and no group differences were observed during this period (Supplementary Table 1).
The primary finding of this trial is that 12
This is the first randomized controlled trial to report a PRT-induced increase in lean body mass in HNSCC patients. The results confirm the observations from the DAHANCA 25A non-controlled feasibility trial , in which an increase in lean body mass within groups was observed after 12
Rogers et al.  found no lean body mass change following 12
The observed changes in maximal muscle strength clearly suggest a specific effect on maximal muscle strength regardless of PRT start-up time. In EE PRT induced significant increases in maximal isometric KE and isokinetic KF strength larger than the change following self-chosen PA in DE from baseline to week 12. However, there was no significant difference between EE and DE in isokinetic KE and isometric KF in this period. From week 12 to week 24 all measures of maximal muscle strength increased significantly more in DE than EE. The findings of non-significant group differences in two of four maximal muscle strength tests from baseline to week 12 may question the superior effect of PRT, although most likely caused by the substantial within-group variance observed in both groups. Nonetheless, the mean increases in EE were consistently greater in all maximal muscle strength tests.
Despite inducing significant increases in all functional performance tests from baseline to week 12, PRT had no superior effect compared to self-chosen physical activity. This suggests that resuming to more normal levels of daily physical activities such as walking, cycling and different types of domestic activities has an equal positive effects when functional performance is as low as observed at baseline. All functional tests reflected tasks of common daily activities and are affected by other factors than maximal muscle strength, such as increased participation and performance in residential everyday activities of the patients, which may explain the increase in DE from baseline to week 12. From week 12 to week 24 we observed a significant larger increase in three of four functional performance tests in DE. This indicates that increasing functional performance after reaching a certain level was only effective by means of PRT, further suggesting that the increase in maximal muscle strength induced in DE in this period lead to further improvements in functional performance. Despite these differences, the overall increases from baseline to week 24 was identical between groups in all functional performance tests (Supplementary Table 1) why favoring one start-up time over the other is not substantiated.
Interestingly, QoL increased following PRT from baseline to week 12, where two measures of QoL (Global Health and Cognitive Function) increased to a greater extent in EE than in DE. Thus, participation in 12
As discussed previously , the logistic advantages minimally supervised and locally based PRT may facilitate the implementation of this training modality in the future training of HNSCC patients. Further strengths of the present study are the reliable methods used to evaluate the effects of PRT on both primary and secondary endpoints. We recognize the risk of selection bias including that the weakest patients might refuse to participate or are not included due to co-morbidity or other conditions that could inhibit training completion. Furthermore, the dimensions of the statistical analyses were based on the primary endpoint only. Thus, we acknowledge the issue of multiple testing when interpreting results from the analyses on secondary endpoints.
In summary, we conclude that 12
Conflicts of interest
The authors report no conflicts of interest.
The project was further supported by The Danish Cancer Society, Beckett Fonden, Arvid Nillsons Fond, Dansk Kraeftforskningsfond and Andersen-Isted Fonden. The authors would like to thank Berit Eide (Dept. of Oncology, Aarhus University Hospital) and Dorthe Grunske Schmidt (Dept. of Oncology, Odense University Hospital) for their unlimited assistance in patient recruitment, Ditte Møller Nielsen for her invaluable handling of logistics related to patient training and associate professor Bo Martin Bibby from Sect. for Biostatistics, Department of Public Health, Aarhus University, for statistical counseling.
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a Dept. of Experimental Clinical Oncology, Aarhus University Hospital, Denmark Dept. of Experimental Clinical Oncology, Aarhus University Hospital, Denmark
b Dept. of Public Health, Section for Sport Science, Aarhus University, Denmark Dept. of Public Health, Section for Sport Science, Aarhus University, Denmark
c Dept. of Oncology, Aarhus University Hospital, Denmark Dept. of Oncology, Aarhus University Hospital, Denmark
d Dept. of Oncology, Odense University Hospital, Denmark Dept. of Oncology, Odense University Hospital, Denmark
e Institute of Sports Science and Clinical Biomechanics, SDU Muscle Research Cluster (SMRC), University of Southern, Denmark Institute of Sports Science and Clinical Biomechanics, SDU Muscle Research Cluster (SMRC), University of Southern, Denmark
f Dept. of Endocrinology, Odense University Hospital, Denmark Dept. of Endocrinology, Odense University Hospital, Denmark
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