Objectives There is growing awareness of the relationship between sarcopenia (loss of muscle mass and function), and outcomes in cancer, making it a potential target for future therapies. In order to inform future research and practice, we undertook a systematic review of factors associated with loss of muscle mass, and the relationship between muscle function and muscle mass in lung cancer, a common condition associated with poor outcomes.
Design We conducted a computerised systematic literature search on five databases. Studies were included if they explored muscle mass as an outcome measure in patients with lung cancer, and were published in English.
Setting Secondary care.
Participants Patients with lung cancer.
Primary outcome Factors associated with loss of muscle mass and muscle function, or sarcopenia, and the clinical impact thereof in patients with lung cancer.
Results We reviewed 5726 citations, and 35 articles were selected for analysis. Sarcopenia, as defined by reduced muscle mass alone, was found to be very prevalent in patients with lung cancer, regardless of body mass index, and where present was associated with poorer functional status and overall survival. There were diverse studies exploring molecular and metabolic factors in the development of loss of muscle mass; however, the precise mechanisms that contribute to sarcopenia and cachexia remain uncertain. The effect of nutritional supplements and ATP infusions on muscle mass showed conflicting results. There are very limited data on the correlation between degree of sarcopenia and muscle function, which has a non-linear relationship in older non-cancer populations.
Conclusions Loss of muscle mass is a significant contributor to morbidity in patients with lung cancer. Loss of muscle mass and function may predate clinically overt cachexia, underlining the importance of evaluating sarcopenia, rather than weight loss alone. Understanding this relationship and its associated factors will provide opportunities for focused intervention to improve clinical outcomes.
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
Strengths and limitations of this study
Timely systematic review considering the increasingly recognised phenomenon of sarcopenia as it relates to cachexia.
Evaluation of sarcopenia in lung cancer, as an example of a common cancer associated with poor outcomes and a significant prognostic impact.
Limited to publications in English only.
Over the last decade, there has been increasing recognition of the clinical importance of sarcopenia as part of the cancer cachexia syndrome, and its impact has been evaluated in a wide range of malignancies including lung, breast, upper gastrointestinal, hepatocellular and colorectal cancers.1–5 The term sarcopenia is derived from the Greek meaning ‘poverty of flesh’ and is characterised by a triad of progressive loss of skeletal muscle mass, muscle strength and physical performance.6 It was originally described in the elderly non-cancer population, and is often now defined as a geriatric syndrome associated with functional impairment, increased risk of falls, fractures and reduced survival.7–9 Sarcopenia becomes more prevalent with increase in age—of 1421 healthy adults aged 45 years or over, the overall prevalence was 15%, rising to 64% over the age of 85.10 This loss of muscle mass is usually gradual and not necessarily associated with significant or sudden weight loss.
The detrimental effects of sarcopenia can also be seen in younger patients in association with muscle disuse, malnutrition or inflammatory conditions, particularly cancer. Interest in sarcopenia as a poor prognostic indicator in cancer is rising; in various populations with cancer sarcopenia is associated with poorer performance status (PS),1 reduced overall survival11 ,12 and increased risk of chemotherapy toxicities.2 ,4 This interest is reflected in a recent international consensus on the definition of cancer cachexia, which established sarcopenia as a key diagnostic criterion.13
The hallmark of sarcopenia is low muscle mass, more specifically an appendicular skeletal muscle mass index of more than 2 SDs below the sex-specific mean of healthy adults (ie, 5.45 kg/m2 for women and 7.26 kg/m2 for men).8 However, central to the concept of sarcopenia is the recognition that overall neuromuscular function, rather than muscle mass alone, is essential for maintenance of independence. Therefore, when defining sarcopenia, it is vital to assess muscle strength, or physical performance, in addition to muscle mass, as the relationship between muscle mass and strength is non-linear.14 ,15
While many different techniques have been used to measure muscle mass and strength, few have been incorporated into routine assessment of the cancer population. The current gold standards are CT, MRI and dual-energy X-ray absorptiometry (DEXA) scans. CT and MRI allow precise differentiation between fat and other soft tissue including muscle and are therefore investigations of choice. CT focuses on a specific area of the body—for example, muscle cross-sectional area at the third lumbar vertebra—which can be related to whole body muscle mass. It is the current gold standard in body composition research and has the advantage that many patients will have CT scans as part of their diagnostic and treatment assessments. However, DEXA involves less radiation exposure compared with CT and accurately and precisely differentiates between lean and fat body compartments.16 More indirect techniques for measuring muscle mass include bioelectrical impedance analysis which is non-invasive but less accurate compared with DEXA. It includes a measure of organ mass other than skeletal muscle, but is easily performed in clinical settings.17 Measurements of mid-upper arm circumference and arm muscle area using skinfold thickness methods have also been used,18 although these assessments are less accurate and there exists considerable interobserver variability. Measurements of muscle strength in the literature have mainly centred around handgrip strength (HGS) and quadriceps strength, although in non-cancer elderly patients, functional assessments such as the Short Physical Performance Battery and sit-to-stand tests19 ,20 have been shown to correlate with adverse outcomes.
From the literature it is clear that there is marked diversity in current clinical practice in assessing the degree of muscle loss in patients with cancer and in quantifying its functional implications. If the loss of muscle mass and strength have significant clinical implications for patients with cancer, then standardised, validated diagnostic thresholds are clearly needed. Furthermore, while the effects of sarcopenia have been extensively studied in the elderly patients, factors associated with loss of muscle mass and strength in cancer remain unclear. As the pathophysiological mechanisms responsible for loss of muscle mass in cancer differ, at least in part, from those in sarcopenia of ageing, it is necessary to evaluate cancer-specific causative factors and clinical implications.
We therefore undertook a systematic literature review to further understand the relationship between muscle function and muscle mass and its implications for research and clinical practice within the context of cancer. We limited the review to focus on lung cancer as an example of a common cancer, associated with poor outcomes, in which sarcopenia has been shown to have a significant prognostic impact. Lung cancer has a worldwide incidence rate of 1.61 million cases per year,21 and frequently presents in the advanced stages. Despite advances in anticancer therapies, survival benefits in patients with lung cancer over the past 30 years have been relatively small compared with those seen in breast, colorectal and prostate cancers.22 While reasons for this are complex, many patients with lung cancer are ineligible for radical treatment at presentation due to poor PS or comorbidity, while others fail to receive their intended treatment plan because of functional decline.23 ,24 Non-small cell lung cancer (NSCLC) has a particularly strong association with loss of muscle mass—of 441 patients consecutively referred to a regional oncology service, 47% were found to be sarcopenic.25 This prevalence can be compared with 16% of a cohort of 471 survivors with breast cancer26 and 39% in a cohort of 234 patients with preoperative colorectal cancer.5 We conducted this systematic review with this in mind.
Search strings and data sources
We not only executed a broad literature search, including various terminologies used to describe loss of muscle mass, but also specifically used ‘sarcopenia’ as a multipurpose field search term. Recognising that changes in muscle mass may impact on muscle strength and physical function, we included these terms in our search. We united two search strings: loss of muscle mass (and its implications) and lung cancer (see table 1). The search was limited to English language and humans, with a publication date from 1946 to October 2013. We used the same search strings to develop strategies in the following five databases in order to ensure maximal coverage: MEDLINE, MEDLINE In-Process, EMBASE, AMED and the Cochrane library.
Citations were independently screened by two researchers (JCo and SN) and included for initial analysis if they described muscle mass measurements or body composition in patients with lung cancer. Both prospective and retrospective original articles were included, but conference abstracts, citations without abstracts, case reports, review articles and opinion pieces were excluded. All studies that had a cohort of patients with lung cancer were included, even if there were patient groups with other cancer types analysed. Retrieved articles were searched for additional relevant references.
Inclusion criteria and data extraction
The selected articles were reviewed in full by two independent researchers (JCo and SN) for consideration of inclusion in the review. Where discordance in selection was observed, the article in question was discussed until consensus was reached. As there were many articles describing muscle mass as part of routine anthropometry or body composition assessments, without directly exploring it, we only included articles in which muscle mass was explored as an outcome measure. Data including patient characteristics and numbers, histological subtype and TNM (tumour, node, metastasis) stage were collated and tabulated (tables 2 and 3). We also noted units of muscle mass measurements, and techniques used to measure these.
Using our broad search terms in five databases, we found an initial 5726 citations, from which we identified 64 potentially relevant articles. Three further potential articles27–29 were identified from the references of these articles. From these, we excluded 11 abstracts with no published articles, 2 further abstracts that did not mention muscle mass,30 ,31 and a systematic review of cancer cachexia.32 Of the 53 final articles, we excluded a further 13 articles which mentioned muscle mass in baseline anthropometry details but did not use it as an outcome measure,33–45 4 articles which described weight loss rather than loss of muscle mass,46–49 and 1 article describing the same results obtained from the same patient population as another article,50 with slightly different secondary endpoints.51 During the process of data extraction, a number of recurring themes became apparent. We have presented these under two main headings—factors associated with loss of muscle mass, and degree of loss of muscle mass and physical functioning. A number of studies explored multiple variables associated with loss of muscle mass, and are therefore mentioned under more than one heading.⇓
For the final analysis, 4 randomised controlled studies, 17 cross-sectional studies and 14 longitudinal studies met the established criteria: 35 articles in total. Muscle mass data were reported variously as fat-free mass (FFM), body cell mass, lean body mass, appendicular skeletal muscle mass, smooth muscle area at the levels of lumbar vertebra L3 and thoracic vertebra T4, mid-upper arm circumference and arm muscle area. Notably, most studies described muscle mass in more than one way. Muscle function was described as HGS and/or quadriceps strength,17 ,27 ,52–54 intensity of physical activity,55 patient-reported physical functioning28 and muscle strength and physical performance.56
As the studies in our review expressed muscle mass in different ways, we have used the term FFM or loss of muscle mass in the body of our article in order to allow direct comparison. In addition, where the studies in this review defined a patient group as having sarcopenia, they did so based on loss of muscle mass alone, without evaluation of muscle strength or performance. This needs to be borne in mind wherever the term sarcopenia is used throughout this review.
Factors associated with loss of muscle mass
In this review, many studies found that those with cachexia and/or weight loss also had coexistent loss of muscle mass.25 ,28 ,58 ,67 ,68 ,71 ,74 Despite this, none of the studies prospectively evaluated the impact of loss of muscle mass on cancer outcomes, specifically relating to treatment. Three studies explored the loss of muscle mass comparing men and women, finding that a significantly greater percentage of men were affected,25 ,64 and that they exhibited a decreasing trend in FFM after chemotherapy compared with baseline, whereas women did not.29 Reflecting the process of loss of muscle mass in the different stages of cancer, a study of 60 patients with preoperative NSCLC with stage I and II disease showed no difference in FFM compared with controls,27 whereas in a cohort of 352 patients with advanced cancer, 84% of those with cachexia had a reduced FFM.74
The pathophysiology of loss of muscle mass in patients with lung cancer is complex, as illustrated in the diversity of articles exploring this. Low FFM has been associated with low albumin and high acute phase protein concentrations,57 ,58 ,71 reflecting the inflammatory pathways involved. Abnormal protein metabolism is implicated in the development of sarcopenia; however, in this review, neither anabolic58 nor proteolytic pathways59 ,55 had any consistent effect on loss of muscle mass. The exception to this was the lysosomal protease cathepsin-B, which was significantly increased in depleted FFM patients.59 The pathophysiology may also differ depending on disease stage and cachexia phase. There is some evidence, for example, that in patients with precachectic NSCLC, despite weight loss, the ubiquitin–proteasome proteolytic pathway may not be activated.55 ,80 Different ACE-gene polymorphism allelic combinations52 and leptin expression70 have not been shown to have significant effects on muscle mass. FFM is the major determinant of energy metabolism in humans, represented by resting energy expenditure (REE), and there exists a linear relationship between REE and FFM in healthy adults.81 In lung cancer cachexia, this relationship seems to be distorted69 ,71 but results have been conflicting as to whether REE contributes to the development of lung cancer cachexia.67 ,68 ,72 ,73
The use of CT images for diagnosis of muscle mass depletion alone showed a high prevalence of this phenomenon in patients with NSCLC,25 regardless of body mass index and even among the obese.1 CT images were also used to chart progressive muscle loss over time, and to create a prognostic model for survival based on weight loss, muscle mass and muscle attenuation.65 ,66 The presence of muscle mass attenuation was associated with poorer functional status and overall survival.
Nine interventional studies explored the effect of either nutritional supplements or ATP infusions on muscle mass and function. A randomised controlled study with 518 participants, examining the effect of eicosapentaenoic acid (found in fish oil) supplements, revealed increased patient-rated physical functioning, but no significant change in FFM, at the end of the study period.28 A similar, smaller study of eight participants concurred.75 By contrast, one study of fish oil supplementation demonstrated a reduction in the rate of loss of muscle mass; however, the number of studies was small—40 patients in total. In addition, those considered sarcopenic were found to have lower plasma fatty acids than those without, in a study with 41 patients with NSCLC.76 ,77 An interventional randomised controlled study with 66 participants found that cysteine-rich protein supplements increased FFM, as well as HGS, compared with conventional protein supplements,54 and a small case-control study with 10 patients found that hyperaminoacidaemia stimulated a normal anabolic protein response even in the presence of insulin resistance, in patients with cancer cachexia.78 Two randomised controlled studies investigating the effect of ATP infusions on body composition gave conflicting reports, one (N=58) finding that ATP slowed the rate of loss of muscle mass50 while the other (N=100) did not.79 Only the study by Fearon et al28 described power calculations to detect a statistically significant difference.
Degree of sarcopenia or loss of muscle mass and physical functioning
There was very little direct evaluation of the relationship between muscle mass and muscle function. However, the studies that evaluated muscle mass alongside muscle function show that there is limited correlation. Muscle strength seemed to be affected, regardless of loss of muscle mass. In patients with precachexia, exercise capacity was significantly reduced, despite maintenance of muscle mass,55 and resistance exercise training increased all parameters of muscle strength and physical performance, with no difference to muscle mass.56 In this review, patients with cachexia showed reduced strength in terms of walking distance61 and quadriceps strength62 compared with controls.
Loss of muscle mass, as part of a weight-losing syndrome, is a central feature of cancer cachexia. However, changes in muscle mass, and/or performance, may predate clinically overt cachexia, as part of ageing or secondary to inflammation/disuse. This implies that consideration of both muscle mass and function, rather than weight loss alone, is clinically important. Understanding this relationship, and the factors associated with each, will provide opportunities for focused intervention to improve clinical outcomes.
The findings of our review highlight several important issues. While studies exploring molecular and metabolic factors associated with loss of muscle mass have contributed to a better understanding of the pathophysiology of cancer cachexia, there remains considerable uncertainty in relation to mechanisms. Our review in patients with lung cancer demonstrates inconsistency of findings as to the factors implicated in the development of cachexia, compared with other cancer sites. It highlights the lack of clear therapeutic targets and emphasises the need for concerted, appropriately-sized exploration of predictive and prognostic factors in lung cancer cachexia.
This uncertainty with regard to precise pathophysiological mechanisms is reflected in the lack of consistent effect of interventions aimed at slowing the rate of loss of muscle mass and improving muscle function in lung cancer. Studies reviewed which refer to cachexia management support a multimodal approach, including targeted exercise, nutritional counselling, social support and pharmacological intervention.82 This review highlights inherent challenges of such an approach, with nutritional interventions in particular failing to demonstrate efficacy,83 although the role of exercise is emerging.56 ,84 It also suggests the need to represent patients with NSCLC adequately within trials of new interventions, such as myostatin antibody therapies, rather than assuming a class effect across tumour sites.
Strikingly, our review has demonstrated that, to date, there has not been due attention to the concept of sarcopenia as a distinct, if overlapping syndrome, in a condition affecting a largely elderly population. It also highlights the difficulty in making comparisons between studies, due to the heterogeneity of methods employed in measuring muscle mass and different cut-off values used for defining sarcopenia. Current standardised values were derived from a large elderly cohort and the cut-off values were based on healthy young adult reference values. These values have been used to define sarcopenia in cancer,13 ,85 including one in this review.53 The relevance of this definition to patients with cancer is debatable, for a number of reasons. First, sarcopenia manifests in patients with cancer of all ages and is not isolated to the elderly alone. Second, the pathophysiology of sarcopenia in patients with cancer may differ at least in part to that of the non-cancer elderly population.86 With this in mind, the more recent international consensus document recommending a reference value of absolute muscularity below the fifth centile is to be welcomed.13 Finally, the recognition of muscle strength and performance as a defining component of sarcopenia in the elderly patients needs consideration, within the context of cancer cachexia.
The argument for the objective evaluation of physical performance is pertinent, particularly as part of the definitive assessment of sarcopenia alongside measurements of muscle mass. Currently, physical fitness for treatment is determined largely by the PS score. This score is imperfect as it is subjective, with reports of interobserver variability,87 and there is only a modest correlation between PS and observed physical performance.88 Interclinician PS discordance has led to a lower percentage of PS 0 and 1 patients appearing to get chemotherapy,89 and has led to a call for objective evaluation of physical functioning.90 Some proposed methods include tests of gait speed and muscle strength. It is postulated that objective measures of muscle mass and strength together may complement, or even outperform, PS as a predictor of fitness for systemic treatment, provided that they can be readily performed in routine clinical settings.
Our review has several limitations. The heterogeneity of the studies included in this review made it difficult to account for individual risk of bias, not least because we included a broad range of studies from large randomised controlled trials to small observational studies. This limitation also means that some articles included in this review, while being relevant to sarcopenia, were more broadly related to muscle mass outcomes in cancer cachexia, rather than assessing sarcopenia directly. Our search also was limited to studies published in English, and although our review included some studies with negative or inconclusive findings, there may indeed exist some publication bias for which we are unable to account.
The article by Temel et al,91 which demonstrated that early palliative care involvement increased patient survival, as well as quality of life, has highlighted the importance of supportive measures in a poor-prognosis population receiving active oncological intervention. As such, focusing research on the identification and management of sarcopenia in patients with lung cancer may prove to be a tolerable and cost-effective adjunct to the current lung cancer care.
While development of a clearer definition of cancer cachexia provides an additional component of a robust, objective clinical framework for stratification of patients for focused interventions, the enhanced role of muscle strength/performance as a defining assessment of sarcopenia requires attention. A standardised definition of cancer-related sarcopenia which can be used clinically and in the research setting will harmonise reporting, allowing for direct comparison of results as well as meta-analysis of data. In the era of stratified medicine, this review identifies opportunities to examine cellular and genetic factors associated with sarcopenia in lung cancer coherently and to link them with changes in tumour phenotype which impact on morbidity and survival.
Contributors JCo and SN were responsible for the conception and design of this review, independently reviewed the citations, and were responsible for analysing and interpreting the data. JCo and BC conducted the searches. SN, JCh, AB and JCo drafted the article and revised its content to its final version.
Funding JCo is funded by Cardiff and Vale University Health Board under the Clinical Research Fellowship scheme.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional data are available.