Association of sarcopenia and observed physical performance with attainment of multidisciplinary team planned treatment in non-small cell lung cancer: an observational study protocol

Lung cancer is a common disease, with a global incidence of 1.61 million in 2008 [1, 2]. Non-small cell lung cancer (NSCLC) is the most common cell type, with the majority of patients presenting with advanced disease. Despite advances in anticancer treatments, the mortality risk of lung cancer remains high worldwide, with an annual mortality to incidence ratio of 88 % [3]. In the United Kingdom, annual mortality from NSCLC is similarly poor, with an overall 5-year survival rate of 8.6 % [4].

Despite this, survival rates in NSCLC are consistently superior in patients who receive specific anticancer treatment, compared to those who do not [5‐7]. Potentially curative treatment strategies using surgery, radical radiotherapy or multimodality treatment is feasible in a minority of patients (12–19 %), whilst systemic anti-cancer therapy is recommended for those with incurable disease [8‐10]. Multidisciplinary team (MDT) assessment of fitness for optimal treatment – be it surgery, radiotherapy or chemotherapy, singly or in combination – is crucial, as all these modalities are poorly tolerated by patients with low baseline physical function [11, 12]. Currently assessment of fitness for treatment is based on initial clinical examination, consideration of co-morbidities and clinician assessment of functioning, most often reported as Eastern Cooperative Oncology Group (ECOG) or Karnofsky performance status (PS) [13, 14]. Evidence suggests that PS assessment at baseline is predictive of overall survival [15, 16]. However, there is less evidence of sensitivity to change over time or of reliable correlations with tolerance of treatment. Furthermore, PS assessment is subjective, with reports of inter-observer variability [17, 18], and there may only be a modest correlation between PS and observed physical performance [19]. Most tellingly, recent evidence also suggests that up to 33 % of NSCLC patients for whom active treatment is recommended by the MDT do not go on to receive it, mainly due to functional reasons [20, 21].

Physical function is largely dependent on maintenance of muscle mass and neuromuscular function. Although weight loss has long been recognised as an adverse feature of cancer cachexia, it is the depletion of skeletal muscle mass – sarcopenia – with or without loss of fat mass, which is now an integral part of the diagnosis of cancer cachexia [22]. Its presence is associated with an increased risk of post-operative morbidity, longer hospital stays, as well as poorer survival [23‐26]. Depletion of muscle mass may also give rise to chemotherapy toxicities and a poorer response to chemotherapy. In a study of NSCLC patients, variation in muscle mass per unit of body surface area accounted for up to three times the variation of chemotherapy volume of distribution, thus contributing to under- or over-dosing [26]. Clinically, this may manifest as increased risk of dose-limiting toxic side effects in sarcopenic patients, as has been reported in breast, hepatocellular and renal cancer [27‐29].

Whilst these studies attest to the importance of muscle mass, less attention has been paid to muscle function (strength and physical performance) as part of the evaluation of sarcopenia in cancer. Muscle mass is linked to muscle function in a non-linear fashion in the elderly, and consequently muscle mass alone cannot fully account for poor outcomes associated with sarcopenia [30‐32]. As a geriatric syndrome, therefore, the importance of overall neuromuscular function is recognised, with the recommendation that sarcopenia be defined as a combination of loss of physical performance as well as muscle mass [33]. However, the value of assessing physical performance in lung cancer, particularly with regards to tolerance of treatment, is not known.

In light of this gap in knowledge, calls have been made for objective assessments of physical performance which have prognostic value, to evaluate tolerance of systemic treatment [34, 35]. The gold standard method of assessing physical fitness (cardiopulmonary exercise testing) is laboratory-based and not always feasible for use in patients with malignancy [36]. In addition, it is not widely available and takes over 2 hours to perform and report one case. Other more commonly used tests such as the 6-minute walk test (6MWT) can be challenging to use in clinical practice and is often reserved as research tools [34, 37]. The term ‘physical performance’ in this context implies the ability to undertake physical tasks which are dependent on different physiological domains [38]. Utilising a measurement tool which assesses overall function is therefore more appropriate, and is in keeping with guidelines for the elderly. The Short Physical Performance Battery (SPPB) is one such test, measuring balance, gait speed, lower limb strength and endurance – all crucial in performing activities of daily living. It is a valid, reliable and feasible measure of physical performance in older people [39, 40]. It is quick to perform, easily replicable, requires little additional equipment, and with basic training can be performed by most healthcare personnel.

In the assessment of sarcopenia, current gold standard techniques of measuring muscle mass include computed tomography (CT) and dual energy x-ray absorptiometry (DXA) [41]. However, these techniques involve radiation and either additional investigations (DXA) or extension of current CT staging scans to the L3 level with additional software and expertise for interpretation. By contrast, bioelectrical impedance (BIA) measures muscle mass quickly and easily in clinic, with no radiation exposure. It operates through the application of a small, painless electrical current through the body, which enables calculation of the proportions of fat and muscle mass [42]. It is one of the key methods for assessment of muscularity cited in the new definition of cancer cachexia [22], and is a practical tool for measurement of body composition in cancer patients [43‐45].

Whilst current retrospective evidence suggests that muscle mass depletion is associated with increased treatment-related adverse events, it is unclear to what extent measures of muscle mass as well as function at baseline can predict ability to receive and tolerate treatment, and whether they might outperform current methods of MDT assessment. Understanding this may enable more efficient delivery of treatment to this vulnerable patient group, enabling rationalisation of healthcare provision. In addition, it may identify targets for intervention allowing optimisation of patient performance in anticipation of systemic treatment.