Skeletal muscle radiodensity is prognostic for survival in patients with advanced non-small cell lung cancer

Summary

Background & aims

Recent research indicates that severe muscular depletion (sarcopenia) is frequent in cancer patients and linked to cachexia and poor survival. Our aim was to investigate if measures of skeletal muscle hold prognostic information in advanced non-small cell lung cancer (NSCLC).

Methods

We included NSCLC patients with disease stage IIIB/IV, performance status 0–2, enrolled in three randomised trials of first-line chemotherapy (n = 1305). Computed tomography (CT) images obtained before start of treatment were used for body composition analyses at the level of the third lumbar vertebra (L3). Skeletal muscle mass was assessed by measures of the cross sectional muscle area, from which the skeletal muscle index (SMI) was obtained. Skeletal muscle radiodensity (SMD) was measured as the mean Hounsfield unit (HU) of the measured muscle area. A high level of mean HU indicates a high SMD.

Results

Complete data were available for 734 patients, mean age 65 years. Both skeletal muscle index (SMI) and muscle radiodensity (SMD) varied largely. Mean SMI and SMD were 47.7 cm²/m² and 37.4 HU in men (n = 420), 39.6 cm²/m² and 37.0 HU in women (n = 314). Multivariable Cox regression analyses, adjusted for established prognostic factors, showed that SMD was independently prognostic for survival (Hazard ratio (HR) 0.98, 95% CI 0.97–0.99, p = 0.001), whereas SMI was not (HR 0.99, 95% CI 0.98–1.01, p = 0.329).

Conclusion

Low SMD is associated with poorer survival in advanced NSCLC. Further research is warranted to establish whether muscle measures should be integrated into routine practice to improve prognostic accuracy.

Introduction

In advanced cancer, estimates of individual patients' survival are essential for several reasons. These estimates are needed to select the appropriate treatment approach, provide adequate patient information, enable advance care planning, and ensure timely provided palliative care. This is particularly relevant for patients with a poor prognosis such as advanced non-small-cell lung cancer (NSCLC) patients.

NSCLC accounts for approximately 85% of new cases of lung cancer, the leading cause of cancer deaths worldwide [1]. The majority is diagnosed with advanced disease [2], and median overall survival is relatively short [3], [4], [5]. Although several prognostic factors have been identified in advanced NSCLC, performance status (PS) remains the cornerstone to guide treatment decisions in daily clinical practice [6]. There are, however, large variations in survival within each PS group, and to improve outcomes and avoid both over- and undertreatment, there is a need for more precise prognostic factors.

Cachexia, a wasting syndrome linked to loss of weight and appetite, is believed to account for 20% of cancer related deaths [7], and is frequent in NSCLC [8]. Severe muscular depletion is a more recently recognised indicator of cachexia and appears to be a strong negative prognostic factor in ageing, several chronic diseases [9], as well as in malignancies, irrespective of cancer diagnosis, stage and treatment [10]. The majority of cancer studies hitherto performed are, however, small and the most convincing evidence arises from colorectal cancer, hepatocellular carcinoma and other gastrointestinal cancers [10], [11], [12], [13]. From two studies on mixed samples there are also indications that severe loss of muscle mass may be predictive of survival in lung cancer [13], [14].

In studies on cancer patients, muscle mass has been quantified by the cross sectional muscle area on computed tomography (CT) scans, and severe loss of muscle mass is referred to by the term sarcopenia. There is to date no general agreement of cut points to define this entity [10]. To discriminate between sarcopenic and non-sarcopenic patients, survival related thresholds identified in the cohort under investigation have been used [12], [13], [14], [15], [16]. General muscularity varies with several factors including ethnicity, age, gender and prevalence of obesity, and the identified thresholds seem to vary accordingly between populations [12], [13], [14], [15], [16].

In non-cancer settings, the definition of sarcopenia has been expanded to include both muscle mass and function [17]. Hence the quality of the muscle mass in general and the skeletal muscle radiodensity (SMD) in particular has received attention [18]. Assessed by CT imaging, SMD is expressed as the mean Hounsfield Units (HU) of a measured cross sectional muscle area. Low values reflect increased fat deposits, and have been linked to obesity, diabetes and several negative outcomes in non-cancer patients, including reduced physical performance and increased risk of hip fracture [19]. Relatively recent studies have suggested that low SMD may also be a significant prognostic factor in cancer patients [13], [20], [21], [22]. As for sarcopenia, there are no well-established thresholds to define abnormally low SMD [19].

The main aim of the present study was to test the hypothesis that measures of muscle mass and muscle radiodensity are independent prognostic factors for overall survival in advanced NSCLC patients receiving first line palliative chemotherapy, and hence are factors that should be considered in clinical practice to improve prognostic estimates.