Skipworth, Richard

Wigmore, Stephen

Ramage, Michael Iain

other

2020-06-23T11:48:09Z

2020-06-23T11:48:09Z

2020-06-27

Cancer cachexia is a constellation of symptoms affecting many cancer patients as their disease progresses. These include loss of muscle mass as well as function, and the utility of computed tomography (CT) in defining this muscle loss has come to the fore in recent years. It is not clear, however, the degree to which CT can be relied on when defining cachexia, interpreting Quality of Life (QoL) metrics, and how this relates to biochemical and functional assessments of skeletal muscle clinically. Accordingly, the aim of this work was to assess the relationship between CT body composition analysis (CT-BCA) measurements, the consensus cancer cachexia definition, QoL metrics, biochemical, and functional assessments of skeletal muscle. The hypothesis was that there would be a relationship between CT-BCA measurements and muscular assessment, and that this could be used to inform future research directions. Patients for this study were recruited from a single tertiary referral centre and were identified through cancer MDTs, and elective admissions. Blood was taken, and CT scans performed, as part of routine clinical work. QoL metrics and functional assessments were performed pre-operatively. Additional blood samples, and Rectus Abdominis muscle samples were obtained intra-operatively. Rectus samples were snap-frozen in optimal cutting temperature compound (OCT) and stored at -80C before being sectioned and fibre diameters measured using an automated process. Muscle protein content was measured using a standard bicinchoninic acid (BCA) method. CT analysis was performed using validated semi-automated software. Statistical analysis was performed in R. 194 patients were recruited into 3 groups (n,M:F): Live donor nephrectomy (LDN) (53, 24:29) (healthy control), Vascular (AAA) (52, 44:8) (non-cancer control), Upper GI cancer (UGIC) (89, 62:27). Using published criteria utilising both CT-BCA and body mass index (BMI) cut-points, the prevalence of sarcopenia was (n, %): LDN (21, 39.6), AAA (29, 55.8), UGIC (42, 47.2). Cachexia according to published cancer cachexia consensus definition criteria was present in (n, %): AAA (11, 21.2), UGIC (53, 59.6). The prevalence of patients meeting cancer cachexia definitions in the vascular cohort was unexpected, and may represent a previously unrecognised component of this disease. Using the healthy control group (LDN) to define population-specific cut-points in order to assess prevalence of sarcopenia produced values which excluded the majority of patients. Differences in QoL metrics were noted between patient groups, with better values noted in LDN patients as could be expected (Mean Overall QoL (lower number indicates better QoL): LDN 6, AAA 30.1, UGIC 29.0). There were, however, few statistically and clinically significant differences in reported QoL metrics or in objective functional measures when patient groups were segregated by CT measures. This may represent the preservation of QoL in a pre-operative cohort; patients sufficiently fit for surgery are likely to have good function and thus QoL, or it may represent a lack of sensitivity of QoL questionnaires to detect aspects or areas of concern to pre-operative patients. An initial analysis of protein content and CT variables suggested a relationship between skeletal muscle radiodensity (SMD) and protein content. On inclusion of the entire cohort, however, there was no strong demonstrable relationship between CT variables and muscle protein content. This continued to be the case after segregation by CT and BMI cut-points. Attempting to define “normal” muscle protein content utilising the healthy control group was negated by the wide range of measured values across all cohorts: (All,M,F microg/mg wet weight) LDN (44.45-335.4, 59.59-303, 44.45-335.4), AAA (42.4-312.96, 42.4-300.33, 62.63-312.96), UGIC (30.99-314.82, 30.99-314.82, 31.84-250.95). Muscle fibre cross-sectional area (CSA) was investigated graphically initially. Using this technique, it was possible to partially separate groups of muscle CSA using CT. When using more mathematical methods, however, it was not clear that these separations were significant. Additionally, the derived weighted mean value did not demonstrate a strong relationship with CT variables. Using anastomotic leak following Ivor-Lewis Oesophagectomy as a surrogate for severe inflammation allowed investigation of this mechanism of cachexia development. Comparison of pre-operative with post-operative scan results produced changes in CT variables which may further confound interpretation (mean skeletal muscle area (SMA) pre- vs post-operative: Male 154.4 vs 162.9, Female 85.4 vs 122.9, mean SMD pre- vs post-operative: Male 32.1 vs 28.1, Female 36.6 vs 27.7). These suggest a possible underlying inflammatory reason for changes seen late in cachexia, and a possible masking of early deterioration in muscle mass. Currently-used CT cut-points for sarcopenia find higher than expected prevalence in healthy groups, and whilst population-specific values should be derived, they may not always represent a true reflection of muscularity in all groups. Pre-operative patients of all types have globally preserved function and QoL, and more sensitive metrics are required for this group of patients. CT changes may not reflect QoL reduction until the disease is advanced. The relationship between CT muscle variables and individual components of biochemical muscle composition is unclear and further consideration of alternate muscle constituents such as the nucleus and the sarcoplasmic retuculum is warranted. Inflammation has a marked impact on CT variables, and interpretation of CT variables should include an assessment of systemic inflammation. The current linear paradigm relating muscle mass to function and hence to patient outcome may need to be reconsidered, and this will potentially have an impact on informing the design of and recruitment to future cachexia intervention trials. CT is a useful tool in the assessment of skeletal muscle and the variables provided can help to indicate prognosis. CT does not, however, reliably inform about QoL; patient function; or muscle constituents; and should not be used in isolation for patient assessment.

https://hdl.handle.net/1842/37182

http://dx.doi.org/10.7488/era/483

en

The University of Edinburgh

The relationship between muscle protein content and CT-derived muscle radio-density in patients with upper GI cancer Michael I Ramage, Neil Johns, Christopher D. A. Deans, James A. Ross, Thomas Preston, Richard J. E. Skipworth, Carsten Jacobi, Kenneth C. H. Fearon Clin Nutr. 2018 Apr;37(2):752-754. doi: 10.1016/j.clnu.2016.12.016. Epub 2016 Dec 27.

The relationship between muscle mass and function in cancer cachexia – smoke and mirrors? Ramage MI, Skipworth RJE Curr Opin Support Palliat Care. 2018 Dec;12(4):439-444. doi: 10.1097/SPC.0000000000000381.

MacDonald A, Miller J, Ramage M, Greig C, Stephens N, Jacobi C, et al. Cross sectional imaging of truncal and quadriceps muscles relates to different functional outcomes in cancer. Clinical Nutrition 2018. https://doi.org/https://doi.org/10.1016/j.clnu.2018.12.023.

cachexia

low density muscle

sarcopenia

quality of life

muscle fibre area

CT scan measurements

clinical trial design

Critical assessment of computed tomography as a valid means of muscular body composition analysis in cancer cachexia

Thesis or Dissertation

Doctoral

MD Doctor of Medicine