Sarcopenia and sarcopenic obesity: do they predict inferior oncologic outcomes after gastrointestinal cancer surgery?

Early definitions of sarcopenia rely upon measures of muscle mass and neglect a functional specification. Evidence suggests the relationship between low muscle mass and adverse outcomes is not linear or direct; rather, they are linked when low muscle mass is associated with muscle weakness (Cruz-Jentoft et al. 2010; Studenski et al. 2014). Recent definitions have evolved to additionally include measures of muscle performance or strength (Table 1).

In 2010, the European Working Group on Sarcopenia in Older People established a working clinical definition of sarcopenia as the presence of both abnormally low muscle mass and low muscle function, either physical performance or strength, in the form of low gait speed or low handgrip strength (Cruz-Jentoft et al. 2010).

In 2014, the Foundation for the National Institutes of Health alternatively defined sarcopenia as a “differential diagnosis” reached through sequential screening for poor physical function, muscle weakness, and low muscle mass. Low gait speed manifested poor physical performance, and inability to rise from a chair (without using arms) or time required to complete five chair stands were also useful standards. Muscle strength was assessed through unadjusted grip strength and muscle mass via body mass-adjusted appendicular lean mass (Studenski et al. 2014).

Sarcopenia is further distinguished from general cancer-related cachexia, “a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment,” which encompasses varying levels of body fat and muscle loss (Dodson et al. 2011; Fearon et al. 2006; Fearon et al. 2011; Fouladiun et al. 2005). Sarcopenia specifically denotes muscle loss (Peng et al. 2012). While cancer cachexic patients experience weight loss and diminished BMI, sarcopenic patients can have normal or increased BMI. As a result, it is still important to screen cancer surgery patients for sarcopenia (Fearon et al. 2011).

During aging and malignancy, lean body mass is lost while fat mass remains constant or increases, possibly leading to SO. SO is defined by subjects who fulfill the combination of criteria for sarcopenia and a given measure of adiposity, such as BMI, waist circumference (WC), computerized tomography (CT)-derived total body fat (TBF), or dual x-ray energy absorptiometry (DXA)/bioelectric impedance analysis (BIA)-derived body fat (Batsis et al. 2013; Lieffers et al. 2012) (Table 1). Metrics of adiposity more precise than BMI, which fluctuates with changes in both muscle and adiposity, may predict cancer outcomes more accurately. Traditional BMI cutoffs have poor diagnostic accuracy when identifying obesity, especially in older populations (Batsis et al. 2016; Romero-Corral et al. 2008).

Previously, decreases in muscle mass were considered largely responsible for muscle weakness and mobility impairment in patients with SO, but current research suggests that deterioration of muscle quality (evidenced by phenomena such as “marbling” or fat infiltration into muscle) is an overlooked contributor (Cruz-Jentoft et al. 2010). Both aging and obesity are associated with decline in muscle quality and higher rates of fat infiltration (Zamboni et al. 2008). Studies find that although obese elderly subjects often acquire a higher absolute muscle mass than non-obese frail and normal counterparts to compensate for body habitus (Visser et al. 2002), they have the poorest muscle quality and strength and, like the non-obese frail, exhibit reduced functional status, aerobic capacity, strength, balance, and gait speed (Villareal et al. 2004). This suggests that sarcopenia and SO may be seriously underdiagnosed, since previous definitions largely ignore muscle quality and the retrospective nature of many existing studies investigating sarcopenia and cancer surgery limits them to criteria relying on muscle mass. Moreover, there remains variability within cutoffs used across studies and uncertainty regarding the applicability of these criteria to all ethnic groups (Studenski et al. 2014).

Various morphometric measures are used to quantify muscle mass (Table 1), including appendicular skeletal muscle (ASM) index (the sum of lean soft-tissue masses for the arms and legs adjusted by height) (Fig. 1) (Baumgartner et al. 1998) and those of core muscles such as total skeletal muscle cross-sectional area at the level of the third lumbar vertebrae (L3mi) (Prado et al. 2008), total psoas area (TPA) (Peng et al. 2011), and psoas density (PD) (Sabel et al. 2011).

Muscle mass has traditionally been measured using BIA or DXA (Chien et al. 2008), but presently, CT and magnetic resonance imaging (MRI) are considered the gold standard methods of assessing body composition in research (Cruz-Jentoft et al. 2010; Bonekamp et al. 2008; Malafarina et al. 2012). CT and MRI are not routinely used in clinical practice for sarcopenia assessment or adiposity assessment, due to concerns about radiation and high cost (Cruz-Jentoft et al. 2010). DXA is inexpensive, most precise for measuring appendicular muscle mass, and exposes patients to minimal radiation but is not portable nor widely available for sarcopenia assessment or adiposity assessment (Bauer and Sieber 2008; Cruz-Jentoft et al. 2010). BIA is an inexpensive, readily reproducible, portable alternative, but results are easily confounded by a number of factors, especially fluid status, and is not preferred for adiposity assessment (Bauer and Sieber 2008).

New image analysis software packages can be used with CT or MRI to streamline segmentation and obtain more consistent body composition measures for sarcopenia assessment. Semi-automated processes like SliceOmatic, NIHImageJ, Analyze, and EasyVision have yielded similar results in terms of reproducibility, while only HippoFat, a fully automated program, has shown to be slightly inferior (Bonekamp et al. 2008). While SliceOmatic segments fastest, NIHImageJ and HippoFat are free. Overall, these software packages have comparable results in analyzing MRI (Bonekamp et al. 2008) and CT images (Irving et al. 2007) but have yet to be incorporated into routine clinical practice.

In patients >65, SO was associated with a two to three times higher chance of reporting an instrumental activities of daily living (IADL) disability than lean sarcopenic, non-sarcopenic obese, or patients with normal body composition (Baumgartner et al. 2004). While non-sarcopenic obesity and SO were both associated with lower physical activity than non-obese sarcopenic and normal body types, only SO was significantly associated with onset of IADL disability, and low physical activity was not associated with IADL disability in the absence of SO. Thus, SO is considered a worst-case scenario compounding health risks of obesity and depleted lean mass (i.e., malnutrition) (Villareal et al. 2004; Kyle et al. 2005; Roubenoff 2004; Davison et al. 2002), and cancer patients with SO are at higher risk of oncologic treatment-related toxicities and mortality (Tsai 2012).

While sarcopenia assessment can help identify cancer surgery patients at risk of worse outcomes, it is important to note that sarcopenia and SO themselves are modifiable. The most effective interventions to date are physical exercise and adequate nutritional protein intake (Deutz et al. 2014; Bauer et al. 2013). Pharmacological therapies for sarcopenia including inhibitors of myostatin, testosterone, selected androgen receptor modulators, ghrelin agonists, and angiotensin-converting enzyme (ACE) inhibitors have been evaluated, but preliminary trials have found that they are less effective than postulated (Molfino et al. 2016; Morley et al. 2014). In older adults vulnerable to functional decline, moderate-intensity physical activity significantly reduces risk of onset of major mobility disability compared to health education and, to a larger degree, risk of persistent mobility disability (Pahor et al. 2014). Since the primary outcome of sarcopenia is mobility disability, a proven intervention from the mobility disability literature, moderate physical activity, is a promising intervention for non-aging sarcopenic patients as well. In addition, relative sarcopenia in obese elderly was significantly ameliorated by diet regimens, exercise programs, or their combination (Villareal et al. 2011). Fat mass decreased under diet or exercise programs or their combination, but lean body mass decreased less under diet-exercise than with only diet and increased under an exercise program. A diet and exercise program yielded the greatest improvements in physical performance and the most consistent changes in strength, balance, and gait and thus may be an important therapy for SO subpopulations.