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The impact of sarcopenia on patients undergoing treatment for pancreatic ductal adenocarcinoma

Amundson, Julia R. MD, MPH; Williams, Jelani K. MD; Benjamin, Andrew J. MD, MS; Witmer, Hunter D.D. MD; Roggin, Kevin K. MD

Author Information
doi: 10.1097/JP9.0000000000000046
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Abstract

Introduction

Pancreatic ductal adenocarcinoma (PDAC) represents the 4th leading cause of cancer death in both men and women in the United States.[1] The burden of pancreatic cancer, one of the most deadly cancer diagnoses, with a 5-year survival rate of 2% to 6%, has steadily been rising. As demographics shift toward a more geriatric population, the incidence of pancreatic cancer is expected to continue to rise and rank third in leading causes of cancer-related mortalities in the United States by 2030.[2]

To date, resection remains the only definitive means of cure for those diagnosed with PDAC but is associated with high morbidity and mortality.[3,4] To maximize outcomes, patient selection is paramount. Therefore, the need to identify potentially modifiable, patient-specific factors that predict outcomes in those undergoing treatment for PDAC is critically important. One such predictor of outcomes for patients undergoing major surgery is the presence of sarcopenia,[5] which has been reported in 21.3% to 65.3% of patients undergoing resection of PDAC.[6] This review attempts to summarize the current literature on the impact of sarcopenia in patients undergoing treatment for PDAC.

Defining frailty, sarcopenia, sarcopenic obesity, and cachexia

Frailty

Frailty is a geriatric syndrome that includes physical, cognitive, psychological, and social dimensions. Rockwood defined frailty as dependence on others for activities of daily living (ADLs).[7] A more comprehensive definition was offered by Fried as 3 or more of the following observations: unintentional weight loss ≥10 lb in past year, self-reported exhaustion, weakness on grip strength testing, slow walking speed, and low physical activity as observed in community-dwelling adults ≥65 years of age. Fried's frailty is an independent predictor of adverse events including falls, worsening mobility/ADL disability, hospitalization, and death.[8]

Sarcopenia

Sarcopenia, with a prevalence of 5% to 10% in those >65 years and ∼40% in those >80 years of age,[9,10] is related to both cachexia and frailty. The majority of frail patients will be sarcopenic, but the converse does not hold true.[11] The first consensus definition of sarcopenia was released by the European Working Group on Sarcopenia in Older People (EWGSOP) in 2010 with a recent update in 2019.[11,12] Sarcopenia was defined as a “progressive and generalized skeletal muscle disorder” characterized by both loss of skeletal muscle mass and strength with an associated increased risk of adverse outcomes. Sarcopenia can be either a primary syndrome or secondarily associated with the presence of a malignancy. Emphasis is placed on the fact that declining muscle mass does not hold a linear relationship with functional status, that is, strength or performance, mandating both low muscle mass, and function to define sarcopenia. Similar consensus statements have been released by the International Working Group on Sarcopenia[13] and the Asian Working Group on Sarcopenia.[14] The FNIH Sarcopenia Project released a consensus definition in 2014 focusing on physical performance metrics to define sarcopenia (Table 1).[15]

Table 1
Table 1:
Definitions of sarcopenia.

In the 2019, EWGSOP update and the International Clinical Practice Guidelines for Sarcopenia published in 2018, consensus recommendations were to use a screening tool such as the SARC-F questionnaire when adults >65 years encounter the healthcare system as it is both highly sensitive and specific.[16,17] The SARC-F questionnaire is a 5-item screening tool in which higher scores are correlated with presence of sarcopenia. To confirm a suspected case of sarcopenia, muscle strength/performance should be evaluated with a standardized measure of grip strength or a chair stand test. Other standardized geriatric physical performance assessment tools have also been extensively studied and shown to correlate with a diagnosis of sarcopenia.[12] Imaging modalities can be used to estimate the quantity and/or quality of skeletal muscle as a proxy for sarcopenia (i.e., radiographic sarcopenia), but have limited clinical utility due to the changing definitions of sarcopenia, lack of controlled trials, and paucity of studies that include physical performance testing of patients. Nevertheless, radiographic sarcopenia has been linked to poor outcomes following pancreatic surgery (Table 2).[18–26]

Table 2
Table 2:
Morbidities associated with sarcopenia in patients undergoing pancreatic resection.

Cachexia

Cachexia is a multifactorial syndrome often present in patients with pancreatic malignancy characterized by severe body weight, fat, and muscle loss as well as increased protein catabolism due to underlying disease(s).[27] Cancer cachexia has been defined by consensus definition as 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. Three factors must be presents including weight loss ≥10%, low food intake ≤1500 kcal/day, and systemic inflammation C-reactive protein ≥ 10 mg/L.[28] In individuals with a starting body mass index (BMI) < 20 kg/m2 or sarcopenia, only 2% weight loss in the past 6 months is required for a diagnosis of cachexia.[29,30] Markers of cachexia have been strongly and consistently associated with adverse quality of life, reduced functional abilities, more symptoms, and shorter survival in patients with gastrointestinal (GI) malignancies.[31,32] In contrast to cachexia, which by definition cannot be fully reversed, sarcopenia, which has also been associated with poor outcomes in cancer patients,[20] may be a reversible condition.[33]

Sarcopenic obesity

Sarcopenic obesity represents a subset of patients with sarcopenia, characterized by the loss of skeletal muscle mass and function in addition to an increase in adipose tissue mass, most often defined as increased BMI. This differs from the current definition of obesity based on BMI irrespective of relative body composition.[27] In other words, obese and sarcopenic obese patients may have equivalent BMIs yet differ substantially with regards to functional status due to differing quality and quantity of muscle mass. Sarcopenic obesity may represent a progressive disorder with decrease in lean muscle mass leading to a reduction in resting metabolic rate and physical activity secondary to weakness, predisposing to a positive energy balance and fat accumulation.[34] Proposed mechanisms involved in sarcopenic obesity include increased tissue necrosis factor-alpha and leptin from hormonal activity of fat tissue, influencing insulin resistance, energy metabolism, and growth hormone secretion.[36] Prior cutoffs for sarcopenic obesity have been set at 2 standard deviations below sex-specific mean for a young reference population of appendicular skeletal mass/height squared and percent body fat >27% in men and >38% in women.[10] An alternate definition proposed by Davison et al[35] defines sarcopenic obesity as those who fall into the of upper 2 quintiles of body fat and lower 3 quintiles of muscle mass, due to concern that higher BMI can mask the presence of sarcopenia proposed by Baumgartner et al. However, definitions of sarcopenic obesity tend to ignore muscle quality and infiltration of fat into muscle, emphasizing the importance of function as part of the definition of sarcopenia.[36]

In community-dwelling older adults, sarcopenic obesity has been associated with increased development of instrumental ADL (IADL) disability. This is in contrast to individuals with sarcopenia who were not classified as obese, who showed no increased risk of developing IADL disability.[37] In patients with GI tract malignancies, sarcopenic obesity has been shown to be an independent predictor on multivariable analysis of shorter overall survival (OS) and increased risk of complications when compared to obese patients who are not sarcopenic.[25,38] The International Study Group of Pancreatic Surgery recommend assessment of both sarcopenia and sarcopenic obesity in the preoperative evaluation of all patients before pancreatic surgery as they are strong predictors of poor short- and long-term outcomes.[18–24,39]

Techniques to measure sarcopenia

Muscle mass

Imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) are the most common methods for determining muscle mass and considered to be the gold standard due to their ability to delineate muscle from other soft tissues. However, due to the high cost of both CT and MRI and the hazardous ionizing radiation exposure associated with CT scans, these tests are usually only obtained when clinically indicated. Therefore, we do not have extensive data in healthy or non-acutely ill older patients. In patients with pancreatic cancer, both of these tests are part of the routine diagnostic and staging evaluation. Unfortunately, the cutoffs for identifying sarcopenia are not well defined, and measurements must be adjusted for height, BMI, and the standardized values must be adjusted based on population characteristics.

Muscle quantity is typically reported as total body skeletal muscle, appendicular skeletal muscle, or as cross-sectional areas of specific muscle groups (commonly the psoas or dorsal muscle groups) or at specific levels on CT scan (e.g., at the third lumbar spine vertebra [L3] level). This has evolved over time to more comprehensive measurements such as analytic morphomics, which volumetrically evaluates musculature at multiple levels and has been shown to correlate with perioperative risk across several clinical scenarios, including pancreatic cancer outcomes.[22,25,40] Morphomics allows for in-depth characterization of muscle mass and quality to define parameters of sarcopenia while additionally allowing for correlation with other body imaging factors such as visceral/subcutaneous fat, bone density, or vascular calcification measurements. The complex relationships and associations that are possible with analytic morphomics makes it a promising tool to further characterize and identify sarcopenic patients. Certain imaging modalities have shown a correlation between morphomics and functional status in older patients.[41] As definitions of radiographic or CT-sarcopenia have changed over time, there is limited generalizability of the studies reviewed below (Table 3  ). This underscores the need for a standardized method of defining sarcopenia in different patient populations as well as high quality, prospective data collection.

Table 3
Table 3:
Heterogeneity of studies.
Table 3 (Continued)
Table 3 (Continued):
Heterogeneity of studies.
Table 3 (Continued)
Table 3 (Continued):
Heterogeneity of studies.

Other imaging modalities for measuring muscle mass include dual-energy X-ray absorptiometry (DXA) and bioelectric impedance analysis (BIA). DXA is widely available and can non-invasively measure muscle quantity within minutes with minimal radiation exposure, however results must be adjusted for patient height and weight and there has been found to be wide variation among different DXA machines. In addition, measurements can be impacted by a patient's hydration status. BIA is an inexpensive and facile method for indirectly estimating muscle mass based upon whole-body electrical conductivity that correlates well with estimates from MRI. It is important to consider that BIA models are valid for the populations from which they were derived, and that hydration status can also influence measurements.

Muscle quality

Muscle quality refers to changes in muscle composition and possible function which can be quantified on imaging. Muscle quality can be inferred from characteristics on cross-sectional imaging or via biopsy. For example, muscle Hounsfield units (HU) measured on CT scans can be used as measures of myosteatosis, the infiltration of intramyocellular and intermuscular adipocytes. Previous studies have validated the use of CT attenuation to measure myosteatosis.[42] However, there is notable discrepancy in the cutoff values used for HU representing muscle vs intramuscular adipose tissue (IMAT) as well as cutoff designations for IMAT when measured directly. Radiographic muscle quality has been shown to correlate with clinically significant outcomes in patients undergoing pancreatic surgery, though there is still no universal consensus on assessment of muscle quality on imaging or standards for interpretation based upon the timing of intravenous (IV) contrast administration. Although not often accounted for in studies, it has been shown that the timing of IV contrast administration can cause significant differences in measures of muscle attenuation.[43] As such, it is important to take the phase of a CT into account when assessing for sarcopenia in research or clinical settings.

Muscle strength

Muscle strength has been determined to be one of the most important determinants of sarcopenia and has been recognized as a better predictor of adverse outcomes than muscle quantity or quality.[44,45] Muscle strength is best measured by grip strength, which is easy and inexpensive to obtain. Low grip strength has been shown to predict adverse outcomes, including death.[46,47] Grip strength, often measured using a handheld dynamometer, is easily assessed in the clinic and is moderately correlated with strength in other body compartments, making it a reliable surrogate for a patient's overall strength. Lower extremity strength can be assessed using isometric torque methods when grip strength is not able to be obtained, such as with advanced arthritis or weakness due to stroke. In addition to direct measurements, the chair stand test can indirectly estimate lower extremity strength by measuring the amount of time needed for a patient to stand 5 times from a seated position without the use of their upper extremities. The timed chair stand test is a variation that counts how many times a patient can complete the maneuver in a 30-s interval.[48] Although convenient, both tests require a combination of strength and endurance, and therefore the results of such tests must be interpreted in this context.

Physical performance and geriatric assessments

Measurements of physical performance can be based upon self-report questionnaires, activity logs, or via direct observation. Self-reported methods have shown reliability on the population scale but are subject to recall bias while direct observation has a subjective component to quantifying level of activity. Several examples of self-reported geriatric assessments used to identify frail or sarcopenic patients include the Vulnerable Elders Survey and components of Fried's frailty such as the self-reported exhaustion questionnaire. Self-reported exhaustion is defined as agreement with either of the following 2 statements: within the last 2 weeks, (1) “I felt that everything I did was an effort” and (2) “I could not get going.”[8] Although subjective, self-reported exhaustion has been shown to be a strong predictor of serious complications in patients undergoing pancreatic surgery.[20,40,49] Comprehensive measures of physical performance include validated geriatric assessments such as the Short Physical Performance Battery (SPPB), 6-min walk test, and the Timed-Up and Go (TUG) test. The SPPB consists of timed gait speed over 3 min, 5 timed chair stands, and timed measures of standing balance in 3 positions. The SPPB is scored on a 12-point scale with impairment is defined as a score less than 8. Although gait speed is part of the SPPB, gait speed as an independent measure has been validated as a reliable test for sarcopenia. A speed of <0.8 meters/second (m/s) on the 4-min usual walking speed test has been shown to be a marker of sarcopenia. The TUG test measures the time needed to stand up from a chair, walk a short distance and return to the chair and sit. It measures whole body function including balance and is measured on a 5-point scale.

All of the physical and geriatric assessments can be performed in a clinical setting; however, more complex assessments such as the SPPB may require significant time as well as trained practitioners to administer the test correctly. Alternatively, one of the most informative questionnaire assessments, self-reported exhaustion, can easily be obtained during a routine history and physical. Future research will help elucidate how physical and geriatric assessments are related, perhaps revealing the most time efficient assessments to detect sarcopenia or what combination of clinical and radiographic assessments best defines a patient's phenotype.

Clinical significance of sarcopenia in PDAC

Sarcopenia is an increasingly recognized characteristic of many patients undergoing treatment for PDAC with a prevalence of 21.3% to 86.3%.[49,50] The reported effect of sarcopenia on patients undergoing treatment for PDAC has been debated in studies to date (Table 3  ).

Perioperative morbidity associated with sarcopenia, sarcopenic obesity, and myosteatosis in PDAC resection

Sarcopenia has been shown to independently correlate with increased rates of morbidity in patient undergoing pancreatic resection in several studies, the majority of which are retrospective in nature and included patients undergoing resection for non-PDAC malignancies and/or benign disease.[18–24] Only 2 retrospective studies to date have shown increased morbidity in sarcopenic patients undergoing pancreatic resection solely for PDAC[25,26] while others have shown no statistically significant difference.[51–55] These morbidities include increased overall postoperative complications (odds ratio [OR] 1.80, P < .001),[18] higher incidence of both surgical complications (OR 3.524, P = .005)[21] and Clavien Dindo Class III or higher complications (OR 2.28, P < .001)[18] (34% vs 15.7%, P = .001)[19] (OR 1.69, P = .006),[25,26] higher rates of National Surgical Quality Improvement Program serious complications (P = .008),[20] increased rates of postoperative pancreatic fistula (POPF) (OR 2.896, P = .007)[19] (OR 4.23, P = .014),[22] more general postoperative infections,[23] and a longer length of hospital stay in sarcopenic patients[24–26] (15 vs 13 days, P = .001).[19] Other morbidities associated with sarcopenia include longer intensive care unit stays[26] and increased frequency of discharge to skilled nursing facilities (OR 0.79, P = .019).[22] In one study, among patients who underwent resection for PDAC, 75% (9/12) of those who did not make it to adjuvant therapy were sarcopenic. Sarcopenic patients with PDAC also had a longer delay in initiation of adjuvant chemotherapy following pancreaticoduodenectomy (PD) (37 vs 34 days, P = .043).[19]

Sarcopenic obesity, a measure of frailty with a prevalence of 0.6% to 53% in patients undergoing treatment for PDAC, has been associated with more morbidity than sarcopenia or obesity alone in such patients.[6,54] As such, after PD for PDAC, patients with sarcopenic obesity had increased overall complications (OR 1.39, P = .03)[25] and increased major complications (OR 3.2, P = .008) compared to obese patients without sarcopenia.[54]

Several studies evaluating myosteatosis have evaluated increased fatty deposits in skeletal muscle or IMAT, defined by HU of skeletal muscle on CT, as a proxy measure for sarcopenia with mixed results. Lower skeletal muscle attenuation measured in HU has been correlated with increased morbidity[18,20,22,55–57] or no significant difference.[40,52] Likewise, for studies evaluating IMAT, lower muscle density has been correlated with worse outcomes in several studies[26,58] while others show no correlation.[59] Although the etiology of myosteatosis remains unknown, it has been speculated that this finding may be related to the catabolic state associated with cancer cachexia.[60] A recent study showed that the presence of myosteatosis is associated with an increased risk of major complications (P = .035) in patients undergoing PD for PDAC.[52]

Perioperative mortality and long-term outcomes associated with sarcopenia and sarcopenic obesity in PDAC resection

The long-term impact of sarcopenia on patients undergoing surgical resection of PDAC is uncertain. Often, a preoperative diagnosis of sarcopenia has shown no effect on mortality.[19,26,61,62] Others studies have demonstrated sarcopenia to be an independent predictor of decreased OS (hazard ratio [HR] 2.1, P = .013),[63] 8-month OS (HR 1.79, P = .031),[51] (HR 1.999, P < .001),[64] 3-year OS (HR 1.63, P < .001),[65] and 5-year OS (HR 1.46, P = .006).[25] In addition, interval changes in body composition during treatment have been correlated with long-term outcomes following surgical resection of PDAC. Higher pretreatment psoas muscle cross-sectional area has shown to be predictive of improved survival (HR 0.84, P = .04)[40] and gaining total L3 lean muscle mass 1-year postresection may be protective against mortality.[62] In contrast, the loss of postoperative lean psoas muscle mass following resection of PDAC is associated with shorter OS.[40] The presence of sarcopenia may also have an impact on recurrence following surgical resection of PDAC with 2 studies demonstrating an increased risk of recurrence[55,64] while another reported no correlation.[51]

In a recent systematic review and meta-analysis of all patients undergoing treatment for PDAC, excluding studies that used psoas muscle as a measure of sarcopenia, Mintziras et al showed sarcopenic obesity to be an independent predictor of decreased OS (HR 2.01, P < .001). Sarcopenic obesity, with a prevalence of 0.6% to 25%, was a stronger predictor of mortality than sarcopenia alone.[6] The included studies were Tan et al (HR 2.07, P = .006), Dalal et al (HR 1.808, P = .054), Ninomiya et al (HR 2.1, P = .013), and Okumura et al (HR 2.01, P = .02), evaluating patients undergoing palliative treatment, chemoradiotherapy, and resection for the final 2 studies.[53,55,63,66] Other recent studies using both comparable and broader definitions of sarcopenia have shown similar results, with Pecorelli et al showing visceral fat area/total abdominal muscle area >3.2 to be both an independent predictor of mortality (each 1.6-unit increase with associated OR 1.95, P = .009) and failure to rescue from major complications (OR 5.7, P = .008) following resection of PDAC.[67,68] Stretch et al[52] also observed a 15-month shorter OS (HR 3.084, P = .0048) for patients with sarcopenic obesity undergoing surgical resection of PDAC. Conversely, Cooper et al[69] have shown that sarcopenic obesity does not correlate with OS, disease free survival or progression free survival following resection of PDAC.

Effect of sarcopenia on chemotherapy outcomes for PDAC

Chemotherapy is a mainstay of treatment for PDAC in the adjuvant and neoadjuvant setting, particularly for patients with borderline resectable disease, unresectable disease, or as definitive therapy for metastatic disease.[4] Borderline resectable PDAC has been described as localized tumors defined radiographically as solid tumor contact with superior mesenteric or portal veins (>180 degrees), involvement of the inferior vena cava, abutment of common hepatic artery (without involvement of the celiac axis or hepatic arteries), or less than 180-degree involvement of the superior mesenteric artery.[70] Some studies suggest that sarcopenic patients are at greater risk of severe adverse events during systemic chemotherapy[71,72] as toxicity is significantly associated with lean body mass but not total body surface area, on which most regimens are dosed. Women tend to have a lower lean body mass compared to total body surface area and are at higher risk for dose-limiting toxicities.[73]

It is important to identify those at risk for worse outcomes associated with neoadjuvant therapy. Chemotherapy is known to cause a decrease in both skeletal muscle and adipose tissue. An interval decrease in muscle mass and density during neoadjuvant chemotherapy has been shown to trend toward worse outcomes compared to patients who had upfront surgical resection[40] and to trend toward lower probability of undergoing successful surgical resection in sarcopenic obese patients (70% vs 48%, P = .07) with PDAC.[69] Notably, neither of these studies reached statistical significance. Others have demonstrated a significant association between sarcopenic obesity and worse OS (P = .04) in patients undergoing neoadjuvant chemotherapy.[69] Lean tissue loss during neoadjuvant chemotherapy for borderline resectable PDAC has been associated with higher mortality risk (HR 1.21, 95% confidence interval 1.08–1.35, P = .001) and preservation of muscle mass shown to be independently protective against mortality[74] while an increase in lean muscle mass has been associated with a higher likelihood of successfully undergoing surgical resection (P < .01).[75] Muscle gain was most notable in those being treated with FOLFIRINOX (P = .04).[75] Others have demonstrated that increased muscle mass 1-year postsurgical resection is protective, as evidenced by improved OS.[40] These cohorts must be interpreted in the context of excluding those patients who did not make it to their interval CT scan at 1-year postresection.[40,62]

Few studies have evaluated the effect of sarcopenia on adjuvant chemotherapy for PDAC. The inability to receive adjuvant chemotherapy secondary to sarcopenia has shown an associated reduction in survival and 100% mortality at 5 years.[63] Di Sebastiano et al[76] demonstrated improved survival in sarcopenic patients, confounded by a higher proportion of earlier stage cancers in the sarcopenic subgroup.

A concurrent diagnosis of sarcopenia and PDAC has been shown to predict more morbidity and shorter OS during palliative chemotherapy for locally advanced or metastatic PDAC.[49,50,58] In patients undergoing palliative gemcitabine, 5-FU, or FOLFIRINOX based treatment, a diagnosis of sarcopenia led to a 3.8-month shorter OS in men (HR 1.721, P < .001) but no change in OS in women.[49] In recurrent and metastatic PDAC, patients undergoing palliative gemcitabine-based chemotherapy had the highest prevalence of sarcopenia of any of the studies evaluated at 86.3%, with sarcopenia conferring worse OS (HR 2.97, P = .019). Sarcopenic obesity, myosteatosis, an increased rate of lean muscle loss, or a new diagnosis of sarcopenia while undergoing palliative chemotherapy are predictive of poorer OS.[56] Sarcopenic obesity has been shown to be associated with more grade 3 and 4 hematologic toxicities on univariate analysis (P = .008).[58] Conversely, there are several studies that demonstrate no effect of pre-treatment sarcopenia on outcomes for patients undergoing palliative chemotherapy or chemoradiotherapy for PDAC[56,66] and mixed results regarding ability to tolerate palliative treatment.[53,56]

Treatments and interventions

Prehabilitation programs

Prehabilitation is defined as preoperative interventions that improve the physiological reserve of patients before surgery. These span physical exercises and training, psychological, and nutritional interventions aimed at reducing postoperative complications, decreasing length of hospital stay, and improving quality of life.[77] Physical prehabilitation before surgery has been shown to be superior to rehabilitation after surgery, improving function to better than preoperative levels in patients undergoing colorectal surgery.[78] Resistance exercise has been shown to increase muscle mass, strength and power but with potential for falls and muscular injuries.[79]

Several meta-analyses have evaluated the impact of physical activity programs on sarcopenic patients preoperatively with conflicting results.[80,81] Specifically looking at patients undergoing PD, there is scant literature. In a small randomized controlled trial, Ausania et al[82] compared prehabilitation to standard care in patients undergoing PD for PDAC or periampullary tumors and demonstrated no difference in overall and major complications or POPF formation. There was a statistically lower rate of delayed gastric emptying in the prehabilitation group compared to the control group (5.6% vs. 40.9%, P = .01). While multimodal programs for PDAC patients undergoing palliative chemotherapy have proven feasible with approximately 50% adherence rates, these have not been powered sufficiently to demonstrate improved outcomes.[83] This is of particular importance as recent studies have shown that a diagnosis of frailty, of which sarcopenia is a common characteristic (55.6%), should not preclude curative treatment and interventions to negate the associated morbidity of frailty and sarcopenia should continue to be investigated.[84] Prospective, randomized controlled studies using standardized prehabilitation regimens for patients specifically undergoing resection of PDAC are needed to delineate the value of prehabilitation.

Nutrition

Nutritional optimization has taken a prominent role in perioperative care of malnourished patients undergoing major abdominal surgery,[85] seeking to replete electrolytes and prevent nutrition-related complications such as poor wound healing and arrhythmias.[39,86] The European Society for Clinical Nutrition and Metabolism (ESPEN) recommends 7 to 10 days of nutritional “conditioning” before major GI surgery in malnourished patients and even longer interventions for the severely malnourished.[87] The International Study Group of Pancreatic Surgery published guidelines in 2018 on the nutritional support of patients undergoing pancreatic surgery. They recommend “aggressive preoperative nutritional support” only in severely malnourished patients, defined as >15% weight loss within 6 months, BMI < 18.5 kg/m2, and serum albumin <3 g/dl, with level C evidence.[39] In order to screen for these patients, the group recommends routine preoperative nutritional assessments for all patients undergoing pancreatic surgery with grade 1 strength and level B evidence.

Specific nutritional interventions include preoperative immunonutrition and carbohydrate loading, both of which are supported by moderate levels of evidence. Immunonutrition, or protein supplementation including amino acids such as arginine, theoretically reduces the inflammatory response after surgery. It has been shown to increase muscle mass, synergize with exercise to increase muscle strength and power, and only minimally increase serum creatinine levels.[79] Arginine, a semiessential amino acid, also aids in regulation of vascular dilation and blood flow. When incorporated into enhanced recovery after surgery (ERAS) programs following PD, immunonutrition has been shown to reduce length of hospital stay, overall complications, and readmission rates.[23,86,88] Major surgery such as pancreatic resection generates a large inflammatory response and releases of a cascade of cytokines known to produce substantial changes in metabolism, nutrition, and increased risk of infection.[39,86] Carbohydrate loading, drinking highly concentrated carbohydrate drinks preoperatively, is a component of many ERAS protocols and recommended by the ESPEN group with a grade A/B.[87,89] Although high-quality evidence is lacking, it is thought to decrease postoperative nausea and vomiting, reduce insulin resistance, improve hunger and appetite, promote wound healing, improve overall well-being, and decrease length of hospital stay.[87,89]

Pancreatic exocrine insufficiency, defined by the breath test, has recently been shown to correlate with radiographic sarcopenia (i.e., decreased psoas muscle mass). Although this data shows a correlation and does not define causation, the authors propose that pancreatic exocrine insufficiency may be part of the pathogenesis of sarcopenia in pancreatic adenocarcinoma. Pancreatic exocrine replacement may therefore help to limit sarcopenia and or improve prognosis in pancreatic adenocarcinoma.[59]

Combined physical prehabilitation and nutritional support programs have also been studied. Mazzola et al evaluated patients performing aerobic activity (walking for ≥30 min) and using an incentive spirometer 3 times daily in addition to nutritional supplementation for ≥5 days before oncologic foregut resections.[90] For their primary outcomes, they reported a 14% (P < .01) and 28% (P = .001) reduction in 30-day and 3-month mortality, respectively. Secondarily, they saw reductions in overall complications by 33% (P < .005) and severe complications by 26% (P < .02). Multimodal approaches have been shown to lower costs and decrease length of hospital stay associated with the treatment of sarcopenia and frailty.[91]

Future interventions

To date, data regarding optimal prehabilitation treatment strategies for sarcopenic patients undergoing pancreatic resection for PDAC is still lacking. Published data shows mixed results and evaluates heterogeneous patient populations undergoing procedures other than pancreatic resection and for disease processes other than PDAC. Future directions include optimizing insulin resistance preoperatively, the use of pre and probiotics, omega 3 fatty acids, sex hormones, pharmacologic agents, and targeted antibody therapies.

Pre and probiotics

The use of fiber and symbiotic bacterial flora such as Lactobacillus, also known as ecoimmunonutrition, has been shown to reduce rates of postoperative pneumonia, surgical site infection, and anastomotic leak following colorectal surgery and reduce rates of wound infection following pancreatic and hepatobiliary resections.[87] Supplementation with probiotics immediately following pylorus preserving PD has been shown to significantly decrease rates (12.5% vs 40%, P = .005) of all infections (pneumonia, wound, urinary tract, etc.) when compared to fiber supplementation alone.[92]

Omega 3 fatty acids

Perioperative inflammation disrupts normal immune system function and chronic inflammation is thought to contribute to both sarcopenia and aging, a phenomenon coined “inflammaging.” [93] Thus, the inflammatory state is a potential target in sarcopenic, elderly patients undergoing surgery for PDAC. Omega 3 fatty acids have anti-inflammatory properties and are important in cardiovascular health but may also may affect bone, skeletal muscle, cognitive, and eye health, offering potential benefit in preoperative optimization of sarcopenic patients undergoing resection of PDAC.

Sex hormones

Sex hormones play an important role in muscle health and their decline with age has been directly linked to a decline in muscular strength and the development of sarcopenia. Although exogenous administration has been shown to boost muscle mass and strength, no studies to date have proven a benefit to treating sarcopenia with hormonal therapy.[12,94]

Pharmacologic agents

Currently, there are many pharmacologic agents under investigation for the treatment of sarcopenia. Growth hormone and insulin related growth factor 1 have been shown to increase muscle mass but not muscle strength.[79] A monoclonal antibody to the myostatin receptor, Bimagrumab, has been developed to block and prevent inhibition of skeletal muscle growth.[95] In a double blinded randomized control trial, patients 65 and older demonstrated significantly increased thigh muscle volume, grip strength, and gait speed with Bimagrumab.[95] Other pharmacologic agents under investigation include beta blockers and angiotensin-converting enzyme inhibitors, with associated increased hand grip strength, walking distance, and decreased hip fracture but risk for hypotension, hyperkalemia, and muscle cramps.[79] While these pharmacologic interventions show promise, they remain investigational without strong evidence to support their use in the treatment of sarcopenia.[12]

Discussion

PDAC is a deadly disease with a rising incidence that affects primarily geriatric patients. Long-term outcomes for patients with PDAC remain poor with 5-year survival rates as low as 2% to 6% and surgical resection remains the only method of achieving cure. In an attempt to optimize outcomes, it is important to evaluate the impact of patient-specific preoperative factors such as sarcopenia and sarcopenic obesity. This is particularly true as the demographics of our population shift toward a more obese populace, potentially confounding the value of conventional risk stratification measures such as cachexia that are known to be prognostic in patients undergoing treatment for PDAC.

To date, investigations into the effect of a pre-treatment diagnosis of sarcopenia or sarcopenia obesity on outcomes for patients undergoing treatment for either palliation or curative intent for PDAC have shown mixed results. This is due in part to the heterogeneity of studies including heterogeneous patient populations, definitions, methods of measurement, cutoff values, and follow-up intervals. In addition, the majority of studies to date are retrospective in nature and therefore do not address the second part of the EWGSOP consensus definition which defines sarcopenia by both mass and function. Radiographic measures have been shown to correlate with function of muscle but this has not been studied extensively in a prospective manner.

Going forward, there is a need for standardized definitions of sarcopenia and sarcopenic obesity. This will allow for comparison across studies and broader conclusions regarding the importance of identifying preoperative sarcopenia and sarcopenia obesity in patients diagnosed with PDAC. Highlighting this fact, several published studies compare measures of sarcopenia based on cross-sectional area of muscle and volumetric analysis within the same cohort and demonstrate discrepancy in the predictive value of the measures. Standardized definitions will also allow for all patients to be evaluated based on their imaging studies obtained at the time of diagnosis as a part of their staging work up.

The prevention and treatment of sarcopenia remains of significant clinical importance, particularly for patients undergoing major surgery such as resection of PDAC. The strongest evidence for treatment and prevention of sarcopenia remains resistance exercise, with mounting evidence for nutritional optimization. The use of new and existing pharmacologic agents to treat sarcopenia is promising but to date is not recommended by strong evidence or expert consensus. Multimodal approaches have been shown to lower costs and decrease length of hospital stay associated with the treatment of sarcopenia and frailty. Such interventions need to be investigated in specific populations such as those most at risk for adverse outcomes following major surgery, that is, elderly patients with sarcopenic obesity undergoing pancreatic resection for PDAC.

Eventually, this information could be integrated into a preoperative risk stratification tool that would help to dictate treatment pathways for patients with resectable or borderline resectable disease. Individuals who are likely to have worse outcomes with neoadjuvant therapy can be directed toward up-front surgical resection while patients undergoing neoadjuvant therapy may also benefit from preoperative optimization before definitive resection, which still remains the only definitive means of cure.

Conclusion

PDAC remains a deadly disease and patient-specific factors such as sarcopenia and sarcopenic obesity identified at the time of cancer diagnosis offer potential as risk stratification measures and points of intervention. Standardized definitions, measurement tools and prehabilitation regimens are needed to evaluate the importance of a diagnosis of sarcopenia or sarcopenic obesity in patients with PDAC. The literature to date shows heterogeneous results in terms of the impact of sarcopenia and sarcopenic obesity in this patient population but interpretation is limited by the degree of heterogeneity of the aforementioned studies.

Acknowledgments

None.

Author contributions

JRA: Participated in research design, performance of the research, data analysis, writing of the paper. No conflict of interest. JKW: Participated in data analysis, performance of the research, writing of the paper. No conflict of interest. AJB: Participated in research design, writing of the paper, performance of the research, data analysis. No conflict of interest. HDDW: Participated in writing of the paper, performance of the research, data analysis. No conflict of interest. KKR: Participated in research design, writing of the paper. No conflict of interest.

Financial support

None.

Conflicts of interest

The authors declare no conflicts of interest.

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Keywords:

Frailty, Pancreatic ductal adenocarcinoma, Sarcopenia

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