The Implications of Sarcopenia in the Treatment and Prognosis of Pancreatic Cancer

Review Article

Austin J Surg. 2023; 10(4): 1311.

The Implications of Sarcopenia in the Treatment and Prognosis of Pancreatic Cancer

Elroy Patrick Weledji¹*; Luca Gianotti²; Massimo Oldani²; Fabio Uggeri²

1Department of Surgery, Faculty of Health Sciences, University of Buea, Cameroon, W/Africa

2Department of Surgery, San Gerardo Hospital, Monza, School of Medicine and Surgery, University of Milano-Bicococca, Italy

*Corresponding author: Elroy Patrick Weledji Livanda Kongo Hill, PO Box 126 Limbe, S.W. Region, Cameroon, W/Africa. Tel: 237 699922144 Email: elroypat@yahoo.co.uk

Received: August 01, 2023 Accepted: September 20, 2023 Published: September 27, 2023

Abstract

Sarcopenia is the subclinical loss of skeletal muscle and strength and has been extensively studied in both cancer and surgical patients. Patients with sarcopenia are particularly vulnerable to major physiological stressors including surgery and surgical complications. Sarcopenia has thus gained significant recognition as an important prognostic factor for both complications and survival in cancer patients. The aim of this review was to evaluate the current literature on the effect of sarcopenia on the treatment and prognosis of pancreatic cancer. The prevalence of sarcopenia in pancreatic cancer patients range between 20% to 65% due to the heterogeneous groups of patients, difference in disease stage, and the different methods of measuring sarcopenia. Sarcopenia would be more accurately assessed by utilizing both imaging and clinical data, such as frailty. Although malnutrition could be responsible for the attenuated healing process of pancreatic anastomosis the relationship between sarcopenia and outcome following pancreaticoduodenectomy is debated. Most studies showed a higher risk of Postoperative Pancreatic Fistula (POPF) formation in patients with concurrent sarcopenia and high fat mass (sarcopenic obesity). Sarcopenia seems generally to be associated with lower survival. The assessment of sarcopenia can therefore lead to changes in management strategy, patient selection, and improved informed consent prior to surgical resection of pancreatic cancer. An improved prediction of clinically relevant pancreatic fistula formation after pancreatic surgery using preoperative Computed Tomography (CT) scan, including a fistula risk score using sarcopenic obesity and subcutaneous fat area will be useful. Although treatment for sarcopenia still remains an area of research a protocol to improve nutrition and fitness preoperatively may improve sarcopenia and surgical outcome.

Keywords: Sarcopenia; Sarcopenic obesity; Assessment; Pancreatic cancer; Surgery; Chemotherapy; Outcome

Introduction

Pancreatic cancer is one the most aggressive malignancies with rising incidence. It is the fourth most common cause of cancer death in the Western world because diagnosis is often only established in the advanced stages, and thus the low treatment success rate [1]. Its poor prognosis is manifested in an overall median survival of 4.4 months, and a 5-year survival of 9.7%. In the past 20 years, there is only a modest increase in long-term survival with a median survival of 12 months, and a 5-year survival rate of 15-26% after potentially curative resection [1]. Loss of lean tissue mass (sarcopenia) attributed to malignancy is a well-established complication and has been the focus of a great deal of clinical investigation [2]. Malignancy can result in a hypercatabolic state caused by tumour metabolism, systemic inflammation, and other tumour mediated effects [3]. This derangement in an individual's homeostasis combined with other cancer-mediated effects such as anorexia, fatigue, decreased functional status, and immobility leads to a depletion of skeletal muscle and the development of sarcopenia. Sarcopenia is a syndrome first introduced by Rosenberg in 1989, characterized by progressive and generalized loss of skeletal muscle mass and strength [4]. It is commonly accepted as an age - related process and, in that setting is an important predictor of surgical outcome and discharge destinations [2-6]. There is increasing evidence that the elderly and frail are not the only populations, which suffer from sarcopenia. With an increase in fatty tissue mass: lean tissue mass ratio, patients may also experience sarcopenic obesity. This population is vulnerable to both the adverse health consequences of excess adipose tissue as well as to the complications associated with a decrease in muscle mass [7-9]. Perhaps most striking is the cohort of patients suffering from a malignancy and cancer-related cachexia. The common manifestation of tumour cachexia with an incidence of 60-80%, is a complex syndrome that combines malnutrition with weight loss, decrease in muscle tissue (sarcopenia), anorexia, early satiety, weakness, anaemia and oedema [10]. The impact of sarcopenia in cancer patients has been studied across a broad range of malignancies [8-12], and it has been shown to predict drug toxicity, time to tumour progression, and mortality in patients treated with chemotherapeutic agents [10]. Muscle loss is also exacerbated by the administration of cytotoxic chemotherapy, and an independent prognostic indicator in cancer patients undergoing palliative therapy [11]. While the stepwise progression towards sarcopenia is not yet clearly defined, there is no question of the deleterious effects that it has on clinical outcomes in cancer populations [10,12]. The decision to undergo any surgical intervention is based on weighing the clinical benefits versus potential complications. Patients with sarcopenia are particularly vulnerable to major physiological stressors including surgery and surgical complications [12]. Englesbe et al demonstrated that core muscle size is independently predictive of mortality and complications following major elective general or vascular surgery [13]. Sarcopenia has also been shown to correlate with mortality after liver transplantation, length of stay after colon resection, and surgical site infections following midline laparotomies and colon resections [14,15].

Long-term survival is worse in sarcopenic patients undergoing pancreatic cancer surgery, as shown by meta-analysis [16,17]. As a result the approach towards oncological therapy may be forced towards the use of suboptimal and inadequate treatment. Several factors are considered when evaluating a sarcopenic patient's preoperatively, and include medical co-morbidities and nutritional status [18]. Concomitant with these objective data, is a more subjective ‘eyeball test’ to evaluate for the patient's expected physiologic reserve [18,19]. This will provide the surgeon a more impartial tool for assessing the ability to tolerate surgery. Sarcopenia is a component of body habitus that can be quantified preoperatively and altered over time. The assessment of sarcopenia can lead to changes in management strategy, patient selection, and improved informed consent prior to surgical resection of malignancy. The aim of this review was to discuss the current literature on the association between sarcopenia and surgical outcome following resection of pancreatic cancer.

Discussion

Pancreatic surgery is technically complex and associated with significant postoperative morbidity, mortality, and prolonged hospitalization. Although, in recent decades, survival after pancreatic surgery has improved due to recent advancements in perioperative management and operative technique, post-operative complications occurs in up to 40-50% of patients [20]. Sarcopenia seems to be associated with poorer survival, higher postoperative morbidity, and mortality in patients undergoing pancreatic surgery. The prevalence of sarcopenia in pancreatic cancer patients range from 20% to 65% due to the heterogeneous groups of patients, difference in disease stage, and the different methods of measuring sarcopenia [21-23]. Pancreaticoduodenectomy is the gold standard in the treatment of pancreatic, periampullary, and distal bile duct malignancies. POPF is one of the most common and relevant complications following this procedure. Many possible risk factors have been identified, such as male gender, higher body mass index, prior history of cholangitis, cardiovascular disease, benign rather than malignant indication predisposes narrow pancreatic duct, extrapancreatic tumour location (distal cholangiocarcinoma, ampullary, duodenal) predisposes soft pancreas, blood loss, soft parenchymal texture, narrow pancreatic duct width (<3mm), absence of intraoperative blood transfusion, and higher fluid amylase on postoperative day 1 [24]. The evaluation of the nutritional status of patients undergoing pancreatic surgery has been receiving increasing attention, especially in recent years and according to a position paper of the International Study Group on Pancreatic Surgery (ISGPS), the measurement of nutritional status should be part of the routine preoperative assessment, as malnutrition is a risk factor of surgery-related complications. The group also suggests considering, in addition to the patient’s weight loss and Body Mass Index (BMI), the measurement of sarcopenia and sarcopenic obesity [23,25]. It can be assessed by the routine preoperative staging CT but its role in surgical outcome in particular the occurrence of POPF is still unclear and debatable [26,27]. Predicting POPF using a combination of objective preoperative CT measurements including body composition parameters would still be very useful [26,27].

Method of Quantifying Sarcopenia

Sarcopenia is found in up to 65% of pancreatic cancer patients [28], but there is no standardized methodology for both the assessment and classification of sarcopenia in the clinical setting. The current framework for quantification involves imaging of skeletal muscle and the determination of cut-off values based on individual study populations. There is available evidence on the role of CT scans in both the identification of sarcopenia in patients with abdominal malignancies as well as the predictive value of body composition analysis in clinical outcomes. CT scans can identify reduced muscle mass and predict negative cancer outcomes in patients with abdominal malignancies [26]. The Skeletal Muscle Index (SMI) at the third lumbar vertebra level on preoperative CT was the most common way of assessing sarcopenia, although the cut-offs varied among different studies. In the studies evaluated, imaging modalities used included CT scan, Magnetic Resonance Imaging (MRI), dual energy x-ray absorptiometry, and bioelectrical impedance assay [7] but the majority of studies used CT scans [27]. This can be attributed to the fact that preoperative CT scans are the standard of care for patients undergoing resection of a malignancy. Most studies employed a semi-automated method for taking measurements from the scans; the intended musculature was manually outlined with a preset Hounsfield Unit density threshold. This technique allows for more precise calculation of the muscle area while excluding fat and vasculature that fall outside the preset Hounsfield Unit range [29]. The Hounsfield Unit parameters set by most studies was within -30 to 150 HU [30]. There are several different musculature measurements that are used to quantify sarcopenia. In general, measurements are taken at a particular level of the lumbar spine (primarily L3), or the value is obtained by averaging measurements from two consecutive lumbar vertebral levels (e.g., L4 and L5; Figure 1, Panels A–C). A majority of the studies reviewed obtained the cross sectional area of the abdominal skeletal musculature (including bilateral psoas, erector spinae, quadratus lumborum, transversus abdominis, external and internal oblique, and rectus abdominis) or the cross sectional area of the psoas muscles. A few studies defined sarcopenia based on both psoas muscle area and psoas muscle density, expressed in Hounsfield Units. Psoas muscle density is a proxy for muscle quality as it accounts for fatty infiltration of muscle tissue. This is also known as the Hounsfield Unit Average Calculation, or HUAC. Other measurements included the appendicular skeletal muscle mass and the multifidus muscle with subcutaneous fat [31]. An example of how sarcopenia is quantified by CT imaging is illustrated from a study published by Joglekar and co-workers [32]. In this study, sarcopenia was defined as meeting the lower 25th percentile for gender-specific Total Psoas Index (TPI) and HUAC (Figure 1). In Figure 1, Panel A demonstrates a patient with a normal TPA as seen by the substantial muscle mass. The patient shown in Panel B is illustrative of someone with very small TPA and therefore a low TPI (sarcopenia). The patient shown in Panel C has a substantial muscle mass as shown by visual estimation, but the quality of the muscle is low based on the low HUAC and met criteria for sarcopenia [32]. In many of the studies reviewed, sarcopenia was largely defined as a dichotomous variable by establishing cut-off points for the muscle index used. Cut-off values were commonly determined by lowest gender specific quartile optimum stratification to obtain gender specific cut-offs or two standard deviations below the gender specific mean. Of note, numerous studies obtained their cut-off values by using the optimum stratification model outlined by Prado and co-workers [8,9]. Gender specific cutoffs were used due to the baseline variability in body habitus between males and females. Despite the variability in the specifics of the method for quantifying sarcopenia, the studies included in this review all used an imaging modality to obtain measurements of skeletal muscle mass or density and defined cut-off values based on the skeletal muscle index calculated. In 2019, a revised European concensus on the definition and diagnosis of sarcopenia identifies probable sarcopenia by low muscle strength (criterion1), low muscle quantity or quality (criterion 2) and low physical performance (criterion 3). If criteria 1, 2, and 3 are all met, sarcopenia is considered severe. Lumbar third vertebra imaging by CT is considered among the techniques that can be used to detect low muscle mass [2].

Citation: Weledji EP, Gianotti L, Oldani M, Uggeri F. The Implications of Sarcopenia in the Treatment and Prognosis of Pancreatic Cancer. Austin J Surg. 2023; 10(4): 1311.