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Pancreas Cancer-Associated Weight Loss.

Unintentional weight loss in patients with pancreatic cancer is highly prevalent and contributes to low therapeutic tolerance, reduced quality of life, and overall mortality. Weight loss in pancreatic cancer can be due to anorexia, malabsorption, and/or cachexia. Proper supportive care can stabilize or reverse weight loss in patients and improve outcomes. We review the literature on supportive care relevant to pancreatic cancer patients, and offer evidence-based recommendations that include expert nutritional assessment, counseling, supportive measures to ensure adequate caloric intake, pancreatic enzyme supplementation, nutritional supplement replacement, orexigenic agents, and exercise. Pancreatic Cancer Action Network-supported initiatives will spearhead the dissemination and adoption of these best supportive care practices. IMPLICATIONS FOR PRACTICE: Weight loss in pancreatic cancer patients is endemic, as 85% of pancreatic cancer patients meet the classic definition of cancer cachexia. Despite its significant prevalence and associated morbidity, there is no established approach to this disease entity. It is believed that this is due to an important knowledge gap in understanding the underlying biology and lack of optimal treatment approaches. This article reviews the literature regarding pancreas cancer-associated weight loss and establishes a new framework from which to view this complex clinical problem. An improved approach and understanding will help educate clinicians, improve clinical care, and provide more clarity for future clinical investigation.


SUPPORTIVE CARE WORKING GROUP CONSENSUS PROCESS
The Supportive Care Working Group (SCWG) was formed to establish best supportive care practices across the Precision Promise Consortium (PPC) and to help foster supportive care research. The SCWG consists of scientists, physicians, and a dietician with expertise in pancreatic cancer, nutrition, exercise, cachexia, survivorship, and palliative care. The SCWG compiled all evidence by searching PubMed articles (from 1977 to 2017) on PAWL and other relevant topics. Keywords searched included weight loss, cachexia, anorexia, malabsorption, sarcopenia, pancreatic exocrine insufficiency, malabsorption, pancreatic enzyme replacement therapy, nutrition, and exercise. The group convened quarterly over an 18-month period and corresponded via teleconference bimonthly. The group initially presented the evidence and consensus to the PPC and Steering Committee (SC) in January 2017. The feedback was considered by the SCWG, integrated, and presented back to the PPC and SC in August 2017. Additional feedback was integrated, and the final consensus is presented here.

Anorexia
Anorexia is defined as loss of the desire to eat and is mediated by the inability of the hypothalamus to respond to energy deficit signals [28]. Pain, fatigue, depression, dysmotility, constipation, chemosensory disturbances (changes in smell and taste), vomiting, early satiety, and loss of appetite all contribute to anorexia [10,[33][34][35][36]. An important aspect of anorexia is the negative social impact including changes in social encounters and relationships and a sense of helplessness, anxiety, and distress [37,38]. Patients commonly report distress related to dietary intake and gut symptoms including difficulties with gas, belching, bloating, pain/discomfort, and diarrhea leading to WL [39]. Additionally, current chemotherapy regimens, including gemcitabine/nabpaclitaxel [40], FOLIFIRINOX [41], and nanoliposomal irinotecan/5FU [42], can cause nausea, vomiting, indigestion, diarrhea, and mouth sores [43] and thus contribute to lower food intake and reduced nutrition.

Malabsorption/Pancreatic Exocrine Insufficiency
Pancreatic exocrine insufficiency (PEI), a common complication of PC, occurs when the pancreas is unable to maintain normal digestive function (secretion of proteases, lipase, and amylase), resulting in malabsorption and malnutrition. PEI negatively impacts QOL [44,45] and is associated with poor survival [44][45][46]. Additionally, markers of malabsorption and exocrine secretion impairment, such as fecal elastase-1, are strongly correlated with poor survival in PC [46]. Symptoms of malabsorption include increased abdominal bloating or discomfort, excessive gas causing burping or flatulence, indigestion, nausea, delayed gastric emptying/ early satiety, changes in bowel movements-increased frequency, light color, floating, frothy, oily, and/or foul smelling, and WL despite intake meeting estimated caloric needs.

Cachexia and Sarcopenia
Cachexia results from a complex interaction between tumor, host, and therapy [34,47] characterized by progressive wasting of skeletal muscle mass and to a lesser extent adipose tissue, occurring even before WL becomes apparent (precachexia) [28,48]. Preclinical models indicate that chemotherapy and targeted agents can cause cachexia through mitogen-activated protein kinase-dependent muscle atrophy, mitochondrial depletion, and muscle weakness leading to disuse atrophy [49]. Despite the high prevalence and potential for mortality, PC-associated cachexia is diagnosed and treated in a minority of patients [5], as there is no established treatment [50]. The stages of cachexia occur across a spectrum starting with "precachexia" characterized by WL <5%, then "cachexia" associated with systemic inflammation, and ending with "refractory cachexia defined by a loss of body reserves and rapidly deteriorating nutritional status [10]. Not all patients will progress through all the stages, and no predictive biomarkers have been identified to distinguish patients who will progress [10].
WL is our current measure of cachexia. However, advances in body composition assessment techniques indicate skeletal muscle and adipose tissue may behave independently during WL [51]. In obese patients with cancer, muscle wasting is common and obscured [51]; 40% of PC patients who were found overweight/obese at the time of diagnosis exhibited muscle wasting [6]. Consequently, sarcopenic obesity is linked to functional status, survival, chemotherapy toxicity, and poor outcomes following surgery [52,53].

ASSESSMENT OF PAWL
The morbidity and mortality associated with PAWL compels a comprehensive approach to its assessment and management and should be tailored to each individual. We recommend that all patients be screened for WL, receive clinical and nutritional screening, be assessed for PEI, and receive serum testing. Body composition measurements should be considered in the research setting.

Screening for WL
It is important that clinicians assess and record the weight of a patient at presentation and prior to diagnosis. A quick review of WL history can illuminate the extent of PAWL. Assessment of WL over time is one of the standardized  Table 1 for interpretation). diagnostic characteristics used to identify and document adult malnutrition as recommended by the Academy of Nutrition and Dietetics [54] and the American Society for Parenteral and Enteral Nutrition. Any patient who demonstrates moderate or severe WL and/or evidence of malnutrition or malnutrition risk by these criteria should be directed to a registered dietitian for a more extensive assessment and intervention as described below. The consensus guidelines for interpretation of WL in adults is outlined in Table 1 [55].

Nutrition Screening and Clinical Assessment
Nutrition screening using a validated tool allows for identification and referral of at-risk patients to a registered dietitian for complete nutrition assessment and intervention. Screening should be completed on all patients before the start of treatment and at regular intervals such as weekly during radiotherapy, with each chemotherapy visit, and at each surveillance visit [54, 56,57].
Two nutritional screening tools have been vetted for both inpatient and outpatient use: the malnutrition screening tool (MST) and the patient-generated subjective global assessment (PG-SGA). The MST is a quick, valid, and reliable screening tool. It consists of two questions regarding appetite and recent unintentional WL and has demonstrated high sensitivity and specificity for identification of individuals with or at risk of malnutrition [58]. The PG-SGA is a valid and reliable assessment tool to identify and triage malnourished patients with cancer in both the inpatient and outpatient setting. The abridged PG-SGA forgoes the physical examination used in the PG-SGA and is a practical, informative, and valid tool for use in the outpatient oncology setting for detecting malnutrition [59].
We recommend that patients are screened using one of these tools; those deemed to be at risk for malnutrition should then be referred to a registered dietitian for nutrition assessment. The services of a registered dietitian are important for the early identification of malnutrition and anticipation of nutritional impact on symptoms to help patients maintain weight, stay on their intended treatment, and maintain or improve QOL over the course of their disease.
A full nutrition assessment involves the following elements: obtaining a food history, evaluation of anthropometric measurements, review of medical history, biochemical data, medical tests and procedures, and completion of a nutrition-focused physical assessment [60]. Routine assessment of food intake should include patient estimate of overall food intake and 24-hour food recall [34]. An oncology-focused assessment also involves reviewing the oncologic treatment plan with the goal to determine current and anticipated nutrition issues [54, 57,61]. This information is all assimilated and used to formulate a plan to address existing and potential influences on malnutrition.

Assessment for PEI
Although there are several tests to diagnose pancreatic exocrine insufficiency, their clinical application and use is variable [62,63]. Definitive identification of PEI in PC patients is challenging; thus, PEI is usually a clinical diagnosis. Direct measures of gastric and duodenal contents such as a secretin-cerulein or secretin-pancreozymin tests are expensive, invasive, and only available at specialized centers [64]. Other tests such as fecal fat test, fecal elastase, and coefficient of fat absorption (CFA) are more clinically available but may be cumbersome [64][65][66]. Steatorrhea is classically defined as at least 7 grams of fecal fat over 24 hours, in the context of a 72-hour stool test while on 100 grams of fat daily [67]. However, the stool collection and associated diet is inconvenient and difficult for patients. Therefore, fecal elastase measurements are often used to diagnose PEI [67][68][69]. Fecal elastase is less sensitive (72%) than CFA collection but quite specific (90%). In PC patients, studies have shown a prevalence of PEI varying from 50%-89% when defined by low fecal elastase [46,70,71]. Expert opinion is that fecal elastase is appropriate for unresectable patients but is insufficiently sensitive to detect mild-moderate PEI and unsuitable for postpancreaticoduodenectomy patients [72]. Regardless, in standard PC care, these tests are not routinely performed and the diagnosis is established clinically and based on patients' history and reported symptoms (unintentional WL, change in stool, bloating after meals, etc.). Patients should be clinically assessed for PEI upon diagnosis, at the start of treatment, and on a regular basis throughout the course of their treatment.

Serum Tests
There is no widely adopted serologic evaluation of patients with PAWL. However, WL in cancer patients has been associated with markers of inflammation, low levels of serum testosterone in men, and vitamin deficiencies. A more comprehensive serologic evaluation of patients who present with PAWL will likely improve supportive care.
Measuring serum inflammation in PC patients with a Glasgow Prognostic Score (GPS) has shown prognostic significance in several studies [73,74], and is predictive of surgical outcomes [75,76]. The GPS and other markers of inflammation are consistently associated with WL and cachexia in cancer patients [77,78]. GPS is usually scored 0, 1, or 2 by providing 1 point each for c-reactive protein (CRP) >10 and Albumin <3.5. The GPS was recently studied as a predictive factor for response to a novel therapeutic in advanced PC [79]. Recent studies have also suggested that CRP:Albumin ratio and neutrophil:lymphocyte ratio also have prognostic validity [80,81]. In routine practice, this score could help identify patients at high risk for PAWL and cachexia and could promote early intervention.
Male hypogonadism (MH) is a common complication in advanced cancer [82] and prominent in cancer patients . These findings were concluded from retrospective analysis, and it is not clear whether vitamin D supplementation improves outcomes. We recommend that vitamin D deficiency should be evaluated and supplemented per physician discretion.

Body Composition Measurements
Muscle volumes can be measured and sarcopenia diagnosed using several modalities: computed tomography (CT) or magnetic resonance imaging (MRI); appendicular skeletal muscle index obtained from dual energy x-ray absorptiometry (DEXA); mid-upper-arm muscle area by anthropometry; and whole-body fat-free mass index determined by bioimpedance analysis [10,[96][97][98]. As CT is commonly used in the diagnosis and treatment of PC, this modality has been used to estimate sarcopenia radiographically by total psoas muscle area and radiodensity [96]. However, psoas muscle measurements do not reflect whole-body muscle; thus, measurements of a whole-body slice at the level of lumbar vertebrae are superior [99]. Morphometric analysis of diagnostic CT or MRI slices can be used to calculate whole-body skeletal muscle and adipose tissue, to assess muscle quality, and to detect presence of myosteatosis. Currently, this can be done using dedicated commercial software such as Sliceomatic or Ima-geJ. Skeletal muscle and adipose tissue can behave independently during cancer progression and therapy [51,100], and there may be value in measuring these separate compartments in the research setting.

Role of the Registered Dietitian
Dietitians play a central role in the successful management of PAWL. Nutrition interventions for PAWL have improved weight [30], QOL, and outcomes [29,60,101]. Dietitians can provide essential dietary suggestions, identify PEI, and provide recommendations for oral nutritional supplementation and specialized nutrition support [102]. Dietitians may also provide more detailed advice on diet and pancreatic enzyme supplementation for management of symptoms of PEI [103][104][105][106].

Pancreatic Enzyme Replacement Therapy
Pancreatic enzyme replacement therapy (PERT) has demonstrated benefit for PC patients with PEI. Two randomized controlled trials have evaluated the impact of PERT among patients with PEI due to chronic pancreatitis or surgery. These studies demonstrated an increase in fat absorption, reduced stool frequency, improved stool consistency [107][108][109], and symptom improvement [109]. A previous double-blinded trial of 21 patients with unresectable PC with obstructive jaundice in whom a biliary stent was placed showed that patients randomized to PERT had improved fat absorption and that WL was prevented compared with those who were randomized to placebo [110].
In a retrospective, nonrandomized study of 66 unresectable PC patients receiving PERT with nutritional counseling and palliative care or standard palliative care without PERT, median survival of patients receiving PERT was longer than that of those with standard palliative care (301 days vs. 89 days) [111]. More recently, a randomized study showed an increase in OS in patients randomized to taking enzymes but did not reach statistical significance because of a low enrollment rate [112]. Additionally, a prospective study of unresectable patient receiving chemotherapy showed improved changes in BMI and increased OS of patients who received PERT compared with historical controls [113].
In a retrospective, nonrandomized study of 66 unresectable PC patients receiving PERT with nutritional counseling and palliative care or standard palliative care without PERT, median survival of patients receiving PERT was longer than that of those with standard palliative care (301 days vs. 89 days).
These clinical trials evaluating PERT used doses ranging from 40,000 to 72,000 units of lipase for meals and 20,000-36,000 units of lipase per snack. The maximum effective dose is unclear, guidelines vary, and dosing recommendations for PC are not currently indicated on U.S. Food and Drug Administration labels. Enzymes may be dosed based on body weight, fat content of diet, clinical symptoms, degree of steatorrhea present, or general per meal/snack guidelines. The recommended starting dose per meal is 500 lipase units per kg; dosing should be modified as appropriate and should be tailored to individuals as needed to reflect variations in meal sizes and fat content of the diet, clinical symptoms, and the degree of steatorrhea present. Dosages should not exceed 10,000 lipase units per kilogram body weight per day with a maximum of 2,500 lipase units per kilogram per meal [64]. Patients should be instructed to take enzymes at the start of the meal, and if taking multiple capsules, pills should be taken at intervals at the start and then throughout the meal [114]. A study using the Pancreatic Cancer Action Network's Patient Registry indicated that in patients taking PERT appropriately, symptoms such as a feeling of indigestion and WL were significantly improved [115].

Oral Nutrition Supplements
If patients show signs of deficiency, have prolonged inadequate intake, or have prolonged malabsorption, clinicians should consider evaluation for deficiencies including vitamins A, D, E, B12, and B6 as well as iron, zinc, selenium, biotin, and copper. Supplements should be recommended for replacement of known deficiencies in the diet or serum levels. Serum values may be rechecked approximately 3 months after attempted repletion. For individuals with inadequate intake of calories and/or protein, nutrition supplement drinks may be recommended as part of the nutrition care plan. Unfortunately, there have been few studies investigating the vitamin deficiencies associated with PEI and the benefit of oral nutrition supplements.

Specialized Nutrition Support
Specialized Nutrition Support (SNS) is the use of enteral or parenteral nutrition. Both American and European guidelines for nutrition support recommend against routine use of SNS for oncology patients [116,117]. However SNS may be necessary for patients with a dysfunction of the gastrointestinal tract such as gastric outlet obstruction or who are severely malnourished and will be undergoing major surgery [116][117][118]. If SNS is needed, enteral feeding is preferred because of lower risk of infections or other complications [119,120]. In randomized studies, enteral feeding has shown benefit over other forms of artificial nutrition in patients following a pancreaticoduodenectomy [121].
Parenteral nutrition may improve weight [122] and maintain or improve performance status in selected patients, but it is not routinely recommended. Careful evaluation should be employed to identify those patients who would benefit and to avoid indiscriminate use of artificial nutrition [123], especially in cases of futile care and at end of life. Benefits may be limited to the perioperative setting for patients who are unable to tolerate oral nutrition, although there is a need for more explicit criteria for use [121,124].
Parenteral nutrition may improve weight and maintain or improve performance status in selected patients, but it is not routinely recommended. Careful evaluation should be employed to identify those patients who would benefit and to avoid indiscriminate use of artificial nutrition, especially in cases of futile care and at end of life.

Pharmacologic Interventions
Advances in the understanding of etiology of cachexia are leading to pharmaceutical interventions aimed at targets upstream (inhibiting systemic inflammation) or downstream (blocking catabolic pathways, stimulating anabolic pathways, and reducing anorexia) [51].
Appetite stimulants are frequently prescribed for patients with PAWL. Progestogens, such as megestrol acetate and corticosteroids, are used as orexigenics [5,[125][126][127]. Their mechanism of action is also through inhibition of cytokines (including interleukin-6 and tumor necrosis factor) and de-repression of appetite. Anecdotal evidence suggests cannabis improves appetite and food intake in patients with PAWL, and synthetic delta-9-tetrahydrocannabinol, dronabinol, is approved for use in acquired immunodeficiency syndrome-related cachexia and emesis from chemotherapy. However, insufficient data exist for prescribing cannabis for cachexia [128], and a randomized study in advanced cancer patients demonstrated superiority of megesterol acetate over dronabinol [129]. Novel agents for appetite stimulation include grehlin and grehlin mimetics, notably anamorelin, for which significant increase in lean body mass was observed in non-small cell lung cancer patients from two phase III trials [130,131].
Nonsteroidal anti-inflammatory (NSAID) agents, thalidomide, and omega-3 fatty acids modulate cytokine production, thereby inhibiting inflammation. Previous studies of these agents have not shown conclusive benefit, and their routine use is not recommended. Agents targeting the cytokine activin and the related muscle growth inhibitor myostatin have also been evaluated, without report of benefit to date (NCT01433263 and NCT01505530]. Newer therapies include monoclonal antibodies against cytokines, including interleukin-1 alpha (NCT03207724) [132]. Combination therapy with NSAID, nutritional supplementation, dietary consultation, and exercise showed benefit in a multicenter, randomized phase II trial of patients with lung or pancreatic cancer, and has now moved to phase III (MENAC, NCT02330926). Investigations of many novel agents are ongoing; however, there are currently no standard systemic therapies for PAWL or PC cachexia [133].

Exercise
Physical activity (PA) and exercise could benefit patients with PAWL. In cancer patients, PA has been shown to improve health-related QOL and symptom burden. PA resulted in improved treatment tolerance [134,135] and is associated with improved PFS and OS [136], suggesting that the benefit of PA is not confined to disease-free survivors.
Gradual resistance training and aerobic exercise can also maintain and restore lean muscle mass [137]. In addition, prescribed exercise resulted in improved appetite and general well-being in patients with advanced cancer receiving palliative care [138].
PA interventions have been deemed safe and feasible in PC patients [139] and may attenuate cachexia by modulating insulin sensitivity and inflammation [140][141][142]. Progressive postoperative exercise programs have also been demonstrated to be feasible, resulting in lower levels of fatigue and pain and improved perception of general health [143]. In advanced disease, a home-based walking intervention was associated with increased endurance © AlphaMed Press 2018 Pancreas Cancer-Associated Weight Loss and improved symptom burden, with patients increasing their average duration of moderate-intensity exercise [144]. Given the potential for high symptom burden and poor survival outcomes in PC, Groupe Cooperateur Multidisciplinaire en Oncologie has initiated a large randomized trial of adapted physical activity in PC [139]. This study will formally evaluate the benefits of aerobic and resistance exercises on fatigue and health-related QOL, but also investigate the effects of intervention on nutritional status, insulin resistance, cancer treatment tolerance, and survival.
One hundred fifty minutes per week of moderateintensity aerobic exercise and at least two sessions of resistance training per week is the recommended physical activity for cancer patients and survivors [145][146][147]. The optimal form and duration of exercise is unclear, and recommendations should be tailored to an individual's current fitness level, treatment-related late/long-term toxicities, and comorbidities. Referral to physical therapy or other exercise professionals to guide initiation and engagement in physical activity may improve success and thus should be considered for all patients [145][146][147].
Consensus Statement and Recommendation (Fig. 3) Slowing WL in patients with PC should improve quality and length of life both directly through maintaining function and indirectly through enhancing treatment delivery and response. In many cases, favorable response to therapy will translate to overall improvement in symptoms and QOL. We recommend all patients who have significant WL and/or evidence of malnutrition be directed to a registered dietician for a more extensive evaluation. As needed, patients should be provided pancreatic enzyme replacement therapy, correction of hormonal and micronutrient deficiencies, and oral nutrition supplementation. Appetite stimulants should be considered. Patients should be warned against inactivity, and moderateintensity exercise should be encouraged and supported. Measures to optimize appetite, nutritional intake, micronutrients, and anabolic potential, while reducing disuse and catabolism, should be implemented and integrated as part of treatment planning as thoughtfully and aggressively as antitumor therapy.