Next Article in Journal
A Comprehensive View of the Cancer-Immunity Cycle (CIC) in HPV-Mediated Cervical Cancer and Prospects for Emerging Therapeutic Opportunities
Next Article in Special Issue
Role of Therapeutic Endoscopic Ultrasound in Management of Pancreatic Cancer: An Endoscopic Oncologist Perspective
Previous Article in Journal
Implications of Transglutaminase-Mediated Protein Serotonylation in the Epigenetic Landscape, Small Cell Lung Cancer, and Beyond
Previous Article in Special Issue
The Development of a Prediction Model Based on Random Survival Forest for the Postoperative Prognosis of Pancreatic Cancer: A SEER-Based Study
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 15
Issue 4
10.3390/cancers15041331
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Challenges in Diagnosis and Treatment of Pancreatic Exocrine Insufficiency among Patients with Pancreatic Ductal Adenocarcinoma

by
Xiaoyang Lan
1,
Gabrielle Robin
1,
Jessica Kasnik
2,
Grace Wong
3 and
Omar Abdel-Rahman
4,*
1
Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada
2
Nutrition Services, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada
3
Pharmacy Department, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada
4
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(4), 1331; https://doi.org/10.3390/cancers15041331
Submission received: 15 January 2023 / Revised: 14 February 2023 / Accepted: 16 February 2023 / Published: 20 February 2023
(This article belongs to the Special Issue Recent Advances in Diagnosis and Treatment of Pancreatic Cancer)
Browse Figure
Versions Notes

Abstract

:

Simple Summary

Pancreatic ductal carcinomas (PDACs) are difficult to diagnose at an early stage and carry a poor overall prognosis for patients. Many patients with PDACs have serious nutritional deficiencies relating to their cancer. Typically, the pancreas produces enzymes resulting in food digestion. However, patients with pancreatic cancer often have a limited ability to digest their food due to decreased enzyme function, known as pancreatic enzyme insufficiency (PEI). These patients then become malnourished, which lowers their quality of life and reduces their survival. Unfortunately, PEI in PDACs is sometimes missed by healthcare providers. This paper reviews past studies describing malnutrition in PDAC, focusing on PEI and its treatment. It focuses on guidelines and recommendations for the appropriate treatment of PEI. We also review knowledge gaps of healthcare professionals regarding PEI to enhance treatment uptake and improve future patients’ quality of life.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and is associated with an extremely poor prognosis. Many PDAC patients suffer from profound nutritional complications such as nutrient deficiencies, weight loss, malnutrition, and cancer cachexia. These complications cause barriers to effective anticancer treatments, gravely influence their quality of life, and decrease their overall survival. Pancreatic exocrine insufficiency (PEI) is defined as impaired digestion due to inadequate secretion of pancreatic enzymes and is a common cause of malnutrition in PDAC. This review first summarizes the existing literature around malnutrition in PDAC, with a particular focus on PEI and its management with pancreatic enzyme replacement therapy (PERT). Second, we summarize existing guidelines and recommendations for the management of PEI among patients with PDAC. Lastly, we highlight potential gaps of knowledge of PEI among healthcare providers resulting in underdiagnosis and treatment, which may have implications for the quality of life and overall survival of PDAC patients.

1. Introduction

Pancreatic ductal adenocarcinomas (PDACs) account for 80–90% of pancreatic cancers [1,2,3,4,5]. Arising primarily from pancreatic ductal cells, this malignancy carries the worst prognosis between pancreatic cancer subtypes [1,2,3,4,5,6]. Although there has been modest progress in the detection and management of pancreatic cancers, the overall prognosis remains poor [2,5]. A 2023 report from the American Cancer Society estimates that the 5-year overall survival of pancreatic cancer patients is approximately 12% [2,7]. Pancreatic cancers are currently the fourth leading cause of cancer-related death, and they are predicted to further increase in prevalence over the next several years [1,2].
The incidence of pancreatic cancer is correlated with age, where 80–90% of cases are diagnosed over the age of 55 [1,2,3]. Men also carry a higher incidence of pancreatic cancer than women (5.5 vs. 4.0 in 100,000) [1,2,5,8]. Geographically, pancreatic cancer is more common in developed regions such as North America and Western Europe [3,8,9]. This distribution is attributed to increased imaging and data access, as well as increased risk factor exposures [2,4,9].
Prominent risk factors for pancreatic cancer include smoking and family history [1,2,3]. Smoking is the most important environmental risk factor, increasing the risk of pancreatic cancer nearly two-fold in smokers when compared to non-smokers [1,4,5]. In Canada, approximately 17% of pancreatic cancers are attributed to smoking [2]. Family history is also pertinent, as 5–10% of patients with pancreatic cancer describe an associated pertinent family history [1,3,5]. Hereditary pancreatitis, Lynch syndrome, and certain genetic mutations, such as BRCA 1/2 and ATM, are implicated [2,4,5]. Some evidence exists for serial pancreatic cancer screening in high-risk populations such as those with a genetic predisposition [2,4,5]. Additional non-modifiable risk factors include ethnicity (highest in African Americans), diabetes mellitus (type I and II), chronic pancreatitis, and intraductal papillary mucinous neoplasms (IPMNs) [1,3,4,5]. Modifiable risk factors include excess alcohol intake (≥3 drinks per day), increased body weight, and the consumption of processed or fatty foods [1,2,3,4,5,8].
Based on the location of the pancreas in the abdomen, new pancreatic masses can develop for weeks to months without causing clinical signs or symptoms [2]. As such, early-stage pancreatic cancers are often missed as patients are typically asymptomatic [1,10]. Eventually, as the mass affects nearby structures, signs or symptoms begin to occur [2,6,10,11]. With late symptom onset, most (>60%) of pancreatic cancers are diagnosed at an advanced stage [1,2,11]. The most common clinical presentations include constitutional symptoms, pain, and jaundice [11,12], but may also include fatigue, anorexia with early satiety, dyspepsia, nausea, weight loss, pruritis, and acholic stool [1,2,3].
Typical late-stage diagnoses limit successful surgical resections, with ~80–85% being unresectable at the time of diagnosis [1,2,5,6,8,11,13]. However, surgical resection is the mainstay curative-intent treatment [2,5,8,11]. Importantly, prognostic factors such as TMN stage at diagnosis impact the feasibility of curative-intent surgical resection [1,4,12,13]. If patients proceed with surgery, adjuvant chemotherapy has been shown to delay recurrence and improve survival. First-line options for adjuvant treatment include combination therapy with modified FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and fluorouracil), Gemcitabine-Capecitabine combination [14], or single-agent gemcitabine [2,15]. Neoadjuvant chemotherapy has the potential to improve resection rates for locally advanced PDAC and is also an area of active investigation for resectable PDAC [16]. Of note, a recent meta-analysis of resectable PDAC demonstrated improved rates of R0 resection and overall survival with neoadjuvant chemotherapy [17].
Current systemic therapy options in the metastatic setting include modified FOLFIRINOX or gemcitabine +/− nab-paclitaxel [15,18,19]. Ultimately, palliative care consultation is recommended to ensure symptom management and psychosocial support are accessible to patients [2,5]. Earlier access to palliative and supportive treatments has been shown to improve outcomes among patients with advanced PDAC [20,21,22,23]. The spectrum of supportive care involvement in these cases includes (but is not limited to) pain management, psychosocial interventions, and nutritional interventions.

2. Malnutrition and Pancreatic Cancer

Nutritional status in pancreatic cancer is negatively impacted through a variety of mechanisms and may have profound implications for patients’ quality of life as well as overall outcomes [24]. The diagnostic criteria for malnutrition in adults were defined in a consensus statement from the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition, requiring two or more of the following: insufficient energy intake, weight loss, loss of muscle mass, loss of subcutaneous fat, localized or generalized fluid accumulation, or diminished hand-grip strength [25]. Nutritional status may also be assessed using standardized patient questionnaires, such as the Patient-Generated Subjective Global Assessment (PG-SGA) [26]. A PG-SGA score of 2 or higher indicates that pharmacological intervention is necessary for a patient’s nutrition [27]. Weight loss is also a well-recognized complication of pancreatic cancer and can often be present at the time of diagnosis as one of the earliest symptoms [24,28,29]. There are three proposed categories of weight loss in pancreatic cancer based on etiology: anorexia, malabsorption, and cachexia or sarcopenia [29]. Importantly, both weight loss and malnutrition have been demonstrated to negatively impact performance status, quality of life, and overall prognosis of pancreatic cancer patients [27,30].
Cancer cachexia is a syndrome of loss of skeletal muscle mass resulting from dysregulated metabolism and poor nutrition. In 2011, cancer cachexia was defined through international consensus as weight loss greater than 5% over 6 months, weight loss greater than 2% in individuals with body mass index (BMI) <20 kg/m2 or the presence of sarcopenia [31]. There also exists significant heterogeneity in cachexic patients, as it may manifest as three different clinical subtypes, including patients with fat and muscle wasting, fat-only wasting, and no wasting [32]. Approximately two-thirds of PDAC patients meet the criteria for cancer cachexia at the time of diagnosis [33]. The cause of cancer cachexia is multifactorial, driven by mechanical complications of cancer that impair food intake and absorption, as well as the release of tumor- and host-derived factors that result in systemic inflammation and catabolism [34]. Sarcopenia is defined by the International Working Group on Sarcopenia (IWGS) to include low skeletal muscle mass and either low muscle strength or low muscle performance [35].
Importantly, the presence of cachexia and/or sarcopenia may be associated with poorer outcomes in pancreatic cancer [36,37,38,39]. In a retrospective study of 408 patients who underwent pancreaticoduodenectomy for primary pancreatic adenocarcinoma, Pausch et al. [36] demonstrated a higher 90-day mortality for patients with BMI <18.5 kg/m2 and an increased risk of both operative and non-operative complications in patients suffering from unintentional weight loss. A 2015 systematic review from Ozola Zalite et al. [38] also concluded that severe weight loss and sarcopenic obesity may be negative prognostic factors for PDAC, although the analysis was limited by heterogeneity in the definition of cachexia. In a 2022 study, Hou et al. [40] further assessed the independent contributions of cancer cachexia and sarcopenia in 232 patients with advanced pancreatic cancer. In this cohort, the prevalence of cancer cachexia and sarcopenia was 83.6% and 49.1%, respectively [40]. Interestingly, while cancer cachexia was identified as a poor prognostic factor for all patients, sarcopenia was only a poor prognostic indicator for patients with a high BMI or those who were on chemotherapy [40]. Cachexia and sarcopenia are therefore partially overlapping clinical features for PDAC patients, with individual implications for patient outcomes [40].
Malnutrition can be a significant contributor to the functional decline of pancreatic cancer patients, with potential implications for whether patients are candidates for systemic treatment. FOLFIRINOX and Gemcitabine with nab-paclitaxel are the mainstays of palliative intent chemotherapy for PDAC [18,41]. However, the FOLFIRINOX study excluded patients with an Eastern Cooperative Oncology Group (ECOG) score of 2 or higher, while only 8% of patients in the study of Gemcitabine and nab-paclitaxel had an ECOG score of 2 [18,41]. Systemic treatment for patients with ECOG 2 in the metastatic setting is therefore limited to gemcitabine alone with or without nab-paclitaxel [42]. In a 2019 study, Bicakli et al. [27] demonstrated that worsening malnutrition as defined by the PG-SGA score is associated with a higher ECOG score and poorer survival outcomes. Strikingly, 100% of patients with an ECOG score of 2 or higher had a PG-SGA score between 3 to 4 [27]. These results are supported in a 2021 study by Santos et al. of 41 patients with pancreatic cancer that demonstrated a significant correlation between nutritional status and overall function [43].
Nutritional interventions, including dietitian consultation and the use of nutritional supplements for pancreatic cancer patients being treated with chemotherapy can improve quality of life and functional status [44,45]. The use of home parenteral intervention has also been demonstrated to result in improved quality of life, performance, and nutritional status [46,47]. Importantly, the use of parenteral nutrition to maintain patients’ nutritional and functional status can ensure longer treatment courses with potential impacts on survival [46]. Several pharmacological approaches have been trialed to target cancer cachexia in pancreatic cancer, including the use of progestogens, corticosteroids, cannabinoids, anti-inflammatory agents, and Omega-3 fatty acids [34,48]. There has also been increasing interest in the use of ghrelin receptor agonists in the targeted management of cancer cachexia [49,50]. For example, Hamauchi et al. [51] performed a multicenter, single-arm trial of the ghrelin receptor agonist Anamorelin in 50 patients with advanced and unresectable gastrointestinal cancers, demonstrating improvements in patient-reported appetite, nutritional status, as well as mean lean body mass (1.89 ± 0.36 kg) and body weight (1.41 ± 0.61 kg).
In addition to specific nutritional interventions, systemic therapy for PDAC may also modify nutritional outcomes by directly targeting the underlying etiology of cachexia. In a 2018 study of 977 patients with PDAC, Hendifar et al. [33] demonstrated that cachectic patients not receiving treatment had a 40% increase in the risk of death, while cachectic patients receiving treatment had a similar prognosis to non-cachectic patients. Sandini et al. [52] examined the body composition of 193 pancreatic cancer patients who underwent neoadjuvant chemotherapy followed by surgical resection, demonstrating that patients experienced a loss of adipose tissue without a loss of lean mass. In addition, patients who were ultimately candidates for surgical resection experienced an average of 5.9% increase in skeletal muscle mass, compared with 1.7% decrease in those who were not surgical candidates [52]. This suggests that cancer directed treatments can downregulate tumor-associated signaling pathways that are responsible for the catabolic state in pancreatic cancer [52]. Overall, multiple lines of evidence demonstrate the impact of malnutrition on the functional status and outcomes of PDAC patients as well as highlight the importance of nutritional intervention as a standard component of cancer care.

3. Diagnosis of Pancreatic Exocrine Insufficiency (PEI) in PDAC

Pancreatic exocrine functions are commonly affected in PDACs, causing many patients to be malnourished (30%), lose weight (80%), and become cachectic through a variety of mechanisms [6,13]. PEI is defined as a reduction in the activity of pancreatic enzymes within the gastrointestinal system that results in impaired digestion [53,54,55]. The most common etiology of PEI is chronic pancreatitis, although it may also be seen in conditions such as cystic fibrosis, type 1 and type 2 diabetes, celiac disease, inflammatory bowel disease, pancreatic cancer, and following pancreas surgery [54,55,56]. PEI may result from decreased production of pancreatic enzymes due to the loss of pancreatic tissue from cancer itself or surgical resection, obstruction of pancreatic ducts, decreased stimulation of pancreatic enzyme production, or asynchrony between secretion of pancreatic enzymes and meals [54,57]. Historical evidence suggests that the exocrine pancreas has a large functional reserve, and patients can remain asymptomatic until pancreatic lipase reaches 10% of normal levels [58]. Therefore, timely diagnosis of PEI requires a high degree of clinical suspicion and a standardized approach to both patient assessment and laboratory testing.
The symptoms of PEI are non-specific and can include gastrointestinal manifestations of steatorrhea, abdominal pain, bloating, flatulence, foul-smelling stools, diarrhea, and unexplained weight loss [54,59]. PEI may cause malabsorption in all macronutrients including fat, protein, complex carbohydrates, micronutrients, fat-soluble vitamins (Vitamins A, D, E, K), and lipoproteins [57]. Secondary complications such as reduced bone mineral density or osteoporosis due to vitamin D deficiency may occur [54]. In pancreatic cancer, PEI is a major contributor to weight loss and cachexia along with contributions from the systemic inflammatory response and tumor metabolism [60]. The severity of PEI may be classified into mild (reduced secretion of enzymes, with normal bicarbonate and fecal fat excretion), moderate (reduced enzyme secretion and bicarbonate with normal fecal fat excretion), or severe (reduced enzyme secretion, reduced bicarbonate concentration, and steatorrhea) [61,62]. Standardized screening tools for PEI such as the pancreatic exocrine insufficiency questionnaire (PEI-Q) have been developed, which may improve the accuracy of PEI diagnosis [63].
There are multiple diagnostic tests available for PEI, both direct and indirect (Figure 1A). One indirect approach is the measurement of fecal elastase-1 (FE-1). FE-1 is an enzyme exclusively produced by the pancreas that is not susceptible to breakdown in the intestine, making it a measurement of the secretory capacity of the pancreas [55,60]. In pancreatic cancer, a severe reduction of FE-1 level (<20 mcg/g) is an independent predictor of poor survival [64]. Notably, the measurement of FE-1 is a reliable and reproducible screening tool for severe PEI when compared to secretin tests [65]. In a systematic review and meta-analysis, Vanga et al. [66] calculated an overall sensitivity of 0.77 and a specificity of 0.88 of the FE-1 assay in detecting PEI. They also identified an FE-1 level of above 200 mcg/g as a reasonable cut-off point to rule out PEI. However, FE-1 is not sensitive to mild to moderate PEI, where less than 50% of patients will have an abnormal FE-1 test [62].
Several additional indirect diagnostic tests for PEI have been described in the literature. First, the N-benzoyl-L-tyrosyl-p-aminobenzoic acid (BT-PABA) test measures the activity of chymotrypsin to identify exocrine insufficiency [67]. Second, the measurement of the coefficient of fat absorption (CFA) is currently considered the gold standard test for fat maldigestion. However, the CFA is not specific to PEI, requires adherence to a specific diet and collection of stool samples over 72 h, and is therefore challenging to obtain for clinical applications [57,68]. Lastly, Dominguez-Munoz et al. [69] developed a non-invasive breath test which measures the breakdown product of a standard 13C-labeled fatty substrate. The 13C-mixed triglyceride breath test is well correlated to CFA and is less cumbersome to perform [69]. However, this test is less sensitive to mild PEI and is not widely available in clinical settings [55]. Presently, no laboratory testing beyond the FE-1 is widely available for routine clinical use for PDAC patients.
Direct approaches to the measurement of PEI are generally more sensitive and involve measuring pancreatic secretion following stimulation with either cholecystokinin (CCK) or secretin. Traditionally, this requires intubation of the duodenum. An alternative approach that uses sample collection using upper endoscopy may not be sufficiently sensitive and specific for routine clinical application [70,71]. Regardless, direct testing of PEI is labor-intensive and more invasive, and therefore may not be appropriate for the pancreatic cancer population. As no single diagnostic test is recommended for PEI, anthropometric data such as Body Mass Index, serial assessment of clinical symptoms, and nutritional markers such as the levels of fat-soluble vitamins, plasma proteins, minerals, and serum lipids may also be considered in the diagnostic schema of PEI [72,73].
Overall, no single test or screening tool is recommended for PEI. Whereas CFA remains the gold standard of PEI, it is invasive and cumbersome to perform, and its alternative, the 13C-mixed triglyceride breath test, is not widely available. A general diagnostic approach to PEI was developed by the Australasian Pancreatic Club (APC), utilizing clinical symptoms, pre-test probability of PEI, and FE-1 measurement [54]. Patients with a high likelihood of PEI, such as those who have undergone total pancreatectomy, or have tumors that destroy the head of the pancreas are recommended a trial of pancreatic enzyme replacement therapy (PERT), while other patients are recommended to undergo further imaging or assessment of pancreatic function [54]. This is supported by a 2020 review from Pezzilli et al. [74], which suggested that the prevalence of PEI in patients with pancreatic head tumors is high enough that they should be treated with PERT without investigation. Similarly, the United Kingdom practical guidelines recommend an initial measurement of FE-1 when there is suspicion of PEI [73]. Based on these guidelines, a suggested approach to the diagnosis of PEI in pancreatic cancer is summarized in Figure 1B.

4. Prevalence of PEI in Pancreatic Cancer

The prevalence of PEI in pancreatic cancer is still not well researched and, with a lack of awareness and/or variation in diagnostic testing, has been difficult to diagnose and treat. In a 2020 systematic review and meta-analysis that included 11 studies, PEI was estimated to affect 72% of patients with advanced pancreatic cancer [13]. Interestingly, while patients with pancreatic head tumors were more likely to suffer from PEI, 32% of patients with pancreatic body or tail tumors were also determined to have PEI [13]. Surgical resection is an independent risk factor of PEI as well. For example, Roeyen et al. [75] performed a study of 78 patients undergoing pancreaticoduodenectomy for oncological indications, finding that 20.5% of patients had PEI preoperatively while 64.1% of patients required PERT postoperatively. The rate of PEI after surgical resection can be impacted by the type of surgery performed. By definition, 100% of patients undergoing total pancreatectomy will have PEI. Reported postoperative rates of PEI after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) vary, although PD is generally associated with a higher risk of PEI [76,77,78]. In a 2016 systematic review, Tseng et al. [77] reported the median preoperative and postoperative prevalence of PEI for patients undergoing PD to be 44% and 74% (36–100%), respectively. Patients undergoing DP had a median preoperative prevalence of 20% and a postoperative prevalence of 67–80% [77]. Additionally, the use of pancreaticojejunal anastomosis rather than pancreaticogastric anastomosis following pancreaticoduodenectomy has been demonstrated to help preserve pancreatic exocrine function [79]. For patients undergoing resection, remnant pancreatic volume is also a predictive factor for postoperative PEI [80]. In a recent systematic review and meta-analysis of 20 studies, Budipramana et al. [81] further identified preoperative main pancreatic duct diameter >3 mm, hard pancreatic texture, and the use of adjuvant chemotherapy as risk factors for the development of pancreatic insufficiency.
The prevalence of PEI among patients with locally advanced and metastatic PDAC is more difficult to determine accurately and would be better informed by further research. This may be an underappreciated problem among this subset of patients (which represents most patients with PDAC). Diagnostic challenges in this setting might stem from a lack of knowledge of PEI and the overwhelming symptomatic nature of PDAC diagnosis, which can be associated with symptoms of abdominal pain, discomfort, nausea/ vomiting, and bowel disturbances, among others. Many of these symptoms overlap with the symptoms of PEI. Likewise, systemic chemotherapy regimens commonly prescribed in this setting (e.g., FOLFIRINOX or gemcitabine/nab-paclitaxel) might be associated with considerable digestive toxicities which might further compound the accuracy of diagnostic reasoning. Moreover, patients and providers alike become rightly occupied by questions of prognosis, survival, and systemic treatment options for this lethal disease. Therefore, it is possible that PEI takes a back seat in this setting and is never properly addressed among many patients, which is unfortunate as the treatment of PEI can greatly impact their quality of life. Overall, specialized nutrition support from a dietitian is strongly recommended for all PDAC patients [82].

5. Practical Considerations of PEI Management

The optimal management of PEI in pancreatic cancer has been previously outlined in multiple international consensus statements, as summarized in Figure 1B [54,59,73,83]. General principles of PEI management involve a standardized approach to PEI diagnosis, dietary consultation, and the use of PERT. A comprehensive nutritional assessment, intake of smaller and more frequent meals, as well as replacement of any deficiencies in fat-soluble vitamins, vitamin B12, iron, and lipoproteins, are also important aspects of PEI management [54]. Here, we discuss some important practical considerations in the prescription of PERT for PEI.
The goal of PERT is the delivery of pancreatic enzymes such as lipase, amylase, and protease into the intestinal lumen with meals to allow for proper digestion and absorption [54,59]. Most available pancreatic enzyme formulations are encapsulated into microgranules or minimicrospheres that dissolve at pH > 5.5 or higher to prevent the inactivation of lipase in the acidic environment of the stomach. Although uncoated formulations are also available [59,83,84], they are not indicated in patients with gastric secretions. The use of coated PERT has been associated with greater weight gain [85]. In addition, a 2017 meta-analysis also demonstrated a trend toward improved CFA when coated enzymes were compared to uncoated enzymes [86]. Uncoated PERT may theoretically be used for patients who have undergone gastrectomy [85] but are otherwise not recommended for PDAC patients.
Both uncoated and coated PERT have been used in the management of pain associated with chronic pancreatitis, although the use of uncoated PERT in PDAC associated with PEI is more limited [83,87]. This further supports the common practice of using coated PERT in pancreatic cancer patients. Multiple preparations of encapsulated pancreatic enzymes are commercially available, which have demonstrated variation in the distribution of particles, lipase activity, and release of enzymes at acidic pH levels in the in vitro setting [88,89]. Nevertheless, no direct comparison of efficacy has been made for pancreatic cancer patients.
Proton pump inhibitors (PPIs) are commonly prescribed medications for the suppression of gastric acid and the treatment of acid-related disorders. Interestingly, there have been multiple epidemiological studies linking PPIs to an increased risk of pancreatic cancer and other gastrointestinal malignancies [90,91]. The impact of PPIs on PDAC outcomes is controversial, although recent experimental evidence has suggested a protective role [92,93]. In the setting of PEI, PPIs may act to further protect pancreatic enzyme replacements from degradation in the acidic environment of the stomach [83]. Nevertheless, routine use of PPIs concomitantly with PERT is not recommended. PPIs may be considered for patients who do not have an adequate response to PERT, or who have symptoms of dyspepsia [74,83,94,95,96].
Certain oral anticancer medications that are used in the treatment of PDAC (e.g., Capecitabine) may have reduced systemic exposure due to the high pH of the stomach. Capecitabine efficacy has been questioned among patients with colorectal cancer and gastroesophageal cancer when PPIs were used concurrently [97,98]. It is not entirely clear if raising the pH using PPIs would compromise the efficacy of Capecitabine or not. It is also not clear if alternative acid suppressive strategies would improve the absorption of Capecitabine and/or compromise the efficacy of PERT in this setting. Further research is necessary to define the impact of long-term PPI use on the efficacy of Capecitabine and other chemotherapeutic agents in the context of PDAC.
One recommended starting dose of PERT is approximately 40,000–50,000 units of lipase with meals and 25,000 units of lipase with snacks, to be titrated to the relief of clinical symptoms [59,83]. An alternative dosing strategy is 500–2500 units of lipase/kg/meal, half for snacks, to a maximum of 10,000 units of lipase per kg per day [99]. A sensible approach in clinical settings would be to titrate up to the initially recommended dosing over the course of several days. Regular assessment of nutritional status and symptoms is crucial for patients with PEI. For patients who do not respond to PERT, it is also important to ensure that patients understand the importance of proper use and compliance. This is underscored in a 2019 study by Barkin et al. [100], which demonstrated that only 66% of patients appropriately prescribed PERT were compliant and took PERT appropriately. Importantly, patients should be recommended to take PERT with meals and snacks, not after meals or scheduled throughout the day [73,100]. Dosage increases and the addition of PPIs should be considered if patients do not have relief of symptoms (Figure 1B). While there is some variation between different guidelines as to whether a specific maximum dose for PERT exists, it is important to exclude alternate causes for clinical symptoms when dosages exceed 100,000 units of lipase with meals without relief of symptoms [54,73]. Patients should also be counseled that the symptoms of PEI may not resolve completely, even with the appropriate use of PERT [74].

6. Appropriate Use of PERT for Pancreatic Cancer

Several international studies have examined the proportion of pancreatic cancer patients with PEI, in both resectable and non-resectable disease, that are prescribed appropriate PERT (Table 1). In a retrospective study of 129 patients with metastatic pancreatic cancer that were referred to palliative care, Landers et al. [101] found that while 72% of patients had symptoms suggestive of pancreatic insufficiency, only 21% of patients were prescribed PERT. The authors identified several possible contributing factors, including a lack of awareness of PEI or the benefits of PERT and insufficient screening initiatives [101]. Similarly, McCallum et al. [102] studied 183 patients with diagnoses of PDAC and pancreatic neuroendocrine tumors (PNET). In total, 63% of patients had symptoms to suggest PEI, although only 43% of patients received nutritional interventions such as PERT. Interestingly, patients who had received nutritional interventions were more likely to receive systemic chemotherapy, potentially because the nutritional interventions improved patients’ functional status to a point where they were deemed appropriate for chemotherapy [102]. The authors also identified several barriers to appropriate PERT, including clinicians’ assumptions that pancreatic cancer patients will have weight loss, lack of training in screening for PEI, and the burdensome testing for PEI.
The attitudes of clinicians toward PERT were formally evaluated in a study that surveyed 208 hepato-pancreato-biliary surgeons [103]. Whereas the majority believed that PERT improves nutritional status, only a minority believed that PERT improves overall survival (19.7%), disease-free survival (6.25%), or the rate of postoperative complications (28.8%) [103]. Furthermore, inconsistencies were identified in how patients were selected for PERT, the duration of therapy, and how treatment efficacy was monitored [103]. Postoperative PEI can commonly manifest up to 3 months after surgery [104], which can contribute to the underdiagnosis of PEI if symptoms are not assessed at follow-up appointments. Interestingly, regular interaction with dietician colleagues has also been shown to improve the recognition of malnutrition by clinicians [105]. Additionally, a United Kingdom (UK) study of patients with pancreatic cancer or malignant biliary obstruction demonstrated that the rate of PERT was higher for patients with resectable disease when compared to those with unresectable disease (45.3% compared to 74.4%, p < 0.001) [106]. PERT prescription was increased for patients who had a consult with a dietitian and those who had been managed at specialized hepatopancreaticobiliary or pancreatic units [106]. Unfortunately, there is some evidence of an inequality of care where patients being treated with palliative intent are less likely to receive PERT, perhaps due to a lack of perceived benefit [106].
The patient perspective of PEI provides additional clues regarding its sub-optimal management. Dunleavy et al. [107] performed a qualitative study that identified gaps in patient education around PERT, to the point where several patients attributed symptoms of malabsorption to PERT itself. In addition, the social implications of needing to take PERT with meals and concerns around side effects and the frequency of dosing may contribute significantly to inconsistent adherence to treatment [107]. Lander et al. [108] demonstrated that a structured consultation with a specialized palliative team, regular dietary reassessment, and enhanced health literacy allowed patients to become more involved in managing PERT, thus improving adherence.
Overall, these studies demonstrate the underdiagnosis and undertreatment of PEI by clinicians, likely resulting from a combination of factors including challenging diagnostic tests for PEI, lack of training, and a lack of perceived benefit to long-term outcomes such as overall survival, especially for patients with unresectable disease. Longitudinal nutritional support, education, and peer support may serve to improve patient understanding of PEI as well as treatment adherence.
Table
Table 1. Summary of studies examining the frequency of appropriate treatment for exocrine pancreatic insufficiency in patients with pancreatic cancer.
Table 1. Summary of studies examining the frequency of appropriate treatment for exocrine pancreatic insufficiency in patients with pancreatic cancer.
ReferenceStudy PopulationResectable/UnresectableStudy LocationFindings
[101]Retrospective study of 129 patients with metastatic pancreatic cancerBothNew Zealand
  • Whereas 70% of patients had symptoms of malabsorption, only 21% were prescribed PERT.
[102]Retrospective study of 183 patients with PDAC and pNETsBothUK
  • 63% of patients had symptoms of pancreatic enzyme insufficiency, and 43% received a nutritional intervention (PERT, nutritional supplementation, or dietician referral).
[100] 262 patients diagnosed with pancreatic cancerBothUSA
  • 85% of patients surveyed discussed PERT with their healthcare provider, and 75% were prescribed PERT.
  • Of the patients prescribed PERT, only 65% were prescribed appropriately (with all meals and snacks).
[109]32,461 individuals identified with pancreatic cancer from US insurance claims BothUSA
  • 1.9% of patients with pancreatic cancer were tested for exocrine insufficiency, and 21.9% filled a prescription for PERT.
[106] 1350 individuals with malignant pancreatic, peri-ampullary lesions or malignant biliary obstructionBothUK
  • 74.4% of patients with resectable disease and 45.3% of patients with unresectable disease were prescribed PERT.
  • The rate of PERT prescription was increased for patients who had dietician referral (p = 0.001), management at hepatopancreaticobiliary (p = 0.049), or pancreatic unit (0.009). The rate of prescription was inversely correlated with the Charlson comorbidity score.
[103] Survey of 208 hepato-pancreato-biliary surgeonsN/AUSA
  • 86.5% of surgeons prescribed PERT for at least some patients with resectable or borderline resectable PDAC, and 28.1% ordered tests to confirm exocrine pancreatic enzyme insufficiency before starting PERT.
  • 19.7% of surgeons believe PERT impacts overall survival, and 6.25% of surgeons believe PERT impacts disease-free survival.
[110] 95 patients who underwent pancreaticoduodenectomy for suspected/confirmed pancreatic or periampullary (pre)malignancyResectableThe Netherlands
  • 97% of patients developed pancreatic exocrine insufficiency, and 48–79% of patients had vitamin D or K deficiencies.
  • 0–50% of patients with deficiencies received vitamin supplementation.

7. Impact of PERT on Patient Outcomes

Several studies have demonstrated a positive impact of PERT on the nutritional status of patients with pancreatic cancer, although the majority have been retrospective (Table 2). Interestingly, pre-clinical models have also demonstrated that PEI drives peripheral tissue wasting [111]. Results from randomized controlled trials have been generally limited to small cohorts of patients and have been challenging to interpret due to conflicting results. Bruno et al. [112] first performed a randomized trial of 21 patients with unresectable pancreatic head tumors with suspected pancreatic duct obstruction, demonstrating that PERT allowed patients to gain weight while improving fat absorption and daily energy intake. These results are unfortunately not supported by later trials [113,114,115]. In the largest trial to date, Saito et al. [115] examined 88 patients with unresectable pancreatic cancer that were randomized to Pancrelipase and control groups. When comparing the two groups, the authors did not find a statistically significant difference in BMI at 8 weeks or other nutritional markers. The authors hypothesized that the absence of appropriate dietary consultation limited the degree of oral intake for patients and that intensification of systemic chemotherapy with its associated gastrointestinal toxicities limited the impact of PERT in comparison to the earlier study [112,115]. Beyond objective measures of nutrition, symptoms of PEI can also have a significantly negative impact on patients’ quality of life if not properly treated [116].
In addition to its effects on nutrition and quality of life, the potential impact of PERT on survival outcomes in pancreatic cancer has also been evaluated. Interestingly, a study by McCallum et al. [102] that included patients with both PDAC and pancreatic neuroendocrine tumors (PNETs) demonstrated that nutritional interventions for PEI have the potential of improving not only functional status but also eligibility for systemic chemotherapy. However, none of the three randomized controlled trials that specifically examined the impact of PERT on overall survival have demonstrated a statistically significant improvement in overall survival [113,114,115]. Of note, Zdenkowski et al. [114] did identify a numerically greater median survival in the PERT group, although this did not reach statistical significance, owing to the limited sample size (67.6 weeks in the pancreatic extract group compared to 17 weeks in the control group, n = 18). An independent systematic review that only included four randomized controlled trials again failed to identify a significant impact of PERT on overall survival, although the authors acknowledged small sample sizes, heterogeneity in trial design, and endpoints as limitations [117].
There have been multiple retrospective analyses of larger cohorts of patients that have demonstrated improved survival outcomes [102,118,119,120]. In the most recent and largest retrospective study to date, Roberts et al. [120] studied 807 patients with pancreatic adenocarcinoma (PDAC) and demonstrated a longer median survival in patients receiving PERT (274 vs. 140 days, p < 0.001). Importantly, the survival benefit of PERT was maintained even in the subgroup of PDAC patients who did not undergo surgical resection or palliative chemotherapy, representing a significant proportion of patients with advanced pancreatic cancer [120]. In a recent systematic review and meta-analysis that included 11 studies, PERT was associated with an overall survival benefit of 3.8 months (12.6 vs. 8.7 months, p = 0.002) [13].
The conflicting evidence for the survival impact of PERT in pancreatic cancer is limited by the small sample sizes of currently available randomized controlled trials, heterogeneity in patient populations (e.g., the proportion of patients with pancreatic head tumors), and availability of specialized dietary support for these patients. Most studies that investigate the impact of PERT have also focused on patients with unresectable disease (Table 2).
Further studies, ideally multi-center, randomized controlled trials, are necessary to assess the impact of PERT on patient outcomes and may serve to increase the awareness of PEI among clinicians. Alternatively, advocacy initiatives to incorporate PERT as part of the best practices for PDAC management would also provide supporting evidence. One such trial is the Dutch Pancreatic Cancer Project (PACAP), which assesses the impact of best practices in palliative chemotherapy, PERT, and metal biliary stents on overall survival and patient quality of life [121]. Despite the limitations of current literature, there is certainly an under-recognition of PEI in pancreatic cancer patients and of the potential impact of PERT on the quality of life for patients with PDAC.
Table
Table 2. Summary of studies examining the impact of pancreatic enzyme replacement (PERT) on patient outcomes for pancreatic cancer.
Table 2. Summary of studies examining the impact of pancreatic enzyme replacement (PERT) on patient outcomes for pancreatic cancer.
ReferenceStudy PopulationResectable/UnresectableInterventionFindings
[122] Prospective study of 12 patients with biopsy-proven pancreatic ductal adenocarcinomaUnresectablePancreatic Tablets
  • Pancreatic enzyme supplementation improved absorption for patients with moderate to severe fat or protein malabsorption but not in patients with mild fat or protein malabsorption.
[112]Randomized controlled trial of 21 patients with unresectable pancreatic cancer with suspected biliary obstructionUnresectablePanzytrat 25,000 (coated)
  • The use of pancreatic PERT allowed for an average weight gain of 1.2% (0.7 kg), while placebo control patients lost 3.7% (2.2 kg). Patients on PERT also had increased fat absorption coefficient and total daily energy intake compared to placebo controls.
[113]Randomized controlled trial of 67 patients with unresectable pancreatic cancer (34% pancreatic head tumours)UnresectableNorzyme (coated)
  • No statistically significant difference in body weight, patient-generated subjective global assessment score, quality of life, or overall survival was observed between the two groups.
[102] Retrospective study of 183 patients with PDAC and pNETsBothNutritional intervention (including PERT)
  • Patients who received PERT were more likely to receive systemic chemotherapy compared to patients who did not receive PERT (65.8% vs. 50%, univariate p-value 0.03).
[118]Retrospective analysis of 469 patients undergoing pancreaticoduodenectomy for PDAC, cholangiocarcinoma, ampullary carcinoma, or duodenal carcinomaResectable PERT
  • 43.1% of patients received PERT. PERT use was independently associated with improved survival (HR 0.72, 95% CI 0.52–0.99, p = 0.044).
  • The effect of PERT on patient survival was mostly observed in patients with a pancreatic duct ≥3 mm.
[119] Prospective observational study of 46 patients with pancreatic cancer on PERT and 45 historical controls UnresectablePancrelipase
  • Patients on PERT maintained nutritional markers in comparison to historical controls (BMI unchanged at 16 weeks for PERT, decreased from 21.7 to 21.2, p < 0.001 for controls; serum albumin + 0.1 mg/dL for PERT, −0.1 mg/dL in historical controls although not statistically significant).
  • The use of PERT was associated with significantly higher overall survival on univariate analysis, although not significant after adjusting for other factors (HR 0.73; p = 0.367).
[114]Randomized controlled trial of 18 patients with advanced pancreatic cancer UnresectableCreon 25,000 (coated)
  • Pancreatic extract supplementation was not associated with a significant difference in BMI or quality of life. Median overall survival was numerically greater in the pancreatic extract group compared to the control group (67.6 weeks compared to 17 weeks), although did not reach statistical significance.
[115]Randomized controlled trial of 88 patients with unresectable pancreatic cancer receiving chemotherapyUnresectablePancrelipase
  • The addition of PERT did not significantly improve BMI, other nutritional markers, or median overall survival.
[123]Retrospective analysis of 160 patients with unresectable pancreatic cancerUnresectableCreon 25,000 (coated)
  • The use of PERT was significantly associated with improved survival (HR 1.81, 95% CI 1.23–2.66, p = 0.002 in multivariate analysis). Survival of patients treated with PERT due to symptoms of pancreatic insufficiency was similar to that of patients who did not receive PERT due to the absence of symptoms (HR 1.12, 95% CI 0.67–1.89).
[124]Prospective study of 29 patients with metastatic pancreatic adenocarcinoma, excluding those with ECOG ≤ 3 or PPS < 60%UnresectableCreon 25,000 (coated)
  • The use of PERT was associated with a statistically significant improvement in symptoms (diarrhea, pancreatic and hepatic pain, bloating/gas).
[120]Retrospective observational cohort study of 807 patients with pancreatic adenocarcinoma on PERT matched to non-PERT treated controlsBothPERT
  • Patients receiving PERT had longer median survival than patients not receiving PERT (274 vs. 140 days, p < 0.001). The effect was preserved in subgroup analysis, including in patients not receiving chemotherapy or surgery.

8. Conclusions

PEI is a common complication of pancreatic ductal adenocarcinoma, with implications on patients’ nutritional status, quality of life, and overall prognosis. Existing guidelines recommend a standardized nutritional assessment of PDAC patients, the use of FE-1 as an adjunctive test, rapid initiation of PERT for patients that are at high risk of PEI, and regular nutritional assessments. Unfortunately, PEI remains an underrecognized and undertreated condition due to barriers such as a lack of training among clinicians, variation in perceptions regarding its importance in patient outcomes, and uncertainties in the diagnostic approach. Importantly, patients who suffer from PEI benefit from education surrounding this condition and a multidisciplinary approach to its management. Future multi-center randomized trials are necessary to clarify the current uncertainty about the impact of PEI on patient outcomes.

Author Contributions

Conceptualization, X.L. and O.A.-R.; writing—original draft preparation, X.L., G.R. and O.A.-R.; writing—review and editing, X.L., G.R., J.K., G.W. and O.A.-R.; visualization, X.L. and G.R.; supervision, O.A.-R. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

X.L.: None. G.R.: None. J.K.: None. G.W.: None. O.A.-R.: Honoraria/ advisory board with Ipsen; Roche; Lilly; Eisai; Bayer; Amgen.

References

  1. Rawla, P.; Sunkara, T.; Gaduputi, V. Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J. Oncol. 2019, 10, 10–27. [Google Scholar] [CrossRef]
  2. Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2017, Special Topic: Pancreatic Cancer; Canadian Cancer Society’s Advisory Committee on Cancer Statistics: Toronto, ON, Canada, 2017. [Google Scholar]
  3. Ilic, M.; Ilic, I. Epidemiology of Pancreatic Cancer. World J. Gastroenterol. 2016, 22, 9694–9705. [Google Scholar] [CrossRef]
  4. Khalaf, N.; El-Serag, H.B.; Abrams, H.R.; Thrift, A.P. Burden of Pancreatic Cancer: From Epidemiology to Practice. Clin. Gastroenterol. Hepatol. 2021, 19, 876–884. [Google Scholar] [CrossRef] [PubMed]
  5. Park, W.; Chawla, A.; O’Reilly, E.M. Pancreatic Cancer: A Review. JAMA 2021, 326, 851–862. [Google Scholar] [CrossRef]
  6. Gilliland, T.M.; Villafane-Ferriol, N.; Shah, K.P.; Shah, R.M.; Tran Cao, H.S.; Massarweh, N.N.; Silberfein, E.J.; Choi, E.A.; Hsu, C.; McElhany, A.L.; et al. Nutritional and Metabolic Derangements in Pancreatic Cancer and Pancreatic Resection. Nutrients 2017, 9, 243. [Google Scholar] [CrossRef] [PubMed]
  7. Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer Statistics, 2023. CA A Cancer J. Clin. 2023, 73, 17–48. [Google Scholar] [CrossRef] [PubMed]
  8. Khadka, R.; Tian, W.; Hao, X.; Koirala, R. Risk Factor, Early Diagnosis and Overall Survival on Outcome of Association between Pancreatic Cancer and Diabetes Mellitus: Changes and Advances, a Review. Int. J. Surg. 2018, 52, 342–346. [Google Scholar] [CrossRef] [PubMed]
  9. Latenstein, A.E.J.; van der Geest, L.G.M.; Bonsing, B.A.; Groot Koerkamp, B.; Haj Mohammad, N.; de Hingh, I.H.J.T.; de Meijer, V.E.; Molenaar, I.Q.; van Santvoort, H.C.; van Tienhoven, G.; et al. Nationwide Trends in Incidence, Treatment and Survival of Pancreatic Ductal Adenocarcinoma. Eur. J. Cancer 2020, 125, 83–93. [Google Scholar] [CrossRef] [Green Version]
  10. Chari, S.T.; Leibson, C.L.; Rabe, K.G.; Ransom, J.; de Andrade, M.; Petersen, G.M. Probability of Pancreatic Cancer Following Diabetes: A Population-Based Study. Gastroenterology 2005, 129, 504–511. [Google Scholar] [CrossRef]
  11. Porta, M.; Fabregat, X.; Malats, N.; Guarner, L.; Carrato, A.; de Miguel, A.; Ruiz, L.; Jariod, M.; Costafreda, S.; Coll, S.; et al. Exocrine Pancreatic Cancer: Symptoms at Presentation and Their Relation to Tumour Site and Stage. Clin. Transl. Oncol. 2005, 7, 189–197. [Google Scholar] [CrossRef]
  12. Furukawa, H.; Okada, S.; Saisho, H.; Ariyama, J.; Karasawa, E.; Nakaizumi, A.; Nakazawa, S.; Murakami, K.; Kakizoe, T. Clinicopathologic Features of Small Pancreatic Adenocarcinoma. A Collective Study. Cancer 1996, 78, 986–990. [Google Scholar] [CrossRef]
  13. Iglesia, D.; Avci, B.; Kiriukova, M.; Panic, N.; Bozhychko, M.; Sandru, V.; Madaria, E.; Capurso, G. Pancreatic Exocrine Insufficiency and Pancreatic Enzyme Replacement Therapy in Patients with Advanced Pancreatic Cancer: A Systematic Review and Meta-analysis. United Eur. Gastroenterol. J. 2020, 8, 1115–1125. [Google Scholar] [CrossRef] [PubMed]
  14. Neoptolemos, J.P.; Palmer, D.H.; Ghaneh, P.; Valle, J.W.; Cunningham, D.; Wadsley, J.; Meyer, T.; Anthoney, A.; Glimelius, B.; Falk, S.; et al. ESPAC-4: A Multicenter, International, Open-Label Randomized Controlled Phase III Trial of Adjuvant Combination Chemotherapy of Gemcitabine (GEM) and Capecitabine (CAP) versus Monotherapy Gemcitabine in Patients with Resected Pancreatic Ductal Adenocarcinoma: Five Year Follow-Up. JCO 2020, 38, 4516. [Google Scholar] [CrossRef]
  15. Conroy, T.; Hammel, P.; Hebbar, M.; Ben Abdelghani, M.; Wei, A.C.; Raoul, J.-L.; Choné, L.; Francois, E.; Artru, P.; Biagi, J.J.; et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N. Engl. J. Med. 2018, 379, 2395–2406. [Google Scholar] [CrossRef]
  16. Oba, A.; Ho, F.; Bao, Q.R.; Al-Musawi, M.H.; Schulick, R.D.; Del Chiaro, M. Neoadjuvant Treatment in Pancreatic Cancer. Front. Oncol. 2020, 10, 245. [Google Scholar] [CrossRef]
  17. Ghanem, I.; Lora, D.; Herradón, N.; de Velasco, G.; Carretero-González, A.; Jiménez-Varas, M.Á.; Vázquez de Parga, P.; Feliu, J. Neoadjuvant Chemotherapy with or without Radiotherapy versus Upfront Surgery for Resectable Pancreatic Adenocarcinoma: A Meta-Analysis of Randomized Clinical Trials. ESMO Open 2022, 7, 100485. [Google Scholar] [CrossRef]
  18. Von Hoff, D.D.; Ervin, T.; Arena, F.P.; Chiorean, E.G.; Infante, J.; Moore, M.; Seay, T.; Tjulandin, S.A.; Ma, W.W.; Saleh, M.N.; et al. Increased Survival in Pancreatic Cancer with Nab-Paclitaxel plus Gemcitabine. N. Engl. J. Med. 2013, 369, 1691–1703. [Google Scholar] [CrossRef] [Green Version]
  19. Burris, H.A.; Moore, M.J.; Andersen, J.; Green, M.R.; Rothenberg, M.L.; Modiano, M.R.; Cripps, M.C.; Portenoy, R.K.; Storniolo, A.M.; Tarassoff, P.; et al. Improvements in Survival and Clinical Benefit with Gemcitabine as First-Line Therapy for Patients with Advanced Pancreas Cancer: A Randomized Trial. J. Clin. Oncol. 1997, 15, 2403–2413. [Google Scholar] [CrossRef] [Green Version]
  20. Kim, C.; Lelond, S.; Daeninck, P.J.; Rabbani, R.; Lix, L.; McClement, S.; Chochinov, H.; Goldenberg, B.A. The Impact of Early Palliative Care on the Quality of Life of Patients with Advanced Pancreatic Cancer: The IMPERATIVE Study. JCO 2021, 39, 12116. [Google Scholar] [CrossRef]
  21. Bevins, J.; Bhulani, N.; Goksu, S.Y.; Sanford, N.N.; Gao, A.; Ahn, C.; Paulk, M.E.; Terauchi, S.; Pruitt, S.L.; Tavakkoli, A.; et al. Early Palliative Care Is Associated with Reduced Emergency Department Utilization in Pancreatic Cancer. Am. J. Clin. Oncol. 2021, 44, 181–186. [Google Scholar] [CrossRef]
  22. Michael, N.; Beale, G.; O’Callaghan, C.; Melia, A.; DeSilva, W.; Costa, D.; Kissane, D.; Shapiro, J.; Hiscock, R. Timing of Palliative Care Referral and Aggressive Cancer Care toward the End-of-Life in Pancreatic Cancer: A Retrospective, Single-Center Observational Study. BMC Palliat. Care 2019, 18, 13. [Google Scholar] [CrossRef]
  23. Moffat, G.T.; Epstein, A.S.; O’Reilly, E.M. Pancreatic Cancer—A Disease in Need: Optimizing and Integrating Supportive Care. Cancer 2019, 125, 3927–3935. [Google Scholar] [CrossRef]
  24. Witvliet-van Nierop, J.E.; Lochtenberg-Potjes, C.M.; Wierdsma, N.J.; Scheffer, H.J.; Kazemier, G.; Ottens-Oussoren, K.; Meijerink, M.R.; de van der Schueren, M.A.E. Assessment of Nutritional Status, Digestion and Absorption, and Quality of Life in Patients with Locally Advanced Pancreatic Cancer. Gastroenterol. Res. Pract. 2017, 2017, 6193765. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. White, J.V.; Guenter, P.; Jensen, G.; Malone, A.; Schofield, M.; Academy Malnutrition Work Group; A.S.P.E.N. Malnutrition Task Force; the A.S.P.E.N. Board of Directors. Consensus Statement: Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition: Characteristics Recommended for the Identification and Documentation of Adult Malnutrition (Undernutrition). JPEN J. Parenter. Enteral Nutr. 2012, 36, 275–283. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Bauer, J.; Capra, S.; Ferguson, M. Use of the Scored Patient-Generated Subjective Global Assessment (PG-SGA) as a Nutrition Assessment Tool in Patients with Cancer. Eur. J. Clin. Nutr. 2002, 56, 779–785. [Google Scholar] [CrossRef]
  27. Bicakli, D.H.; Uslu, R.; Güney, S.C.; Coker, A. The Relationship Between Nutritional Status, Performance Status, and Survival Among Pancreatic Cancer Patients. Nutr. Cancer 2020, 72, 202–208. [Google Scholar] [CrossRef] [PubMed]
  28. Wigmore, S.; Plester, C.; Richardson, R.; Fearon, K. Changes in Nutritional Status Associated with Unresectable Pancreatic Cancer. Br. J. Cancer 1997, 75, 106–109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Hendifar, A.E.; Petzel, M.Q.B.; Zimmers, T.A.; Denlinger, C.S.; Matrisian, L.M.; Picozzi, V.J.; Rahib, L.; on behalf of the Precision Promise. Consortium Pancreas Cancer-Associated Weight Loss. Oncologist 2019, 24, 691–701. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Davidson, W.; Ash, S.; Capra, S.; Bauer, J. Weight Stabilisation Is Associated with Improved Survival Duration and Quality of Life in Unresectable Pancreatic Cancer. Clin. Nutr. 2004, 23, 239–247. [Google Scholar] [CrossRef] [PubMed]
  31. Fearon, K.; Strasser, F.; Anker, S.D.; Bosaeus, I.; Bruera, E.; Fainsinger, R.L.; Jatoi, A.; Loprinzi, C.; MacDonald, N.; Mantovani, G.; et al. Definition and Classification of Cancer Cachexia: An International Consensus. Lancet Oncol. 2011, 12, 489–495. [Google Scholar] [CrossRef]
  32. Kays, J.K.; Shahda, S.; Stanley, M.; Bell, T.M.; O’Neill, B.H.; Kohli, M.D.; Couch, M.E.; Koniaris, L.G.; Zimmers, T.A. Three Cachexia Phenotypes and the Impact of Fat-Only Loss on Survival in FOLFIRINOX Therapy for Pancreatic Cancer: Distinct Cachexia Phenotypes and Survival in PDAC. J. Cachexia Sarcopenia Muscle 2018, 9, 673–684. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Hendifar, A.E.; Chang, J.I.; Huang, B.Z.; Tuli, R.; Wu, B.U. Cachexia, and Not Obesity, Prior to Pancreatic Cancer Diagnosis Worsens Survival and Is Negated by Chemotherapy. J. Gastrointest. Oncol. 2018, 9, 17–23. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Tan, C.R.; Yaffee, P.M.; Jamil, L.H.; Lo, S.K.; Nissen, N.; Pandol, S.J.; Tuli, R.; Hendifar, A.E. Pancreatic Cancer Cachexia: A Review of Mechanisms and Therapeutics. Front. Physiol. 2014, 5, 88. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Santilli, V.; Bernetti, A.; Mangone, M.; Paoloni, M. Clinical Definition of Sarcopenia. Clin. Cases Miner Bone Metab. 2014, 11, 177–180. [Google Scholar] [CrossRef] [PubMed]
  36. Pausch, T.; Hartwig, W.; Hinz, U.; Swolana, T.; Bundy, B.D.; Hackert, T.; Grenacher, L.; Büchler, M.W.; Werner, J. Cachexia but Not Obesity Worsens the Postoperative Outcome after Pancreatoduodenectomy in Pancreatic Cancer. Surgery 2012, 152, S81–S88. [Google Scholar] [CrossRef] [PubMed]
  37. Bachmann, J.; Büchler, M.W.; Friess, H.; Martignoni, M.E. Cachexia in Patients with Chronic Pancreatitis and Pancreatic Cancer: Impact on Survival and Outcome. Nutr. Cancer 2013, 65, 827–833. [Google Scholar] [CrossRef]
  38. Ozola Zalite, I.; Zykus, R.; Francisco Gonzalez, M.; Saygili, F.; Pukitis, A.; Gaujoux, S.; Charnley, R.M.; Lyadov, V. Influence of Cachexia and Sarcopenia on Survival in Pancreatic Ductal Adenocarcinoma: A Systematic Review. Pancreatology 2015, 15, 19–24. [Google Scholar] [CrossRef]
  39. Bachmann, J.; Heiligensetzer, M.; Krakowski-Roosen, H.; Büchler, M.W.; Friess, H.; Martignoni, M.E. Cachexia Worsens Prognosis in Patients with Resectable Pancreatic Cancer. J. Gastrointest Surg. 2008, 12, 1193–1201. [Google Scholar] [CrossRef]
  40. Hou, Y.-C.; Chen, C.-Y.; Huang, C.-J.; Wang, C.-J.; Chao, Y.-J.; Chiang, N.-J.; Wang, H.-C.; Tung, H.-L.; Liu, H.-C.; Shan, Y.-S. The Differential Clinical Impacts of Cachexia and Sarcopenia on the Prognosis of Advanced Pancreatic Cancer. Cancers 2022, 14, 3137. [Google Scholar] [CrossRef]
  41. Conroy, T.; Desseigne, F.; Ychou, M.; Bouché, O.; Guimbaud, R.; Bécouarn, Y.; Adenis, A.; Raoul, J.-L.; Gourgou-Bourgade, S.; de la Fouchardière, C.; et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. N. Engl. J. Med. 2011, 364, 1817–1825. [Google Scholar] [CrossRef] [Green Version]
  42. Sohal, D.P.S.; Kennedy, E.B.; Cinar, P.; Conroy, T.; Copur, M.S.; Crane, C.H.; Garrido-Laguna, I.; Lau, M.W.; Johnson, T.; Krishnamurthi, S.; et al. Metastatic Pancreatic Cancer: ASCO Guideline Update. JCO 2020, 38, 3217–3230. [Google Scholar] [CrossRef] [PubMed]
  43. Santos, I.; Mendes, L.; Mansinho, H.; Santos, C.A. Nutritional Status and Functional Status of the Pancreatic Cancer Patients and the Impact of Adjacent Symptoms. Clin. Nutr. 2021, 40, 5486–5493. [Google Scholar] [CrossRef] [PubMed]
  44. Bauer, J.D.; Capra, S. Nutrition Intervention Improves Outcomes in Patients with Cancer Cachexia Receiving Chemotherapy? A Pilot Study. Support Care Cancer 2005, 13, 270–274. [Google Scholar] [CrossRef] [PubMed]
  45. Ferrucci, L.M.; Bell, D.; Thornton, J.; Black, G.; McCorkle, R.; Heimburger, D.C.; Saif, M.W. Nutritional Status of Patients with Locally Advanced Pancreatic Cancer: A Pilot Study. Support Care Cancer 2011, 19, 1729–1734. [Google Scholar] [CrossRef]
  46. Richter, E.; Denecke, A.; Klapdor, S.; Klapdor, R. Parenteral Nutrition Support for Patients with Pancreatic Cancer--Improvement of the Nutritional Status and the Therapeutic Outcome. Anticancer. Res. 2012, 32, 2111–2118. [Google Scholar]
  47. Vashi, P.G.; Dahlk, S.; Popiel, B.; Lammersfeld, C.A.; Ireton-Jones, C.; Gupta, D. A Longitudinal Study Investigating Quality of Life and Nutritional Outcomes in Advanced Cancer Patients Receiving Home Parenteral Nutrition. BMC Cancer 2014, 14, 593. [Google Scholar] [CrossRef] [Green Version]
  48. Ruiz Garcia, V.; López-Briz, E.; Carbonell Sanchis, R.; Gonzalvez Perales, J.L.; Bort-Martí, S. Megestrol Acetate for Treatment of Anorexia-Cachexia Syndrome. Cochrane Database Syst. Rev. 2013, 2019. [Google Scholar] [CrossRef]
  49. Garcia, J.M.; Boccia, R.V.; Graham, C.D.; Yan, Y.; Duus, E.M.; Allen, S.; Friend, J. Anamorelin for Patients with Cancer Cachexia: An Integrated Analysis of Two Phase 2, Randomised, Placebo-Controlled, Double-Blind Trials. Lancet Oncol. 2015, 16, 108–116. [Google Scholar] [CrossRef]
  50. Temel, J.S.; Abernethy, A.P.; Currow, D.C.; Friend, J.; Duus, E.M.; Yan, Y.; Fearon, K.C. Anamorelin in Patients with Non-Small-Cell Lung Cancer and Cachexia (ROMANA 1 and ROMANA 2): Results from Two Randomised, Double-Blind, Phase 3 Trials. Lancet Oncol. 2016, 17, 519–531. [Google Scholar] [CrossRef]
  51. Hamauchi, S.; Furuse, J.; Takano, T.; Munemoto, Y.; Furuya, K.; Baba, H.; Takeuchi, M.; Choda, Y.; Higashiguchi, T.; Naito, T.; et al. A Multicenter, Open-label, Single-arm Study of Anamorelin (ONO-7643) in Advanced Gastrointestinal Cancer Patients with Cancer Cachexia. Cancer 2019, 125, 4294–4302. [Google Scholar] [CrossRef] [Green Version]
  52. Sandini, M.; Patino, M.; Ferrone, C.R.; Alvarez-Pérez, C.A.; Honselmann, K.C.; Paiella, S.; Catania, M.; Riva, L.; Tedesco, G.; Casolino, R.; et al. Association Between Changes in Body Composition and Neoadjuvant Treatment for Pancreatic Cancer. JAMA Surg. 2018, 153, 809. [Google Scholar] [CrossRef]
  53. Bartel, M.J.; Asbun, H.; Stauffer, J.; Raimondo, M. Pancreatic Exocrine Insufficiency in Pancreatic Cancer: A Review of the Literature. Dig. Liver Dis. 2015, 47, 1013–1020. [Google Scholar] [CrossRef] [Green Version]
  54. Nikfarjam, M.; Wilson, J.S.; Smith, R.C. Diagnosis and Management of Pancreatic Exocrine Insufficiency. Med. J. Aust. 2017, 207, 161–165. [Google Scholar] [CrossRef] [PubMed]
  55. Capurso, G.; Traini, M.; Piciucchi, M.; Signoretti, M.; Arcidiacono, P.G. Exocrine Pancreatic Insufficiency: Prevalence, Diagnosis, and Management. CEG 2019, 12, 129–139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Singh, V.K.; Haupt, M.E.; Geller, D.E.; Hall, J.A.; Diez, P.M.Q. Less Common Etiologies of Exocrine Pancreatic Insufficiency. WJG 2017, 23, 7059–7076. [Google Scholar] [CrossRef]
  57. Dominguez-Muñoz, J.E. Management of Pancreatic Exocrine Insufficiency. Curr. Opin. Gastroenterol. 2019, 35, 455–459. [Google Scholar] [CrossRef] [PubMed]
  58. DiMagno, E.P.; Go, V.L.W.; Summerskill, W.H.J. Relations between Pancreatic Enzyme Outputs and Malabsorption in Severe Pancreatic Insufficiency. N. Engl. J. Med. 1973, 288, 813–815. [Google Scholar] [CrossRef]
  59. Roeyen, G.; Berrevoet, F.; Borbath, I.; Geboes, K.; Peeters, M.; Topal, B.; Van Cutsem, E.; Van Laethem, J.-L. Expert Opinion on Management of Pancreatic Exocrine Insufficiency in Pancreatic Cancer. ESMO Open 2022, 7, 100386. [Google Scholar] [CrossRef]
  60. Vujasinovic, M.; Valente, R.; Del Chiaro, M.; Permert, J.; Löhr, J.-M. Pancreatic Exocrine Insufficiency in Pancreatic Cancer. Nutrients 2017, 9, 183. [Google Scholar] [CrossRef]
  61. Lankisch, P.G.; Andrén-Sandberg, Å. Standards for the Diagnosis of Chronic Pancreatitis and for the Evaluation of Treatment. Int. J. Pancreatol. 1993, 14, 205–212. [Google Scholar] [CrossRef]
  62. Lankisch, P.G.; Schmidt, I.; Konig, H.; Lehnick, D.; Knollmann, R.; Lohr, M.; Liebe, S. Faecal Elastase 1: Not Helpful in Diagnosing Chronic Pancreatitis Associated with Mild to Moderate Exocrine Pancreatic Insufficiency. Gut 1998, 42, 551–554. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Johnson, C.D.; Williamson, N.; Janssen-van Solingen, G.; Arbuckle, R.; Johnson, C.; Simpson, S.; Staab, D.; Dominguez-Munoz, E.; Levy, P.; Connett, G.; et al. Psychometric Evaluation of a Patient-Reported Outcome Measure in Pancreatic Exocrine Insufficiency (PEI). Pancreatology 2019, 19, 182–190. [Google Scholar] [CrossRef] [PubMed]
  64. Partelli, S.; Frulloni, L.; Minniti, C.; Bassi, C.; Barugola, G.; D’Onofrio, M.; Crippa, S.; Falconi, M. Faecal Elastase-1 Is an Independent Predictor of Survival in Advanced Pancreatic Cancer. Dig. Liver Dis. 2012, 44, 945–951. [Google Scholar] [CrossRef] [PubMed]
  65. Naruse, S.; Ishiguro, H.; Ko, S.B.H.; Yoshikawa, T.; Yamamoto, T.; Yamamoto, A.; Futakuchi, S.; Goto, H.; Saito, Y.; Takahashi, S. Fecal Pancreatic Elastase: A Reproducible Marker for Severe Exocrine Pancreatic Insufficiency. J. Gastroenterol. 2006, 41, 901–908. [Google Scholar] [CrossRef] [PubMed]
  66. Vanga, R.R.; Tansel, A.; Sidiq, S.; El-Serag, H.B.; Othman, M.O. Diagnostic Performance of Measurement of Fecal Elastase-1 in Detection of Exocrine Pancreatic Insufficiency: Systematic Review and Meta-Analysis. Clin. Gastroenterol. Hepatol. 2018, 16, 1220–1228.e4. [Google Scholar] [CrossRef] [Green Version]
  67. Delchier, J.-C.; Soule, J.-C. BT-PABA Test with Plasma PABA Measurements: Evaluation of Sensitivity and Specificity. Gut 1983, 24, 318–325. [Google Scholar] [CrossRef] [Green Version]
  68. Borowitz, D.; Aronoff, N.; Cummings, L.C.; Maqbool, A.; Mulberg, A.E. Coefficient of Fat Absorption to Measure the Efficacy of Pancreatic Enzyme Replacement Therapy in People With Cystic Fibrosis: Gold Standard or Coal Standard? Pancreas 2022, 51, 310–318. [Google Scholar] [CrossRef]
  69. Domínguez-Muñoz, J.E.; Nieto, L.; Vilariño, M.; Lourido, M.V.; Iglesias-García, J. Development and Diagnostic Accuracy of a Breath Test for Pancreatic Exocrine Insufficiency in Chronic Pancreatitis. Pancreas 2016, 45, 241–247. [Google Scholar] [CrossRef]
  70. Raimondo, M.; Imoto, M.; Dimagno, E.P. Rapid Endoscopic Secretin Stimulation Test and Discrimination of Chronic Pancreatitis and Pancreatic Cancer from Disease Controls. Clin. Gastroenterol. Hepatol. 2003, 1, 397–403. [Google Scholar] [CrossRef]
  71. Albashir, S.; Bronner, M.P.; Parsi, M.A.; Walsh, M.R.; Stevens, T. Endoscopic Ultrasound, Secretin Endoscopic Pancreatic Function Test, and Histology: Correlation in Chronic Pancreatitis. Am. J. Gastroenterol. 2010, 105, 2498–2503. [Google Scholar] [CrossRef]
  72. Lindkvist, B.; Phillips, M.E.; Domínguez-Muñoz, J.E. Clinical, Anthropometric and Laboratory Nutritional Markers of Pancreatic Exocrine Insufficiency: Prevalence and Diagnostic Use. Pancreatology 2015, 15, 589–597. [Google Scholar] [CrossRef] [PubMed]
  73. Phillips, M.E.; Hopper, A.D.; Leeds, J.S.; Roberts, K.J.; McGeeney, L.; Duggan, S.N.; Kumar, R. Consensus for the Management of Pancreatic Exocrine Insufficiency: UK Practical Guidelines. BMJ Open Gastroenterol. 2021, 8, e000643. [Google Scholar] [CrossRef] [PubMed]
  74. Pezzilli, R.; Caccialanza, R.; Capurso, G.; Brunetti, O.; Milella, M.; Falconi, M. Pancreatic Enzyme Replacement Therapy in Pancreatic Cancer. Cancers 2020, 12, 275. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Roeyen, G.; Jansen, M.; Hartman, V.; Chapelle, T.; Bracke, B.; Ysebaert, D.; De Block, C. The Impact of Pancreaticoduodenectomy on Endocrine and Exocrine Pancreatic Function: A Prospective Cohort Study Based on Pre- and Postoperative Function Tests. Pancreatology 2017, 17, 974–982. [Google Scholar] [CrossRef]
  76. Speicher, J.E.; Traverso, L.W. Pancreatic Exocrine Function Is Preserved After Distal Pancreatectomy. J. Gastrointest Surg. 2010, 14, 1006–1011. [Google Scholar] [CrossRef]
  77. Tseng, D.S.J.; Molenaar, I.Q.; Besselink, M.G.; van Eijck, C.H.; Borel Rinkes, I.H.; van Santvoort, H.C. Pancreatic Exocrine Insufficiency in Patients with Pancreatic or Periampullary Cancer: A Systematic Review. Pancreas 2016, 45, 325–330. [Google Scholar] [CrossRef]
  78. Petzel, M.Q.B.; Hoffman, L. Nutrition Implications for Long-Term Survivors of Pancreatic Cancer Surgery. Nutr. Clin. Pract. 2017, 32, 588–598. [Google Scholar] [CrossRef]
  79. Rault, A.; SaCunha, A.; Klopfenstein, D.; Larroudé, D.; Dobo Epoy, F.N.; Collet, D.; Masson, B. Pancreaticojejunal Anastomosis Is Preferable to Pancreaticogastrostomy after Pancreaticoduodenectomy for Longterm Outcomes of Pancreatic Exocrine Function. J. Am. Coll. Surg. 2005, 201, 239–244. [Google Scholar] [CrossRef]
  80. Okano, K.; Murakami, Y.; Nakagawa, N.; Uemura, K.; Sudo, T.; Hashimoto, Y.; Kondo, N.; Takahashi, S.; Sueda, T. Remnant Pancreatic Parenchymal Volume Predicts Postoperative Pancreatic Exocrine Insufficiency after Pancreatectomy. Surgery 2016, 159, 885–892. [Google Scholar] [CrossRef]
  81. Budipramana, V.S.; Witarto, A.P.; Witarto, B.S.; Pramudito, S.L.; Ratri, L.C.; Wairooy, N.A.P.; Putra, A.J. Risk Factors for Exocrine Pancreatic Insufficiency after Pancreatic Surgery: A Systematic Review and Meta-Analysis. Can. J. Surg. 2022, 65, E770–E781. [Google Scholar] [CrossRef]
  82. Lee-Ying, R.; Ahmed, O.; Ahmed, S.; Ahmed, S.; Bathe, O.F.; Brunet, B.; Dawson, L.; Davies, J.; Gordon, V.; Hebbard, P.; et al. Report from the 21st Annual Western Canadian Gastrointestinal Cancer Consensus Conference; Calgary, Alberta; 20–21 September 2019. Curr. Oncol. 2021, 28, 3629–3648. [Google Scholar] [CrossRef] [PubMed]
  83. Durie, P.; Baillargeon, J.-D.; Bouchard, S.; Donnellan, F.; Zepeda-Gomez, S.; Teshima, C. Diagnosis and Management of Pancreatic Exocrine Insufficiency (PEI) in Primary Care: Consensus Guidance of a Canadian Expert Panel. Curr. Med. Res. Opin. 2018, 34, 25–33. [Google Scholar] [CrossRef] [PubMed]
  84. Taylor, C.J.; Thieroff-Ekerdt, R.; Shiff, S.; Magnus, L.; Fleming, R.; Gommoll, C. Comparison of Two Pancreatic Enzyme Products for Exocrine Insufficiency in Patients with Cystic Fibrosis. J. Cyst. Fibros. 2016, 15, 675–680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Domínguez-Muñoz, J.E. Pancreatic Enzyme Replacement Therapy: Exocrine Pancreatic Insufficiency after Gastrointestinal Surgery. HPB 2009, 11, 3–6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. De la Iglesia-García, D.; Huang, W.; Szatmary, P.; Baston-Rey, I.; Gonzalez-Lopez, J.; Prada-Ramallal, G.; Mukherjee, R.; Nunes, Q.M.; Domínguez-Muñoz, J.E.; Sutton, R.; et al. Efficacy of Pancreatic Enzyme Replacement Therapy in Chronic Pancreatitis: Systematic Review and Meta-Analysis. Gut 2017, 66, 1354–1355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Ketwaroo, G.A.; Graham, D.Y. Rational Use of Pancreatic Enzymes for Pancreatic Insufficiency and Pancreatic Pain. In Therapeutic Enzymes: Function and Clinical Implications; Labrou, N., Ed.; Advances in Experimental Medicine and Biology; Springer: Singapore, 2019; Volume 1148, pp. 323–343. ISBN 9789811377082. [Google Scholar]
  88. Shrikhande, S.V.; Prasad, V.M.; Domínguez-Muñoz, J.E.; Weigl, K.E.; Sarda, K.D. In Vitro Comparison of Pancreatic Enzyme Preparations Available in the Indian Market. Drug Des. Dev. Ther. 2021, 15, 3835–3843. [Google Scholar] [CrossRef] [PubMed]
  89. Kuhn, R.J.; Eyting, S.; Henniges, F.; Potthoff, A. In Vitro Comparison of Physical Parameters, Enzyme Activity, Acid Resistance, and PH Dissolution Characteristics of Enteric-Coated Pancreatic Enzyme Preparations: Implications for Clinical Variability and Pharmacy Substitution. J. Pediatr. Pharmacol. Ther. 2007, 12, 115–128. [Google Scholar] [CrossRef] [PubMed]
  90. Poly, T.N.; Islam, M.M.; Walther, B.A.; Lin, M.-C.; Li, Y.-C. (Jack) Proton Pump Inhibitors Use and the Risk of Pancreatic Cancer: Evidence from Eleven Epidemiological Studies, Comprising 1.5 Million Individuals. Cancers 2022, 14, 5357. [Google Scholar] [CrossRef]
  91. Zhou, W.; Chen, X.; Fan, Q.; Yu, H.; Jiang, W. Using Proton Pump Inhibitors Increases the Risk of Hepato-Biliary-Pancreatic Cancer. A Systematic Review and Meta-Analysis. Front. Pharmacol. 2022, 13, 979215. [Google Scholar] [CrossRef]
  92. Kearns, M.D.; Boursi, B.; Yang, Y.-X. Proton Pump Inhibitors on Pancreatic Cancer Risk and Survival. Cancer Epidemiol. 2017, 46, 80–84. [Google Scholar] [CrossRef]
  93. Tozzi, M.; Sørensen, C.E.; Magni, L.; Christensen, N.M.; Bouazzi, R.; Buch, C.M.; Stefanini, M.; Duranti, C.; Arcangeli, A.; Novak, I. Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells. Cancers 2020, 12, 640. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Sander-Struckmeier, S.; Beckmann, K.; Janssen-van Solingen, G.; Pollack, P. Retrospective Analysis to Investigate the Effect of Concomitant Use of Gastric Acid–Suppressing Drugs on the Efficacy and Safety of Pancrelipase/Pancreatin (CREON®) in Patients with Pancreatic Exocrine Insufficiency. Pancreas 2013, 42, 983–989. [Google Scholar] [CrossRef] [PubMed]
  95. Dominguez-Munoz, J.E. Optimising the Therapy of Exocrine Pancreatic Insufficiency by the Association of a Proton Pump Inhibitor to Enteric Coated Pancreatic Extracts. Gut 2006, 55, 1056–1057. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Uwagawa, T.; Misawa, T.; Iida, T.; Sakamoto, T.; Gocho, T.; Wakiyama, S.; Hirohara, S.; Yanaga, K. Proton-Pump Inhibitor as Palliative Care for Chemotherapy-Induced Gastroesophageal Reflux Disease in Pancreatic Cancer Patients. J. Palliat. Med. 2010, 13, 815–818. [Google Scholar] [CrossRef] [PubMed]
  97. Sun, J.; Ilich, A.I.; Kim, C.A.; Chu, M.P.; Wong, G.G.; Ghosh, S.; Danilak, M.; Mulder, K.E.; Spratlin, J.L.; Chambers, C.R.; et al. Concomitant Administration of Proton Pump Inhibitors and Capecitabine Is Associated with Increased Recurrence Risk in Early Stage Colorectal Cancer Patients. Clin. Color. Cancer 2016, 15, 257–263. [Google Scholar] [CrossRef] [PubMed]
  98. Chu, M.P.; Hecht, J.R.; Slamon, D.; Wainberg, Z.A.; Bang, Y.-J.; Hoff, P.M.; Sobrero, A.; Qin, S.; Afenjar, K.; Houe, V.; et al. Association of Proton Pump Inhibitors and Capecitabine Efficacy in Advanced Gastroesophageal Cancer: Secondary Analysis of the TRIO-013/LOGiC Randomized Clinical Trial. JAMA Oncol. 2017, 3, 767. [Google Scholar] [CrossRef]
  99. Ng, C.; Major, G.; Smyth, A.R. Dosing Regimens for Pancreatic Enzyme Replacement Therapy (PERT) in Cystic Fibrosis. Cochrane Database Syst. Rev. 2019, 2019, CD013488. [Google Scholar] [CrossRef]
  100. Barkin, J.A.; Westermann, A.; Hoos, W.; Moravek, C.; Matrisian, L.; Wang, H.; Shemanski, L.; Barkin, J.S.; Rahib, L. Frequency of Appropriate Use of Pancreatic Enzyme Replacement Therapy and Symptomatic Response in Pancreatic Cancer Patients. Pancreas 2019, 48, 780–786. [Google Scholar] [CrossRef]
  101. Landers, A.; Muircroft, W.; Brown, H. Pancreatic Enzyme Replacement Therapy (PERT) for Malabsorption in Patients with Metastatic Pancreatic Cancer. BMJ Support Palliat Care 2016, 6, 75–79. [Google Scholar] [CrossRef]
  102. McCallum, L.; Lamarca, A.; Valle, J. Prevalence of Symptomatic Pancreatic Exocrine Insufficiency in Patients with Pancreatic Malignancy: Nutritional Intervention May Improve Survival. Cancer Res. Front. 2016, 2, 352–367. [Google Scholar] [CrossRef]
  103. Jain, T.; Sharma, P.; Giri, B.; Iyer, S.; Sethi, V.; Bava, E.P.; Vaish, U.; Sahay, P.; Datta, J.; Reddy, S.; et al. Prescription Patterns of Pancreatic Enzyme Replacement Therapy for Patients with Pancreatic Cancer in the United States. HPB 2022, 24, 1729–1737. [Google Scholar] [CrossRef] [PubMed]
  104. Lim, P.-W.; Dinh, K.H.; Sullivan, M.; Wassef, W.Y.; Zivny, J.; Whalen, G.F.; LaFemina, J. Thirty-Day Outcomes Underestimate Endocrine and Exocrine Insufficiency after Pancreatic Resection. HPB 2016, 18, 360–366. [Google Scholar] [CrossRef] [Green Version]
  105. Thoresen, L.; Rothenberg, E.; Beck, A.M.; Irtun, Ø.; on behalf of the Scandinavian Nutrition Group (SNG). Doctors and Nurses on Wards with Greater Access to Clinical Dietitians Have Better Focus on Clinical Nutrition. J. Hum. Nutr. Diet 2008, 21, 239–247. [Google Scholar] [CrossRef]
  106. The RICOCHET Study Group on behalf of the West Midlands Research Collaborative Pancreatic Enzyme Replacement Therapy in Patients with Pancreatic Cancer: A National Prospective Study. Pancreatology 2021, 21, 1127–1134. [CrossRef] [PubMed]
  107. Dunleavy, L.; Al-Mukhtar, A.; Halliday, V. Pancreatic Enzyme Replacement Therapy Following Surgery for Pancreatic Cancer: An Exploration of Patient Self-Management. Clin. Nutr. ESPEN 2018, 26, 97–103. [Google Scholar] [CrossRef] [PubMed]
  108. Landers, A.; McKenzie, C.; Pitama, S.G.; Brown, H. Enzyme Replacement in Advanced Pancreatic Cancer: Patient Perceptions. BMJ Support Palliat Care 2020. [Google Scholar] [CrossRef]
  109. Forsmark, C.E.; Tang, G.; Xu, H.; Tuft, M.; Hughes, S.J.; Yadav, D. The Use of Pancreatic Enzyme Replacement Therapy in Patients with a Diagnosis of Chronic Pancreatitis and Pancreatic Cancer in the US Is Infrequent and Inconsistent. Aliment Pharmacol. Ther. 2020, 51, 958–967. [Google Scholar] [CrossRef] [Green Version]
  110. Kroon, V.J.; Daamen, L.A.; Tseng, D.S.J.; de Vreugd, A.R.; Brada, L.J.H.; Busch, O.R.; Derksen, T.C.; Gerritsen, A.; Rombouts, S.J.E.; Smits, F.J.; et al. Pancreatic Exocrine Insufficiency Following Pancreatoduodenectomy: A Prospective Bi-Center Study. Pancreatology 2022, 22, 1020–1027. [Google Scholar] [CrossRef]
  111. Danai, L.V.; Babic, A.; Rosenthal, M.H.; Dennstedt, E.A.; Muir, A.; Lien, E.C.; Mayers, J.R.; Tai, K.; Lau, A.N.; Jones-Sali, P.; et al. Altered Exocrine Function Can Drive Adipose Wasting in Early Pancreatic Cancer. Nature 2018, 558, 600–604. [Google Scholar] [CrossRef]
  112. Bruno, M.J.; Haverkort, E.B.; Tijssen, G.P.; Tytgat, G.N.J.; van Leeuwen, D.J. Placebo Controlled Trial of Enteric Coated Pancreatin Microsphere Treatment in Patients with Unresectable Cancer of the Pancreatic Head Region. Gut 1998, 42, 92–96. [Google Scholar] [CrossRef] [Green Version]
  113. Woo, S.M.; Joo, J.; Kim, S.Y.; Park, S.-J.; Han, S.-S.; Kim, T.H.; Koh, Y.H.; Chung, S.H.; Kim, Y.-H.; Moon, H.; et al. Efficacy of Pancreatic Exocrine Replacement Therapy for Patients with Unresectable Pancreatic Cancer in a Randomized Trial. Pancreatology 2016, 16, 1099–1105. [Google Scholar] [CrossRef] [PubMed]
  114. Zdenkowski, N.; Radvan, G.; Pugliese, L.; Charlton, J.; Oldmeadow, C.; Fraser, A.; Bonaventura, A. Treatment of Pancreatic Insufficiency Using Pancreatic Extract in Patients with Advanced Pancreatic Cancer: A Pilot Study (PICNIC). Support Care Cancer 2017, 25, 1963–1971. [Google Scholar] [CrossRef] [PubMed]
  115. Saito, T.; Nakai, Y.; Isayama, H.; Hirano, K.; Ishigaki, K.; Hakuta, R.; Takeda, T.; Saito, K.; Umefune, G.; Akiyama, D.; et al. A Multicenter Open-Label Randomized Controlled Trial of Pancreatic Enzyme Replacement Therapy in Unresectable Pancreatic Cancer. Pancreas 2018, 47, 800–806. [Google Scholar] [CrossRef] [PubMed]
  116. Gooden, H.M.; White, K.J. Pancreatic Cancer and Supportive Care—Pancreatic Exocrine Insufficiency Negatively Impacts on Quality of Life. Support Care Cancer 2013, 21, 1835–1841. [Google Scholar] [CrossRef] [PubMed]
  117. Ammar, K.; Leeds, J.S.; Ratnayake, C.B.; Sen, G.; French, J.J.; Nayar, M.; Oppong, K.W.; Loveday, B.P.; Pandanaboyana, S. Impact of Pancreatic Enzyme Replacement Therapy on Short- and Long-Term Outcomes in Advanced Pancreatic Cancer: Meta-Analysis of Randomized Controlled Trials. Expert Rev. Gastroenterol. Hepatol. 2021, 15, 941–948. [Google Scholar] [CrossRef]
  118. Roberts, K.J.; Schrem, H.; Hodson, J.; Angelico, R.; Dasari, B.V.M.; Coldham, C.A.; Marudanayagam, R.; Sutcliffe, R.P.; Muiesan, P.; Isaac, J.; et al. Pancreas Exocrine Replacement Therapy Is Associated with Increased Survival Following Pancreatoduodenectomy for Periampullary Malignancy. HPB 2017, 19, 859–867. [Google Scholar] [CrossRef] [Green Version]
  119. Saito, T.; Hirano, K.; Isayama, H.; Nakai, Y.; Saito, K.; Umefune, G.; Akiyama, D.; Watanabe, T.; Takagi, K.; Hamada, T.; et al. The Role of Pancreatic Enzyme Replacement Therapy in Unresectable Pancreatic Cancer: A Prospective Cohort Study. Pancreas 2017, 46, 341–346. [Google Scholar] [CrossRef]
  120. Roberts, K.J.; Bannister, C.A.; Schrem, H. Enzyme Replacement Improves Survival among Patients with Pancreatic Cancer: Results of a Population Based Study. Pancreatology 2019, 19, 114–121. [Google Scholar] [CrossRef]
  121. For the Dutch Pancreatic Cancer Group; Mackay, T.M.; Smits, F.J.; Latenstein, A.E.J.; Bogte, A.; Bonsing, B.A.; Bos, H.; Bosscha, K.; Brosens, L.A.A.; Hol, L.; et al. Impact of Nationwide Enhanced Implementation of Best Practices in Pancreatic Cancer Care (PACAP-1): A Multicenter Stepped-Wedge Cluster Randomized Controlled Trial. Trials 2020, 21, 334. [Google Scholar] [CrossRef] [Green Version]
  122. Perez, M.M.; Newcomer, A.D.; Moertel, C.G.; Go, V.L.W.; Dimagno, E.P. Assessment of Weight Loss, Food Intake, Fat Metabolism, Malabsorption, and Treatment of Pancreatic Insufficiency in Pancreatic Cancer. Cancer 1983, 52, 346–352. [Google Scholar] [CrossRef]
  123. Domínguez-Muñoz, J.E.; Nieto-Garcia, L.; López-Díaz, J.; Lariño-Noia, J.; Abdulkader, I.; Iglesias-Garcia, J. Impact of the Treatment of Pancreatic Exocrine Insufficiency on Survival of Patients with Unresectable Pancreatic Cancer: A Retrospective Analysis. BMC Cancer 2018, 18, 534. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Landers, A.; Brown, H.; Strother, M. The Effectiveness of Pancreatic Enzyme Replacement Therapy for Malabsorption in Advanced Pancreatic Cancer, a Pilot Study. Palliat Care 2019, 12, 117822421882527. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Cancers 15 01331 g001 550
Figure 1. Suggested diagnostic testing (A) and approach (B) to pancreatic exocrine insufficiency (PEI) among patients with pancreatic ductal adenocarcinoma (PDAC).
Figure 1. Suggested diagnostic testing (A) and approach (B) to pancreatic exocrine insufficiency (PEI) among patients with pancreatic ductal adenocarcinoma (PDAC).
Cancers 15 01331 g001
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Lan, X.; Robin, G.; Kasnik, J.; Wong, G.; Abdel-Rahman, O. Challenges in Diagnosis and Treatment of Pancreatic Exocrine Insufficiency among Patients with Pancreatic Ductal Adenocarcinoma. Cancers 2023, 15, 1331. https://doi.org/10.3390/cancers15041331

AMA Style

Lan X, Robin G, Kasnik J, Wong G, Abdel-Rahman O. Challenges in Diagnosis and Treatment of Pancreatic Exocrine Insufficiency among Patients with Pancreatic Ductal Adenocarcinoma. Cancers. 2023; 15(4):1331. https://doi.org/10.3390/cancers15041331

Chicago/Turabian Style

Lan, Xiaoyang, Gabrielle Robin, Jessica Kasnik, Grace Wong, and Omar Abdel-Rahman. 2023. "Challenges in Diagnosis and Treatment of Pancreatic Exocrine Insufficiency among Patients with Pancreatic Ductal Adenocarcinoma" Cancers 15, no. 4: 1331. https://doi.org/10.3390/cancers15041331

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop