Background: Pancreatic cancer is the fourth leading cause of cancer-related mortality in both genders. More than 80% of patients suffer from significant weight loss at diagnosis and over time develop severe cachexia. Early nutritional support is therefore essential. Summary: This review evaluates the different nutritional therapies, such as enteral nutrition, parenteral nutrition and special nutritional supplements, on nutritional status, quality of life and survival. Key Message: Due to the high prevalence of malnutrition and the rapid development of anorexia-cachexia-syndrome, early nutritional intervention is crucial and supported by clinical data. Practical Implications: Enteral nutrition should be preferred over parenteral nutrition. Omega-3 fatty acids and L-carnitine are promising substances for the prevention of severe cachexia, but further randomized controlled trials are needed to establish generally accepted guidelines on nutrition in pancreatic cancer.
Incidence and Prevalence of Pancreatic Cancer
Pancreatic cancer (PC) is the fourth leading cause of cancer-related mortality in both genders, leading to an all-cause mortality rate of 7% worldwide . Given that PC is burdened with an aggressive tumor biology, most of the patients are diagnosed in a metastasized stage with a poor prognosis. With 95% of PC, ductal adenocarcinoma is the most frequent subtype. Due to the late occurrence of clinical symptoms, incidence equals mortality. The 5-year survival rate is 8% with a median survival of 5 months [2,3]. Several risk factors for PC such as age, sex, family history, history of chronic pancreatitis, diabetes, insulin resistance, obesity and cigarette smoking have been identified [4,5,6,7].
More than one third of PC patients experience a significant weight loss of >10% of their initial body weight prior to diagnosis [8,9,10]. The greater number of patients suffer from abdominal pain, anorexia, early satiety, nausea, vomiting and diarrhea or constipation . In addition, patients experience changes in metabolism due to increased protein catabolism and increased energy expenditure .
Incidence of Malnutrition at the Date of Diagnosis
Malnutrition characterized by weight loss and decreased dietary intake is common among PC patients. More than 80% of patients with PC suffer from significant weight loss at diagnosis  and over time develop severe cachexia . Cachexia is a multifactorial syndrome with ongoing loss of skeletal muscle mass with or without fat mass accompanied by impaired body function .
Influence of Malnutrition on Survival
Cachexia is recognized as a major cause of reduced quality of life (QoL), decreased survival and treatment failure in patients with PC . Weight stabilization in case of unresectable PC is thus associated with improved survival and QoL . Patients maintaining stable weight and body composition have a better prognosis [15,16]. Various studies have revealed that malnutrition leads to skeletal muscle wasting and fat degradation, longer hospital stay, increased risk of complications as well as reduced response to treatment, shorter survival time, reduced QoL and increased morbidity and mortality [17,18,19]. If oral nutritional intake is not sufficient, additional nutritional therapy is absolutely essential for PC patients to stabilize body weight and composition. This review evaluates the different nutritional therapies, such as enteral nutrition (EN), parenteral nutrition (PN) and special nutritional supplements, on nutritional status, QoL and survival.
Search Strategy and Selection Criteria
A PubMed search was performed for publications from January 1980 through October 2015, using the following key words: ‘pancreatic cancer' OR ‘nutrition' OR ‘enteral nutrition' OR ‘parenteral nutrition' OR ‘dietary factors' OR ‘nutritional supplements' OR ‘quality' OR ‘life' OR ‘survival' OR ‘antioxidants' OR ‘omega-3 fatty acids' OR ‘L-carnitine' and combinations of these terms. We restricted our search to studies in English and those reporting human studies.
We excluded case reports, review articles and studies not providing primary data on nutritional support in patients with PC. The application of these criteria resulted in 11 studies concerning enteral and PN and 8 studies on supplementation of omega-3 fatty acids (n-3 FAs) or L-carnitine shown in table 1.
Enteral versus Total Parenteral Nutrition in Patients Undergoing Pancreaticoduodenectomy
The six studies identified are listed in table 1. All these trials randomized patients after pancreaticoduodenectomy to receive different treatment regimens of postoperative nutritional support. Three studies compared EN with total parenteral nutrition (TPN). They revealed that EN is superior in improving the nutritional status compared to PN. TPN is associated with an increased rate of complications, loss of body weight, longer duration to first bowel movement and a longer time period until normal diet is tolerated. EN is superior to TPN in improving nutritional status. Three studies [20,21,22] showed that especially immunomodulating EN is associated with lower postoperative complications, shorter length of hospital stay and lower mortality and morbidity compared to standard EN and TPN.
The effect of PN compared to standard dextrose-containing solution was examined in one study . The authors could not show a benefit by the use of PN and complications were significantly greater in the TPN group.
Parenteral Nutrition in Patients with Cancer Cachexia
Data on the effect of PN in patients with severe cancer cachexia were available from two studies. In the first one , patients with cancer cachexia received home PN over 1, 2 or 3 months. There was an improvement in global QoL (from 37.1 to 49.2; p = 0.02), Subjective Global Assessment (SGA) and weight (from 57.6 to 60.0 kg; p = 0.04) after 2 months and in global QoL (from 30.6 to 54.4; p = 0.02), SGA and weight (from 61.1 to 65.9) after 3 months of treatment. In the second one, Pelzer et al.  showed a benefit of additional PN on parameters of body composition in patients with PC. Body mass index (BMI) increased from 19.7 to 20.5, median phase angle improved by 10% from 3.6 to 3.9 and extracellular mass/body cell mass index improved down from 1.7 to 1.5.
Oral Supplementation in Patients with Pancreatic Cancer
Weight stabilization by the use of oral supplementation was examined in two studies [8,26]. Over an 8-week period the authors found an improvement in weight by 0.5 kg (p = 0.052), but they did not detect a difference in lean body mass (LBM). Patients with stable weight had a higher energy intake (p = 0.004) in comparison to patients with weight loss. Patients with stable weight had a median survival of 259 days (95% CI 229-289 days) compared to 164 days (95% CI 97-231 days) for patients who continued to lose weight. The authors also concluded that patients with stable weight reported a better QoL .
Fish Oil Supplementation in Pancreatic Cancer Patients
Five studies concerning oral supplementation of eicosapentaenoic acid (EPA) pure or in the form of an oral nutritional supplement and one with a supplementation to TPN were identified and are listed in table 1. All patients recruited to the studies had lost weight prior to study entry. The amount of EPA given ranged from 2.2 g in the oral supplements and was dosed from 1.0 to 6.0 g EPA daily over 4 weeks in the pure oral supplementation study of Wigmore et al. . An oral supplementation of high-purity EPA was used in weight-losing advanced PC patients. Median weight loss decreased significantly after 4 weeks of EPA supplementation and remained significant after 8 and 12 weeks. There was no change in anthropometric data, body composition, nutritional intake or performance status. Fearon et al.  showed a dose-response relationship of EPA on weight gain and LBM gain. Increased plasma levels of EPA were associated with weight gain and LBM gain. Weight gain was also associated with an improved QoL, but only in the EPA-supplemented group. The three studies of Barber et al. [29,30,31] revealed an effect of EPA on weight gain, decreasing resting energy expenditure (REE) and improved performance status and appetite. They also demonstrated that this anabolism is associated with a significant decline in peripheral blood mononuclear cell IL-6 production, a rise in serum insulin concentrations, a decrease in the cortisol to insulin ratio and a decline in the proportion of patients excreting proteolysis-inducing factor. In the fasting state, cancer patients had a lower serum insulin concentration, elevated REE per unit weight and an increased rate of fat oxidation. Under EPA the fasting insulin concentration increased and a normalization of energy expenditure, with a fall in REE per unit weight and a rise in the apparent metabolic cost of feeding, was documented. Substrate utilization was also normalized.
Fish Oil and Parenteral Nutrition in Postoperative Pancreatic Cancer Patients
In the study by Heller et al. , postoperative patients received TPN supplemented with fish oil versus TPN with soy oil for 5 days. The fish oil TPN improved liver and pancreas parameters in the postoperative course and patients maintained their weight in contrast to soy oil-supplemented TPN. Patients with an increased risk of developing sepsis showed a tendency for a shorter intensive care unit stay under fish oil.
Fish Oil and Gemcitabine in Pancreatic Cancer Patients
The study of Arshad et al.  demonstrated that intravenous n-3 FAs in combination with gemcitabine resulted in improved activity and benefit to QoL in patients with advanced PC.
L-Carnitine Supplementation in Pancreatic Cancer Patients
The study by Kraft et al.  revealed that supplementation with L-carnitine decreased weight loss, increased BMI and improved the nutritional status and QoL in PC patients in contrast to placebo.
Conclusions and Advices for Daily Practice
Unfortunately there are only few studies on the nutritional aspects of PC, partly explained by the short survival of those patients. Because of the high prevalence of malnutrition and rapid development of the anorexia-cachexia-syndrome, early nutritional intervention is crucial as suggested by the studies discussed above. EN should be preferred in comparison to PN whenever possible. There are some investigations that examined specific nutritional supplements like fish oil and L-carnitine. The results of these studies are somehow limited due to the low number of participants and in some studies control groups are lacking. However, all studies show a positive trend for those compounds with a beneficial impact on the reduction or reversion of weight loss and tissue wasting. Further randomized controlled trials are needed to establish generally accepted guidelines for nutrition in PC.
This work was supported by the Deutsche Krebshilfe/Dr. Mildred-Scheel-Stiftung (109102), the European Union (EU-FP-7: EPC-TM) and EFRE-State Ministry of Economics MV (V-630-S-150-2012/132/133).
All authors of the study substantially contributed to this review. None of the authors has any commercial conflict of interest in this review and none has received direct salary support from industry.
S. Gärtner and J. Krüger contributed equally to this work.