Nutrition therapy in esophageal cancer—Consensus statement of the Gastroenterological Society of Taiwan

Nutrition therapy in esophageal cancer—Consensus statement of the Gastroenterological Society... SUMMARY A number of clinical guidelines on nutrition therapy in cancer patients have been published by national and international societies; however, most of the reviewed data focused on gastrointestinal cancer or non-cancerous abdominal surgery. To collate the corresponding data for esophageal cancer (EC), a consensus panel was convened to aid specialists from different disciplines, who are involved in the clinical nutrition care of EC patients. The literature was searched using MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the ISI Web of Knowledge. We searched for the best evidence pertaining to nutrition therapy in the case of EC. The panel summarized the findings in 3 sections of this consensus statement, based on which, after the diagnosis of EC, an initial distinction is made between the patients, as follows: (1) Assessment; (2) Therapy in patients with resectable disease; patients receiving chemotherapy or chemoradiotherapy prior to resection, and patients with unresectable disease, requiring chemoradiotherapy or palliative therapy; and (3) Formula. The resulting consensus statement reflects the opinions of a multidisciplinary group of experts, and a review of the current literature, and outlines the essential aspects of nutrition therapy in the case of EC. The statements are: Patients with EC are among one of the highest risk to have malnutrition. Patient generated suggestive global assessment is correlated with performance status and prognosis. Nutrition assessment for patients with EC at the diagnosis, prior to definitive therapy and change of treatment strategy are suggested and the timing interval can be two weeks during the treatment period, and one month while the patient is stable. Patients identified as high risk of malnutrition should be considered for preoperative nutritional support (tube feeding) for at least 7–10 days. Various routes for tube feedings are available after esophagectomy with similar nutrition support benefits. Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and self-expanding metal stent (SEMS) or jejunal tube. Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides benefits of maintaining weight, decreasing toxicity, and preventing treatment interruption. Tube feeding or SEMS can offer nutrition support in patients with unresectable esophageal cancer, but SEMS is not recommended for those with neoadjuvant chemoradiation before surgery. Enteral immunonutrition may preserve lean body mass and attenuates stress response after esophagectomy. Administration of glutamine may decrease the severity of chemotherapy induced mucositis. Enteral immunonutrition achieves greater nutrition status or maintains immune functions during concurrent chemoradiation. INTRODUCTION The treatment of esophageal carcinoma (EC) generally entails surgery, chemotherapy, and radiotherapy. Accurate diagnosis, a multidisciplinary approach in treatment, and the perioperative management of patients with EC remain crucial for positive prognoses. Nutrition therapy has been demonstrated to improve patients’ tolerance to treatment, as well as the quality of life, and long-term outcomes. The current consensus focuses on the essential aspects of EC and includes cancer staging, surgical techniques, and perioperative management or palliative treatment.1–3 However, no consensus has been achieved with regards to nutrition therapy in EC patients. A number of clinical guidelines on nutrition in cancer patients have been published by various national and international societies in terms of the involvement of a multidisciplinary team, malnutrition risk prevention, and nutrition therapy. However, the consensus on their adoption in the case of EC patients is limited, as most of the evidence is related to gastrointestinal (GI) cancers or abdominal surgery.4–6 The anatomy, type of dysphagia, surgical reconstruction techniques, alterations in metabolism, and calorie insufficiency in the case of EC patients are different from those of other cancers; thus, ideal consensus statements must focus on evidence related to esophageal cancers. METHODS To collate evidence pertaining to these aspects of EC, a consensus panel was convened by The Gastroenterological Society of Taiwan. The consensus panel comprises gastroenterology, chest surgery, hemato-oncology, and radio-oncology experts, as well as dietitians. The present guidelines aim to help specialists from different medical disciplines who are involved in the clinical care of EC patients. Based on the review of the literature, the draft statements of this consensus selected clinical questions which are relevant in daily practice and were established by leaders from each field. The literature review focused on recent data for the development of draft statements and the determination of the levels of evidence. The literature was searched using MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the ISI Web of Knowledge. This structured procedure was supplemented by the intensive hand-searching of journals and previously formulated guidelines. We searched for the best evidence on each issue and aspect. The keywords used in the search were ‘esophageal cancer,’ ‘nutrition,’ ‘assessment,’ ‘therapy,’ ‘immunonutrition,’ ‘esophagectomy,’ ‘enteral,’ and ‘parenteral.’ The literature review focused on the unique findings related to EC, in order to compare them with the findings of major articles pertaining to GI cancers. Thirty gastroenterology, surgery, oncology, radio-oncology, and dietitian experts from Taiwan conducted a consensus conference. Based on a modified Delphi process with 2 separate iterations, all the participants voted anonymously for the first round of statements, and modified these statements through discussions. A second round of voting was conducted, until a consensus of 12 statements was reached (with the agreement of at least 80% of the experts). Statements were rejected if the agreement was <80%. For each statement, the level of evidence was defined according to the modified grading system of the Oxford Centre for Evidence-Based Medicine Levels of Evidence. The recommendation grade ranged from A to D, and each grade was defined by the votes (Table 1). Table 1 Shows all the statements, with the levels of scientific evidence and grades of recommendation Statement Evidence level Agreement Grade of recommendation 1 Patients with esophageal cancer are among those with the highest risk of malnutrition development, and nutrition assessment may be considered. 2b 100% A 2 Various tools and scoring systems are available for the evaluation of the malnutrition risk in patients with esophageal cancer. The patient-generated suggestive global assessment (PG-SGA) is correlated with the performance status and prognosis. 2b 96.7% A 3 Nutrition assessment at the diagnosis, prior to definitive therapy, and a change of treatment strategy are suggested for esophageal cancer patients. 2b 96.7% A 4 In esophageal cancer patients, the time interval for nutrition assessment can range from 2 weeks during treatment, to 1 month when stability is achieved after the completion of treatment. 2b 93.3% B 5 Patients identified as having a high risk of malnutrition development should be considered for preoperative nutrition support (tube feeding) for at least 7–10 days. 2b 83.3% B 6 Various routes of tube feeding are available for esophageal cancer patients, after esophagectomy, with similar nutrition support benefits. 2a 100% A 7 Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and a self-expanding metal stent (SEMS) or jejunal tube. 2b 100% B 8 Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides the benefits of weight maintenance, reduced toxicity, and the prevention of treatment interruption. 2b 100% A 9 Tube feeding or self-expanding metal stents can offer nutrition support in patients with unresectable esophageal cancer, but self-expanding metal stents are not recommended for those with neoadjuvant chemoradiation before surgery. 1a 96.7% A 10 Enteral immunonutrition may preserve the lean body mass and attenuate the stress response post esophagectomy compared to standard enteral nutrition. 1b 96.7% A 11 Administration of glutamine may decrease the severity of chemotherapy-induced mucositis in esophageal cancer patients. 2a 96.7% A 12 Enteral immunonutrition helps in the achievement of a better nutrition status or maintains the immune functions during concurrent chemoradiation for esophageal cancer. 1b 90% B Statement Evidence level Agreement Grade of recommendation 1 Patients with esophageal cancer are among those with the highest risk of malnutrition development, and nutrition assessment may be considered. 2b 100% A 2 Various tools and scoring systems are available for the evaluation of the malnutrition risk in patients with esophageal cancer. The patient-generated suggestive global assessment (PG-SGA) is correlated with the performance status and prognosis. 2b 96.7% A 3 Nutrition assessment at the diagnosis, prior to definitive therapy, and a change of treatment strategy are suggested for esophageal cancer patients. 2b 96.7% A 4 In esophageal cancer patients, the time interval for nutrition assessment can range from 2 weeks during treatment, to 1 month when stability is achieved after the completion of treatment. 2b 93.3% B 5 Patients identified as having a high risk of malnutrition development should be considered for preoperative nutrition support (tube feeding) for at least 7–10 days. 2b 83.3% B 6 Various routes of tube feeding are available for esophageal cancer patients, after esophagectomy, with similar nutrition support benefits. 2a 100% A 7 Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and a self-expanding metal stent (SEMS) or jejunal tube. 2b 100% B 8 Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides the benefits of weight maintenance, reduced toxicity, and the prevention of treatment interruption. 2b 100% A 9 Tube feeding or self-expanding metal stents can offer nutrition support in patients with unresectable esophageal cancer, but self-expanding metal stents are not recommended for those with neoadjuvant chemoradiation before surgery. 1a 96.7% A 10 Enteral immunonutrition may preserve the lean body mass and attenuate the stress response post esophagectomy compared to standard enteral nutrition. 1b 96.7% A 11 Administration of glutamine may decrease the severity of chemotherapy-induced mucositis in esophageal cancer patients. 2a 96.7% A 12 Enteral immunonutrition helps in the achievement of a better nutrition status or maintains the immune functions during concurrent chemoradiation for esophageal cancer. 1b 90% B View Large Table 1 Shows all the statements, with the levels of scientific evidence and grades of recommendation Statement Evidence level Agreement Grade of recommendation 1 Patients with esophageal cancer are among those with the highest risk of malnutrition development, and nutrition assessment may be considered. 2b 100% A 2 Various tools and scoring systems are available for the evaluation of the malnutrition risk in patients with esophageal cancer. The patient-generated suggestive global assessment (PG-SGA) is correlated with the performance status and prognosis. 2b 96.7% A 3 Nutrition assessment at the diagnosis, prior to definitive therapy, and a change of treatment strategy are suggested for esophageal cancer patients. 2b 96.7% A 4 In esophageal cancer patients, the time interval for nutrition assessment can range from 2 weeks during treatment, to 1 month when stability is achieved after the completion of treatment. 2b 93.3% B 5 Patients identified as having a high risk of malnutrition development should be considered for preoperative nutrition support (tube feeding) for at least 7–10 days. 2b 83.3% B 6 Various routes of tube feeding are available for esophageal cancer patients, after esophagectomy, with similar nutrition support benefits. 2a 100% A 7 Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and a self-expanding metal stent (SEMS) or jejunal tube. 2b 100% B 8 Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides the benefits of weight maintenance, reduced toxicity, and the prevention of treatment interruption. 2b 100% A 9 Tube feeding or self-expanding metal stents can offer nutrition support in patients with unresectable esophageal cancer, but self-expanding metal stents are not recommended for those with neoadjuvant chemoradiation before surgery. 1a 96.7% A 10 Enteral immunonutrition may preserve the lean body mass and attenuate the stress response post esophagectomy compared to standard enteral nutrition. 1b 96.7% A 11 Administration of glutamine may decrease the severity of chemotherapy-induced mucositis in esophageal cancer patients. 2a 96.7% A 12 Enteral immunonutrition helps in the achievement of a better nutrition status or maintains the immune functions during concurrent chemoradiation for esophageal cancer. 1b 90% B Statement Evidence level Agreement Grade of recommendation 1 Patients with esophageal cancer are among those with the highest risk of malnutrition development, and nutrition assessment may be considered. 2b 100% A 2 Various tools and scoring systems are available for the evaluation of the malnutrition risk in patients with esophageal cancer. The patient-generated suggestive global assessment (PG-SGA) is correlated with the performance status and prognosis. 2b 96.7% A 3 Nutrition assessment at the diagnosis, prior to definitive therapy, and a change of treatment strategy are suggested for esophageal cancer patients. 2b 96.7% A 4 In esophageal cancer patients, the time interval for nutrition assessment can range from 2 weeks during treatment, to 1 month when stability is achieved after the completion of treatment. 2b 93.3% B 5 Patients identified as having a high risk of malnutrition development should be considered for preoperative nutrition support (tube feeding) for at least 7–10 days. 2b 83.3% B 6 Various routes of tube feeding are available for esophageal cancer patients, after esophagectomy, with similar nutrition support benefits. 2a 100% A 7 Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and a self-expanding metal stent (SEMS) or jejunal tube. 2b 100% B 8 Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides the benefits of weight maintenance, reduced toxicity, and the prevention of treatment interruption. 2b 100% A 9 Tube feeding or self-expanding metal stents can offer nutrition support in patients with unresectable esophageal cancer, but self-expanding metal stents are not recommended for those with neoadjuvant chemoradiation before surgery. 1a 96.7% A 10 Enteral immunonutrition may preserve the lean body mass and attenuate the stress response post esophagectomy compared to standard enteral nutrition. 1b 96.7% A 11 Administration of glutamine may decrease the severity of chemotherapy-induced mucositis in esophageal cancer patients. 2a 96.7% A 12 Enteral immunonutrition helps in the achievement of a better nutrition status or maintains the immune functions during concurrent chemoradiation for esophageal cancer. 1b 90% B View Large After the initial diagnosis of EC, an initial distinction is made between those patients with a resectable locoregional disease, requiring chemoradiation as a bridge to surgical intervention, and those in need of palliation. Nutrition therapy is an integral part of treatment for EC patients, in the curative and palliative setting. The panel summarized the findings in 3 sections of this consensus statement: (1) Assessment; (2) Therapy: patients with resectable disease; patients receiving chemotherapy or chemoradiation prior to resection and; patients with unresectable disease, requiring chemoradiation or palliation; and (3) Formula (Fig. 1). Fig. 1 View largeDownload slide A diagram showing the key points of nutritional assessment and support in esophageal cancers. Fig. 1 View largeDownload slide A diagram showing the key points of nutritional assessment and support in esophageal cancers. Consensus statements Section I: Assessment Statement 1: Patients with esophageal cancer are among those with the highest risk of malnutrition development, and nutrition assessment may be considered. Evidence level: 2b Agreement: 100% Grade of recommendation: A: 70%, B: 30%, C: 0%, D: 0% Cancer-associated malnutrition can result from local mass effects (such as dysphagia), systemic responses to tumors (such as the production of pro-inflammatory cytokines) and anticancer therapies such as chemotherapy or chemoradiotherapy, and other complications.7 In a study which enrolled 1000 screened patients from 17 centers in the US, it was observed that the weight loss was higher in the case of EC patients, with a 15.9% decrease in the baseline weight, followed by in pancreatic cancer and gastric cancer patients. Similarly, a Nutritional Risk Screening score (NRI) ≥3, which is required for nutrition assessment, was observed in a majority of EC patients.8 In a large survey of 5044 patients with EC, as part of the American College of Surgeons Patient Care Evaluation Study, in 1997; it was found that dysphagia (74%) and weight loss (57.3%) were the most common symptoms of EC.9 Statement 2: Various tools and scoring systems are available for the evaluation of the malnutrition risk in patients with esophageal cancer. The patient-generated suggestive global assessment (PG-SGA) is correlated with the performance status and prognosis. Evidence level: 2b Agreement: 96.7% Grade of recommendation: A: 56.7%, B: 43.3%, C: 0%, D: 0% There are no current standardized and widely accepted tools and scoring systems for the nutrition assessment of patients with EC; this may impair the proper assessment of malnutrition in academic study between groups. In order to be efficient, screening should be brief and inexpensive, and have high specificity. In clinical practice, a preferred alternative is the use of a single prognostic index, or perhaps a tool with a few indices to grade the severity of malnutrition, and a subjective assessment through questionnaires. In a previously conducted study, the PG-SGA scores comprised 2 sections that were completed by a patient or clinician.10 An Asian cross-sectional study was conducted to determine the nutrition assessment in patients with advanced EC, using the PG-SGA, and to examine the relationship between their performances through the Karnofsky performance score (KPS) or Eastern cooperative oncology group (ECOG) performance score. The PG-SGA was found to be strongly correlated with the KPS (r = −0.717) and ECOG score (r = 0.672).11 Statement 3: Nutrition assessment at the diagnosis, prior to definitive therapy, and a change of treatment strategy are suggested for esophageal cancer patients. Evidence level: 2b Agreement: 96.7% Grade of recommendation: A: 50%, B: 46.7%, C: 3.3%, D: 0% Regardless of the different treatment approaches, the goals of nutrition therapy are to prevent long-term malnutritional risk from the time of diagnosis, and to reduce treatment-related morbidity and mortality. With the assessment, we can also set treatment goals and simultaneously evaluate the effectiveness of nutrition therapy with relevant prognostic aspects such as changes in body weight, food intake, nutrition impact symptoms, and performance status.12 Maintaining lean body mass may protect the patient from complications during the treatment13 because muscle provides amino acids necessary for the repair of tissue and adequate functioning of the immune system. The nutrition therapy aimed to improve the intake of the patient toward 1.2–1.5 g protein per kilogram of body weight per day. The energy goal was calculated using the Harris–Benedict equation multiplied by 1.3–1.5 for intended weight gain. Nutritional goals on intake of protein, specific amino acids, energy and micronutrients in relation to preservation of lean body mass during treatment may not be specific for patients undergoing treatment for esophageal cancer, but are not less relevant. Assessment should be repeated at adequate intervals to judge the requirement and adjustment for nutrition intervention, and to monitor its effects. Twohundred and fifty-eight patients with advanced EC were randomly allocated to undergo definitive chemoradiotherapy in the SCOPE1, a randomized controlled phase II/III trial in the UK.14 Nutrition intervention improved survival if provided at the baseline, with a hazard ratio (HR) of 0.13 (P < 0.003), but a similar benefit was not observed if it was provided later in the treatment course. It was also found that ongoing nutrition assessments in patients receiving defined chemoradiation therapy significantly reduced weight loss and incidences of unplanned hospital admissions, and resulted in greater radiotherapy completion rates. In addition, it was suggested that early and regular nutrition assessments and interventions resulted in improved outcomes for EC patients.15 Statement 4: In esophageal cancer patients, the time interval for nutrition assessment can range from 2 weeks during treatment, to 1 month when stability is achieved after the completion of treatment. Evidence level: 2b Agreement: 93.3% Grade of recommendation: A: 36.7%, B: 63.3%, C: 0%, D: 0% Serial assessments, both in the inpatient and outpatient settings, may have some utility, provide prognostic information and decrease the chance of perioperative and postoperative complications in EC patients. Some studies supported the importance of dietary counseling as part of multimodal treatment including chemoradiotherapy14 and surgery in EC patients.16 In a prospective study on EC patients who underwent an esophagectomy, a more favorable outcome was observed in 28 patients who received intensive nutritional support intervention compared with controls.16 This study shows that dietician-delivered intensive nutritional support decreases severe postoperative complications in patients with esophageal cancer prior to treatment and during recovery after discharge. The program also resulted in a relative preoperative weight gain of +4.8% (P = 0.009, adjusted) if the intensive nutritional support was last at least for one a year, compared to the control group, in these neoadjuvant-treatment patients after surgery. Section II: Therapy Statement 5: Patients identified as having a high risk of malnutrition development should be considered for preoperative nutrition support (tube feeding) for at least 7–10 days. Evidence level: 2b Agreement: 83.3% Grade of recommendation: A: 26.7%, B: 53.3%, C: 20%, D: 0% Esophageal resection exerts enormous stress on EC patients and is associated with pain, asthenia, and anorexia. Postoperative malnutrition can have a negative effect on wound-healing, rehabilitation, postoperative adaptation, and infection rates, and can increase the rate of hospitalization.17 Patients are considered to be at a severe nutrition risk if at least 1 of the following criteria is fulfilled: weight loss of 10–15% of the body weight within 6 months, BMI < 18.5 kg/m2, Subjective Global Assessment Grade C or serum albumin level <30 g/L, according to ESPEN guidelines.6 For patients at a severe nutrition risk, major surgery should be postponed until the nutrition status has been corrected. The ESPEN 2016 guidelines on nutrition in cancer patients suggest that those with a severe nutrition risk benefit from nutrition support that is provided 10–14 days prior to major surgery, even if the surgery has to be delayed (Grade A). The evidences are adapted from 2 earlier randomized studies that suggested oral or nasogastric feeding for up to 10 days may reduce postoperative morbidity or mortality by up to 50% compared to the control group.18,19 Statement 6: Various routes of tube feeding are available for esophageal cancer patients, after esophagectomy, with similar nutrition support benefits. Evidence level: 2a Agreement: 100% Grade of recommendation: A: 56.7%, B: 43.3%, C: 0%, D: 0% For patients who have undergone an esophagectomy, access to the functional gastrointestinal tract, bypass the fresh anastomoses utilization instead of the early initiation of parenteral support can reduce postoperative infections and lengths of stay.20 A study supported the use of jejunal access during operation in 204 patients who underwent esophagectomy; 95% of these patients were successfully fed through this route and approximately 13% of them required jejunostomy tubes for more than 30 days.21 The placement of a nasojejunal tube is a simple option, but after 20 days, it is not well tolerated, with high rates of tube dislodgement and interruptions in feeding. For this reason, many surgeons favor the placement of jejunostomy tubes during the index operation.21,22 Five randomized control trials (RCTs) and 1 case-control trial, with 344 EC patients, were included in a systematic review.23 In the RCTs, no route was suggested to be superior to the other because there were no difference in complications and efficacy and it was hard to weight the risks and benefits among the various routes of tube feeding. There is a lack of strong direct evidence supporting the use of the single feeding access route in esophagectomy patients. If enteral feeding is chosen, the placement of jejunostomy feeding tubes may be superior to that of nasojejunal or duodenal tubes due to lower rates of tube dislodgement and interruptions in feeding with the former. Statement 7: Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and a self-expanding metal stent (SEMS) or jejunal tube. Evidence level: 2b Agreement: 100% Grade of recommendation: A: 46.7%, B: 53.3%, C: 0%, D: 0% Physiologically, enteral is preferable to ameliorate surgical stress such as higher serum bilirubin and C-reactive protein levels24 and more common catheter complications25 comparing with total parenteral nutrition (TPN). Cervical anastomotic insufficiencies occur in 25–45% of esophagectomy patients and a majority of them are due to intrathoracic leakages.1 When an anastomotic insufficiency or a leakage is suspected after esophagectomy, the primary goals are the determination of the leak's location and status of the conduit's perfusion, and the observation of the sepsis parameters. Endoscopy in combination with a contrast agent, bronchoscopy, CT, and laboratory parameters can be performed to guide the management. Intrathoracic anastomotic leaks are characterized by a small fistula, which can be sufficiently drained so the patient has no mediastinitis or sepsis. Treatment is conservative, with antibiotic treatment and jejunal tube nutrition.26 If intrathoracic anastomotic leaks are characterized by a large area leakage with a sufficient gastric tube perfusion and no signs of mediastinitis or sepsis, the treatment options are the placement of a covered, self-expanding esophageal stent in combination with antibiotic treatment, and temporary TPN.27 Parenteral nutrition should be considered only when other routes of administration are impractical or not feasible. Statement 8: Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides the benefits of weight maintenance, reduced toxicity, and the prevention of treatment interruption. Evidence level: 2b Agreement: 100% Grade of recommendation: A: 63.3%, B: 36.7%, C: 0%, D: 0% Preoperative chemoradiation improves survival among patients with potentially curable esophageal cancers.28 The side effects of chemotherapy or chemoradiation, including mucositis and gastrointestinal upset (appetite loss, nausea, and diarrhea), can worsen patients’ malnutrition status, leading to the interruption of neoadjuvant chemoradiation therapy. Perioperative enteral nutrition has been reported to reduce morbidity and mortality; however, for patients with EC, who undergo chemotherapy, the effect of EN during chemotherapy or chemoradiation has not been well established. A randomized study of 91 EC patients who received neoadjuvant chemotherapy (5-fluorouracil, cisplatin, and adriamycin) were enrolled to receive either EN (n = 47) or parenteral nutrition (PN) (n = 44). In that study, the incidences of grade 3–4 hematological side effects were significantly lower in the EN group than in the PN group (n = 44 and 47; leukopenia: 17% vs. 41%, P = 0.011; neutropenia: 36% vs. 66%, P = 0.005).29 A cohort study of 48 EC patients found that those in whom a nutrition pathway was followed, incorporating early and periodic nutrition assessment and support, during definite chemoradiation therapy, experienced lesser weight loss (mean weight change −4.2 ± 6.4 kg vs. −8.9 ± 5.9 kg, P = 0.03) and had greater radiotherapy completion rates (92% vs. 50%, P = 0.001), and fewer patients had an unplanned hospital admission (46% vs. 75%, P = 0.04); those that did, had a shorter length of stay (3.2 ± 5.4 days vs. 13.5 ± 14.1 days, P = 0.002).30 Statement 9: Tube feeding or self-expanding metal stents can offer nutrition support in patients with unresectable esophageal cancer, but self-expanding metal stents are not recommended for those with neoadjuvant chemoradiation before surgery. Evidence level: 1a Agreement: 96.7% Grade of recommendation: A: 60%, B: 36.7%, C: 3.3%, D: 0% In patients with unresectable EC, the restoration of body weight and maintenance of the ability to swallow represent the primary goals of supportive care. Enteral food intake should be ensured by the use of a percutaneous endoscopic gastrostomy (PEG) tube or jejunal catheter. Self-expandable metal stents (SEMS) can palliate malignant dysphagia to maintain oral intake. In this, the technical success rate was found to be high but chest pain and stent migration were common side effects.31,32 A review of 12 studies focusing on the efficacy and safety of esophageal stent placement in the neoadjuvant setting for EC found that up to 92.3% patients experienced chest pain, and, sometimes, stent removal or replacement was required.33 A meta-analysis also indicated a high incidence of complications, including 32% cases of stent migration and 51.4% cases of chest discomfort in the stent group, with similar increases in weight and serum albumin levels, compared to the nonstent group, during neoadjuvant chemotherapy.34 A multicenter European cohort study revealed that SEMS insertion was a predictor of poor prognosis (adjusted HR = 1.6; P = 0.038) and led to negative oncology outcomes.35 Therefore, the European Society of Gastrointestinal Endoscopy recently recommended against the use of esophageal stents as a bridge to surgery or prior to chemotherapy/chemoradiotherapy.32 Alternative ways of tube feeding such as nasogastric tube insertion, surgical gastrostomy or jejunostomy can provide similar nutrition support under lower costs.34 In patients with advanced EC and a short expected life-span, endoscopy-assisted nasogastric tube placement was shown to be effective and safe, in studies conducted in Taiwan.36,37 Section III: Formula Statement 10: Enteral immunonutrition may preserve the lean body mass and attenuate the stress response post esophagectomy compared to standard enteral nutrition. Evidence level: 1b Agreement: 96.7% Grade of recommendation: A: 50%, B: 46.7%, C: 3.3%, D: 0% Esophagectomy, including reconstruction, is defined as a major operation associated with a high incidence of complications and marked alterations in metabolism, immunology and physiology. There is a continued debate as to the effectiveness of immunonutrition in postesophagectomy patients. The results of this study should be interpreted in the context of its methodology and heterogeneity. Most of the studies included small size of patients, the duration and timing of administration of immunonutrition were also varied depending on the protocols. Heterogeneity may exist when the study enrolled a range of patients with varies preoperative nutritional status and medical comorbidities. Data from a randomized trial comprising 22 EC patients suggest that perioperative immunonutrition, namely supplementation with arginine, omega-3 fatty acids and nucleotides via jenunostomy, reduced infectious complications and lengths of stay compared to cases of standard enteral feeding.38 In a double-blind study, 53 patients were randomized to a standard EN or a formula enriched with 2.2 g eicosapentaenoic acid (EPA)/d, for 5 days preoperatively (orally), and 21 days postoperatively (via jejunostomy). In the EPA-rich formula group (n = 28) all the aspects of body composition were maintained postoperatively, whereas patients in the standard EN group (n = 25) lost significant amounts of fat-free mass (1.9 kg, P = 0.030) [leg (0.3 kg, P = 0.05), arm (0.17 kg, P = 0.01), and trunk (1.44 kg, P = 0.03)] in comparison. The EPA group had a significantly (P < 0.05) attenuated stress response to TNF-alpha, IL-10, and IL-8 compared to the standard group.39 Preoperative immunonutrition significantly reduced the incidence of postoperative infectious complications, but the optimal regimen of administration remains unclear. In a prospective nonrandomized study which included 20 EC patients who underwent an esophagectomy, immune EN of 500 mL/day (supplemented with arginine 12.8 g/L, n-3 fatty acids 4.1 g/L, and RNA 1.29 g/L) or 1000 mL/day, for 7 days, was administered before the operation. No difference was observed in the perioperative changes in the inflammatory, immunological and nutritional variables.40 Only three small RCTs have evaluated immunonutrition use in patients exclusively undergoing EC surgery, in a systemic review.39,41–43 Although there is evidence suggesting that immunonutrition improved nutrition-related endpoints such as the preservation of lean body mass and the attenuation of stress response, it was not determined if immunonutrition had an impact on clinical outcomes, in terms of the length of hospital stay or postoperative morbidity and mortality. Due to the heterogeneity of the available formulas, identifying the specific components responsible for the improved outcomes is difficult. Statement 11: Administration of glutamine may decrease the severity of chemotherapy-induced mucositis in esophageal cancer patients. Evidence level: 2a Agreement: 96.7% Grade of recommendation: A: 30%, B: 56.7%, C: 13.3%, D: 0% A systematic review of 15 studies conducted in cancer patients receiving chemotherapy or chemoradiation showed that oral glutamine was effective in 11 of the 15 studies. It significantly reduced the incidence of mucositis, and the maximum grade of mucositis. The rates of nausea, vomiting, dry mouth, and anorexia were similar in the glutamine and control groups.44 Thirty-two patients diagnosed with lung cancer were studied in a prospective study comprising 16 patients who received prophylactic oral glutamine powder with 10 g/8 h. Patients were then irradiated with 2 Gy per fraction, daily, 5 days a week. The grading of esophagitis at the end of each daily fraction was recorded until a cumulative dose of 50 Gy was reached. The toxicity grade, weight loss, serum cytokine levels, and esophageal transit times exhibited statistically significant improvement in the glutamine group.45 A small study enrolled 13 EC patients randomized to control or glutamine groups. Glutamine was administered orally in doses of 30 g/day at the start of mediastinal irradiation and chemotherapy, comprising 5-fluorouracil and cisplatin, for 28 days. Oral glutamine prevented a decline in the lymphocyte counts (control 567 ± 96/mm3 vs. glutamine 1007 ± 151/mm3, P < 0.05). The amount of phenolsulfonphthalein excretion in the urine decreased in the glutamine group, indicating a protective effect on the gut barrier function (control 15.4 ± 2.4% vs. glutamine 7.4 ± 1.2, P < 0.05).46 Statement 12: Enteral immunonutrition helps in the achievement of a better nutrition status or maintains the immune functions during concurrent chemoradiation for esophageal cancer. Evidence level: 1b Agreement: 90% Grade of recommendation: A: 36.7%, B: 63.3%, C: 0%, D: 0% Chemoradiation is a treatment option for localized EC, particularly in the case of squamous cell carcinoma or in patients with adenocarcinoma who are deemed unfit for surgery. Nearly half of these patients experience grade 3–4 gastrointestinal toxicities during treatment.47 In an RCT, 37 EC patients received either immune EN (including a polymeric formula enriched with arginine (13 g/L), eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) (EPA + DHA 3.4 g/L), and ribonucleotides (1.3 g/L)), or an isonitrogenous, isoenergetic standard, 5 days prior to and until the end of chemoradiation (5–7 weeks). A significant gain in the total body weight (+2.1 ± 3.1 kg), and the improvement of albuminemia and the nutritional risk index (NRI) were observed in patients who received immune EN. The plasma antioxidant capacity (+100 ± 13 μM EqTrolox), functional capacity, performance status, and Karnofsky index were also maintained in the immunonutrition group.48 In another randomized study, patients who received a combination of omega-3 fatty acids, glutamine, and arginine as part of immune EN were compared to the control group, which received a standard formula. In 71 locally advanced EC patients who were treated with 5-FU and cisplatin and radiation, it was found that the levels of C-reactive protein (P = 0.001) and tumor necrosis factor (P = 0.014) increased more in the control group than the treatment group, during treatment.49 These preliminary data show that immunonutrition can improve the nutrition status together with functional capacity by attenuating the inflammatory cytokine levels in EC patients undergoing chemoradiation. Notes Funding information: The conferences in which this work was performed were underwritten by unrestricted grants from the Gastroenterological Society of Taiwan. Specific author contributions: Ming-Jen Chen, Cheng-Hsin Chu, I-Chen Wu, and Yu-Jen Chen wrote the manuscript. Tsang-En Wang, Yi-Fang Chang, Chueh-Lien Yang, Wen-Chien Huang, Wei-Kuo Chang reviewed the literatures and statements. Bor-Shyang Sheu coordinated as the chairman of the Taiwan expert group to compose the draft of the manuscript. Ming-Shiang Wu served as the co-chairman, Jaw-Town Lin applied the funding for the expert meeting and critically reviewed the article. References 1 Palmes D , Brüwer M , Bader F G et al. German Advanced Surgical Treatment Study Group . Diagnostic evaluation, surgical technique, and perioperative management after esophagectomy: consensus statement of the German Advanced Surgical Treatment Study Group . Langenbecks Arch Surg 2011 ; 396 : 857 – 66 . Google Scholar CrossRef Search ADS PubMed 2 Lordick F , Mariette C , Haustermans K , Obermannová R , Arnold D ; ESMO Guidelines Committee . Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up† . Ann Oncol 2016 ; 27 : v50 – 7 . Google Scholar CrossRef Search ADS PubMed 3 Allum W H , Blazeby J M , Griffin S M , Cunningham D , Jankowski J A , Wong R ; Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, the British Society of Gastroenterology and the British Association of Surgical Oncology . Guidelines for the management of oesophageal and gastric cancer . Gut 2011 ; 60 : 1449 – 72 . Google Scholar CrossRef Search ADS PubMed 4 Di Luzio R , Moscatiello S , Marchesini G . Role of nutrition in gastrointestinal oncological patients . Eur Rev Med Pharmacol Sci 2010 ; 14 : 277 – 84 . Google Scholar PubMed 5 Cerantola Y , Grass F , Cristaudi A , Demartines N , Schäfer M , Hübner M . 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The Swedish version of the patient-generated subjectiveglobal assessment of nutritional status: gastrointestinal vs urological cancers . Clin Nutr 1999 ; 18 : 71 – 77 . Google Scholar CrossRef Search ADS PubMed 11 Quyen T C , Angkatavanich J , Thuan T V , Xuan V V , Tuyen L D , Tu D A . Nutrition assessment and its relationship with performance and Glasgow prognostic scores in Vietnamese patients with esophageal cancer . Asia Pac J Clin Nutr 2017 ; 26 : 49 – 58 . Google Scholar PubMed 12 Wiegert E V M , Padilha P C , Peres W A F . Performance of patient-generated subjective global assessment (PG-SGA) in patients with advanced cancer in palliative care . Nutr Clin Pract 2017 ; 32 : 675 – 81 . Google Scholar CrossRef Search ADS PubMed 13 Boonstra J J , Kok T C , Wijnhoven B P et al. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial . BMC Cancer 2011 ; 11 : 181 . Google Scholar CrossRef Search ADS PubMed 14 Cox S , Powell C , Carter B , Hurt C , Mukherjee S , Crosby T D . Role of nutritional status and intervention in oesophageal cancer treated with definitive chemoradiotherapy: outcomes from SCOPE1 . Br J Cancer 2016 ; 115 : 172 – 7 . Google Scholar CrossRef Search ADS PubMed 15 Odelli C , Burgess D , Bateman L et al. Nutrition support improves patient outcomes, treatment tolerance and admission characteristics in oesophageal cancer . Clin Oncol 2005 ; 17 : 639 – 45 . Google Scholar CrossRef Search ADS 16 Ligthart-Melis GC , Weijs PJ , te Boveldt ND et al. Dietician-delivered intensive nutritional support is associated with a decrease in severe postoperative complications after surgery in patients with esophageal cancer . Dis Esophagus 2013 ; 26 : 587 – 93 . Google Scholar CrossRef Search ADS PubMed 17 Bozzetti F , Braga M , Gianotti L et al. Postoperative enteral versus parenteral nutrition in malnourished patients with gastrointestinal cancer: a randomised multicentre trial . Lancet North Am Ed 2001 ; 358 : 1487 – 92 . Google Scholar CrossRef Search ADS 18 Flynn M B , Leightty F F . Preoperative outpatient nutritional support of patients with squamous cancer of the upper aerodigestive tract . Am J Surg 1987 ; 154 : 359 – 62 . Google Scholar CrossRef Search ADS PubMed 19 Shukla H S , Rao R R , Banu N , Gupta R M , Yadav R C . Enteral hyperalimentation in malnourished surgical patients . Indian J Med Res 1984 ; 80 : 339 – 46 . Google Scholar PubMed 20 Braga M , Gianotti L , Gentilini O , Parisi V , Salis C , Di Carlo V . Early postoperative enteral nutrition improves gut oxygenation and reduces costs compared with total parenteral nutrition . Crit Care Med 2001 ; 29 : 242 – 8 . Google Scholar CrossRef Search ADS PubMed 21 Gupta V . Benefits versus risks: a prospective audit . World J Surg 2009 ; 33 : 1432 – 8 . Google Scholar CrossRef Search ADS PubMed 22 Ryan A M , Rowley S P , Healy L A et al. Post-oesophagectomy early enteral nutrition via a needle catheter jejunostomy: 8-year experience at a specialist unit . Clin Nutr 2006 ; 25 : 386 – 93 . Google Scholar CrossRef Search ADS PubMed 23 Markides G A , Alkhaffaf B , Vickers J . Nutritional access routes following oesophagectomy—a systematic review . Eur J Clin Nutr 2011 ; 65 : 565 – 73 . Google Scholar CrossRef Search ADS PubMed 24 Aiko S , Yoshizumi Y , Sugiura Y et al. Beneficial effects of immediate enteral nutrition after esophageal cancer surgery . Surg Today 2001 ; 31 : 971 – 8 . Google Scholar CrossRef Search ADS PubMed 25 Baigrie R J , Devitt P G , Watkin D S . Enteral versus parenteral nutrition after oesophagogastric surgery: a prospective randomized comparison . ANZ J Surg 1996 ; 66 : 668 – 70 . Google Scholar CrossRef Search ADS 26 Baker A , Wooten L A , Malloy M . Nutritional considerations after gastrectomy and esophagectomy for malignancy . Curr Treat Options Oncol 2011 ; 12 : 85 – 95 . Google Scholar CrossRef Search ADS PubMed 27 Tuebergen D , Rijcken E , Mennigen R , Hopkins A M , Senninger N , Bruewer M . Treatment of thoracic esophageal anastomotic leaks and esophageal perforations with endoluminal stents: efficacy and current limitations . J Gastrointest Surg 2008 ; 12 : 1168 – 76 . Google Scholar CrossRef Search ADS PubMed 28 van Hagen P , Hulshof M C , van Lanschot J J . Preoperative chemoradiotherapy for esophageal or junctional cancer . N Engl J Med 2012 ; 366 : 2074 – 84 . Google Scholar CrossRef Search ADS PubMed 29 Miyata H , Yano M , Yasuda T et al. Randomized study of clinical effect of enteral nutrition support during neoadjuvant chemotherapy on chemotherapy-related toxicity in patients with esophageal cancer . Clin Nutr 2012 ; 31 : 330 – 6 . Google Scholar CrossRef Search ADS PubMed 30 Odelli C , Burgess D , Bateman L et al. Nutrition support improves patient outcomes, treatment tolerance and admission characteristics in oesophageal cancer . Clin Oncol 2005 ; 17 : 639 – 45 . Google Scholar CrossRef Search ADS 31 ASGE Standards of Practice Committee , Evans J A , Early D S , Chandraskhara V et al. ; American Society for Gastrointestinal EndoscopyGastrointest Endosc . The role of endoscopy in the assessment and treatment of esophageal cancer . Gastrointest Endosc 2013 ; 77 : 328 – 34 . Google Scholar CrossRef Search ADS PubMed 32 Spaander M C , Baron T H , Siersema P D et al. Esophageal stenting for benign and malignant disease: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline . Endoscopy 2016 ; 48 : 939 – 48 . Google Scholar CrossRef Search ADS PubMed 33 Jones C M , Griffiths E A . Should oesophageal stents be used before neo-adjuvant therapy to treat dysphagia in patients awaiting oesophagectomy? Best evidence topic (BET) . Int J Surg 2014 ; 12 : 1172 – 80 . Google Scholar CrossRef Search ADS PubMed 34 Nagaraja V , Cox M R , Eslick G D . Safety and efficacy of esophageal stents preceding or during neoadjuvant chemotherapy for esophageal cancer: a systematic review and meta-analysis . J Gastrointest Oncol 2014 ; 5 : 119 – 26 . Google Scholar PubMed 35 Sreedharan A , Harris K , Crellin A , Forman D , Everett S M . Interventions for dysphagia in oesophageal cancer . Cochrane Database Syst Rev 2014 : CD005048 . doi: 10.1002/14651858.CD005048.pub4 . 36 Yang C W , Lin H H , Hsieh T Y , Chang W K . Palliative enteral feeding for patients with malignant esophageal obstruction: a retrospective study . BMC Palliat Care 2015 ; 14 : 58 . Google Scholar CrossRef Search ADS PubMed 37 Lin C H , Liu N J , Lee C S et al. Nasogastric feeding tube placement in patients with esophageal cancer: application of ultrathin transnasal endoscopy . Gastrointest Endosc 2006 ; 64 : 104 – 7 . Google Scholar CrossRef Search ADS PubMed 38 Daly J M , Weintraub F N , Shou J et al. Enteral nutrition during multimodality therapy in upper gastrointestinal cancer patients . Ann Surg 1995 ; 221 : 327 – 38 . Google Scholar CrossRef Search ADS PubMed 39 Ryan A M , Reynolds J V , Healy L et al. Enteral nutrition enriched with eicosapentaenoic acid (EPA) preserves lean body mass following esophageal cancer surgery: results of a double-blinded randomized controlled trial . Ann Surg 2009 ; 249 : 355 – 63 . Google Scholar CrossRef Search ADS PubMed 40 Nakamura M , Iwahashi M , Takifuji K et al. Optimal dose of preoperative enteral immunonutrition for patients with esophageal cancer . Surg Today 2009 ; 39 : 855 – 60 . Google Scholar CrossRef Search ADS PubMed 41 Fukuda T , Seto Y , Yamada K et al. Can immune-enhancing nutrients reduce postoperative complications in patients undergoing esophageal surgery ? Dis Esophagus 2008 ; 21 : 708 – 11 . Google Scholar CrossRef Search ADS PubMed 42 Sakurai Y , Masui T , Yoshida I et al. Randomized clinical trial of the effects of perioperative use of immune-enhancing enteral formula on metabolic and immunological status in patients undergoing esophagectomy . World J Surg 2007 ; 31 : 2150 – 7 . Google Scholar CrossRef Search ADS PubMed 43 Mudge L , Isenring E , Jamieson G G . Immunonutrition in patients undergoing esophageal cancer resection . Dis Esophagus 2011 ; 24 : 160 – 5 . Google Scholar CrossRef Search ADS PubMed 44 Sayles C , Hickerson S C , Bhat R R , Hall J , Garey K W , Trivedi M V . Oral glutamine in preventing treatment-related mucositis in adult patients with cancer: a systematic review . Nutr Clin Pract 2016 ; 31 : 171 – 9 . Google Scholar CrossRef Search ADS PubMed 45 Gul K , Muge A , Taner A , Sehri E . Oral glutamine supplementation reduces radiotherapy-induced esophagitis in lung cancer patients . Asian Pac J Cancer Prev 2015 ; 16 : 53 – 58 . Google Scholar CrossRef Search ADS PubMed 46 Yoshida S , Matsui M , Shirouzu Y , Fujita H , Yamana H , Shirouzu K . Effects of glutamine supplements and radiochemotherapy on systemic immune and gut barrier function in patients with advanced esophageal cancer . Ann Surg 1998 ; 227 : 485 – 91 . Google Scholar CrossRef Search ADS PubMed 47 Crosby T , Hurt CN , Falk S et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial . Lancet Oncol 2013 ; 14 : 627 – 37 . Google Scholar CrossRef Search ADS PubMed 48 Vasson M P , Talvas J , Perche O et al. Immunonutrition improves functional capacities in head and neck and esophageal cancer patients undergoing radiochemotherapy: a randomized clinical trial . Clin Nutr 2014 ; 33 : 204 – 10 . Google Scholar CrossRef Search ADS PubMed 49 Sunpaweravong S , Puttawibul P , Ruangsin S et al. Randomized study of antiinflammatory and immune-modulatory effects of enteral immunonutrition during concurrent chemoradiotherapy for esophageal cancer . Nutr Cancer 2014 ; 66 : 1 – 5 . Google Scholar CrossRef Search ADS PubMed © The Authors 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Nutrition therapy in esophageal cancer—Consensus statement of the Gastroenterological Society of Taiwan

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Oxford University Press
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© The Authors 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.
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1120-8694
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1442-2050
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10.1093/dote/doy016
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Abstract

SUMMARY A number of clinical guidelines on nutrition therapy in cancer patients have been published by national and international societies; however, most of the reviewed data focused on gastrointestinal cancer or non-cancerous abdominal surgery. To collate the corresponding data for esophageal cancer (EC), a consensus panel was convened to aid specialists from different disciplines, who are involved in the clinical nutrition care of EC patients. The literature was searched using MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the ISI Web of Knowledge. We searched for the best evidence pertaining to nutrition therapy in the case of EC. The panel summarized the findings in 3 sections of this consensus statement, based on which, after the diagnosis of EC, an initial distinction is made between the patients, as follows: (1) Assessment; (2) Therapy in patients with resectable disease; patients receiving chemotherapy or chemoradiotherapy prior to resection, and patients with unresectable disease, requiring chemoradiotherapy or palliative therapy; and (3) Formula. The resulting consensus statement reflects the opinions of a multidisciplinary group of experts, and a review of the current literature, and outlines the essential aspects of nutrition therapy in the case of EC. The statements are: Patients with EC are among one of the highest risk to have malnutrition. Patient generated suggestive global assessment is correlated with performance status and prognosis. Nutrition assessment for patients with EC at the diagnosis, prior to definitive therapy and change of treatment strategy are suggested and the timing interval can be two weeks during the treatment period, and one month while the patient is stable. Patients identified as high risk of malnutrition should be considered for preoperative nutritional support (tube feeding) for at least 7–10 days. Various routes for tube feedings are available after esophagectomy with similar nutrition support benefits. Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and self-expanding metal stent (SEMS) or jejunal tube. Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides benefits of maintaining weight, decreasing toxicity, and preventing treatment interruption. Tube feeding or SEMS can offer nutrition support in patients with unresectable esophageal cancer, but SEMS is not recommended for those with neoadjuvant chemoradiation before surgery. Enteral immunonutrition may preserve lean body mass and attenuates stress response after esophagectomy. Administration of glutamine may decrease the severity of chemotherapy induced mucositis. Enteral immunonutrition achieves greater nutrition status or maintains immune functions during concurrent chemoradiation. INTRODUCTION The treatment of esophageal carcinoma (EC) generally entails surgery, chemotherapy, and radiotherapy. Accurate diagnosis, a multidisciplinary approach in treatment, and the perioperative management of patients with EC remain crucial for positive prognoses. Nutrition therapy has been demonstrated to improve patients’ tolerance to treatment, as well as the quality of life, and long-term outcomes. The current consensus focuses on the essential aspects of EC and includes cancer staging, surgical techniques, and perioperative management or palliative treatment.1–3 However, no consensus has been achieved with regards to nutrition therapy in EC patients. A number of clinical guidelines on nutrition in cancer patients have been published by various national and international societies in terms of the involvement of a multidisciplinary team, malnutrition risk prevention, and nutrition therapy. However, the consensus on their adoption in the case of EC patients is limited, as most of the evidence is related to gastrointestinal (GI) cancers or abdominal surgery.4–6 The anatomy, type of dysphagia, surgical reconstruction techniques, alterations in metabolism, and calorie insufficiency in the case of EC patients are different from those of other cancers; thus, ideal consensus statements must focus on evidence related to esophageal cancers. METHODS To collate evidence pertaining to these aspects of EC, a consensus panel was convened by The Gastroenterological Society of Taiwan. The consensus panel comprises gastroenterology, chest surgery, hemato-oncology, and radio-oncology experts, as well as dietitians. The present guidelines aim to help specialists from different medical disciplines who are involved in the clinical care of EC patients. Based on the review of the literature, the draft statements of this consensus selected clinical questions which are relevant in daily practice and were established by leaders from each field. The literature review focused on recent data for the development of draft statements and the determination of the levels of evidence. The literature was searched using MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the ISI Web of Knowledge. This structured procedure was supplemented by the intensive hand-searching of journals and previously formulated guidelines. We searched for the best evidence on each issue and aspect. The keywords used in the search were ‘esophageal cancer,’ ‘nutrition,’ ‘assessment,’ ‘therapy,’ ‘immunonutrition,’ ‘esophagectomy,’ ‘enteral,’ and ‘parenteral.’ The literature review focused on the unique findings related to EC, in order to compare them with the findings of major articles pertaining to GI cancers. Thirty gastroenterology, surgery, oncology, radio-oncology, and dietitian experts from Taiwan conducted a consensus conference. Based on a modified Delphi process with 2 separate iterations, all the participants voted anonymously for the first round of statements, and modified these statements through discussions. A second round of voting was conducted, until a consensus of 12 statements was reached (with the agreement of at least 80% of the experts). Statements were rejected if the agreement was <80%. For each statement, the level of evidence was defined according to the modified grading system of the Oxford Centre for Evidence-Based Medicine Levels of Evidence. The recommendation grade ranged from A to D, and each grade was defined by the votes (Table 1). Table 1 Shows all the statements, with the levels of scientific evidence and grades of recommendation Statement Evidence level Agreement Grade of recommendation 1 Patients with esophageal cancer are among those with the highest risk of malnutrition development, and nutrition assessment may be considered. 2b 100% A 2 Various tools and scoring systems are available for the evaluation of the malnutrition risk in patients with esophageal cancer. The patient-generated suggestive global assessment (PG-SGA) is correlated with the performance status and prognosis. 2b 96.7% A 3 Nutrition assessment at the diagnosis, prior to definitive therapy, and a change of treatment strategy are suggested for esophageal cancer patients. 2b 96.7% A 4 In esophageal cancer patients, the time interval for nutrition assessment can range from 2 weeks during treatment, to 1 month when stability is achieved after the completion of treatment. 2b 93.3% B 5 Patients identified as having a high risk of malnutrition development should be considered for preoperative nutrition support (tube feeding) for at least 7–10 days. 2b 83.3% B 6 Various routes of tube feeding are available for esophageal cancer patients, after esophagectomy, with similar nutrition support benefits. 2a 100% A 7 Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and a self-expanding metal stent (SEMS) or jejunal tube. 2b 100% B 8 Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides the benefits of weight maintenance, reduced toxicity, and the prevention of treatment interruption. 2b 100% A 9 Tube feeding or self-expanding metal stents can offer nutrition support in patients with unresectable esophageal cancer, but self-expanding metal stents are not recommended for those with neoadjuvant chemoradiation before surgery. 1a 96.7% A 10 Enteral immunonutrition may preserve the lean body mass and attenuate the stress response post esophagectomy compared to standard enteral nutrition. 1b 96.7% A 11 Administration of glutamine may decrease the severity of chemotherapy-induced mucositis in esophageal cancer patients. 2a 96.7% A 12 Enteral immunonutrition helps in the achievement of a better nutrition status or maintains the immune functions during concurrent chemoradiation for esophageal cancer. 1b 90% B Statement Evidence level Agreement Grade of recommendation 1 Patients with esophageal cancer are among those with the highest risk of malnutrition development, and nutrition assessment may be considered. 2b 100% A 2 Various tools and scoring systems are available for the evaluation of the malnutrition risk in patients with esophageal cancer. The patient-generated suggestive global assessment (PG-SGA) is correlated with the performance status and prognosis. 2b 96.7% A 3 Nutrition assessment at the diagnosis, prior to definitive therapy, and a change of treatment strategy are suggested for esophageal cancer patients. 2b 96.7% A 4 In esophageal cancer patients, the time interval for nutrition assessment can range from 2 weeks during treatment, to 1 month when stability is achieved after the completion of treatment. 2b 93.3% B 5 Patients identified as having a high risk of malnutrition development should be considered for preoperative nutrition support (tube feeding) for at least 7–10 days. 2b 83.3% B 6 Various routes of tube feeding are available for esophageal cancer patients, after esophagectomy, with similar nutrition support benefits. 2a 100% A 7 Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and a self-expanding metal stent (SEMS) or jejunal tube. 2b 100% B 8 Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides the benefits of weight maintenance, reduced toxicity, and the prevention of treatment interruption. 2b 100% A 9 Tube feeding or self-expanding metal stents can offer nutrition support in patients with unresectable esophageal cancer, but self-expanding metal stents are not recommended for those with neoadjuvant chemoradiation before surgery. 1a 96.7% A 10 Enteral immunonutrition may preserve the lean body mass and attenuate the stress response post esophagectomy compared to standard enteral nutrition. 1b 96.7% A 11 Administration of glutamine may decrease the severity of chemotherapy-induced mucositis in esophageal cancer patients. 2a 96.7% A 12 Enteral immunonutrition helps in the achievement of a better nutrition status or maintains the immune functions during concurrent chemoradiation for esophageal cancer. 1b 90% B View Large Table 1 Shows all the statements, with the levels of scientific evidence and grades of recommendation Statement Evidence level Agreement Grade of recommendation 1 Patients with esophageal cancer are among those with the highest risk of malnutrition development, and nutrition assessment may be considered. 2b 100% A 2 Various tools and scoring systems are available for the evaluation of the malnutrition risk in patients with esophageal cancer. The patient-generated suggestive global assessment (PG-SGA) is correlated with the performance status and prognosis. 2b 96.7% A 3 Nutrition assessment at the diagnosis, prior to definitive therapy, and a change of treatment strategy are suggested for esophageal cancer patients. 2b 96.7% A 4 In esophageal cancer patients, the time interval for nutrition assessment can range from 2 weeks during treatment, to 1 month when stability is achieved after the completion of treatment. 2b 93.3% B 5 Patients identified as having a high risk of malnutrition development should be considered for preoperative nutrition support (tube feeding) for at least 7–10 days. 2b 83.3% B 6 Various routes of tube feeding are available for esophageal cancer patients, after esophagectomy, with similar nutrition support benefits. 2a 100% A 7 Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and a self-expanding metal stent (SEMS) or jejunal tube. 2b 100% B 8 Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides the benefits of weight maintenance, reduced toxicity, and the prevention of treatment interruption. 2b 100% A 9 Tube feeding or self-expanding metal stents can offer nutrition support in patients with unresectable esophageal cancer, but self-expanding metal stents are not recommended for those with neoadjuvant chemoradiation before surgery. 1a 96.7% A 10 Enteral immunonutrition may preserve the lean body mass and attenuate the stress response post esophagectomy compared to standard enteral nutrition. 1b 96.7% A 11 Administration of glutamine may decrease the severity of chemotherapy-induced mucositis in esophageal cancer patients. 2a 96.7% A 12 Enteral immunonutrition helps in the achievement of a better nutrition status or maintains the immune functions during concurrent chemoradiation for esophageal cancer. 1b 90% B Statement Evidence level Agreement Grade of recommendation 1 Patients with esophageal cancer are among those with the highest risk of malnutrition development, and nutrition assessment may be considered. 2b 100% A 2 Various tools and scoring systems are available for the evaluation of the malnutrition risk in patients with esophageal cancer. The patient-generated suggestive global assessment (PG-SGA) is correlated with the performance status and prognosis. 2b 96.7% A 3 Nutrition assessment at the diagnosis, prior to definitive therapy, and a change of treatment strategy are suggested for esophageal cancer patients. 2b 96.7% A 4 In esophageal cancer patients, the time interval for nutrition assessment can range from 2 weeks during treatment, to 1 month when stability is achieved after the completion of treatment. 2b 93.3% B 5 Patients identified as having a high risk of malnutrition development should be considered for preoperative nutrition support (tube feeding) for at least 7–10 days. 2b 83.3% B 6 Various routes of tube feeding are available for esophageal cancer patients, after esophagectomy, with similar nutrition support benefits. 2a 100% A 7 Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and a self-expanding metal stent (SEMS) or jejunal tube. 2b 100% B 8 Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides the benefits of weight maintenance, reduced toxicity, and the prevention of treatment interruption. 2b 100% A 9 Tube feeding or self-expanding metal stents can offer nutrition support in patients with unresectable esophageal cancer, but self-expanding metal stents are not recommended for those with neoadjuvant chemoradiation before surgery. 1a 96.7% A 10 Enteral immunonutrition may preserve the lean body mass and attenuate the stress response post esophagectomy compared to standard enteral nutrition. 1b 96.7% A 11 Administration of glutamine may decrease the severity of chemotherapy-induced mucositis in esophageal cancer patients. 2a 96.7% A 12 Enteral immunonutrition helps in the achievement of a better nutrition status or maintains the immune functions during concurrent chemoradiation for esophageal cancer. 1b 90% B View Large After the initial diagnosis of EC, an initial distinction is made between those patients with a resectable locoregional disease, requiring chemoradiation as a bridge to surgical intervention, and those in need of palliation. Nutrition therapy is an integral part of treatment for EC patients, in the curative and palliative setting. The panel summarized the findings in 3 sections of this consensus statement: (1) Assessment; (2) Therapy: patients with resectable disease; patients receiving chemotherapy or chemoradiation prior to resection and; patients with unresectable disease, requiring chemoradiation or palliation; and (3) Formula (Fig. 1). Fig. 1 View largeDownload slide A diagram showing the key points of nutritional assessment and support in esophageal cancers. Fig. 1 View largeDownload slide A diagram showing the key points of nutritional assessment and support in esophageal cancers. Consensus statements Section I: Assessment Statement 1: Patients with esophageal cancer are among those with the highest risk of malnutrition development, and nutrition assessment may be considered. Evidence level: 2b Agreement: 100% Grade of recommendation: A: 70%, B: 30%, C: 0%, D: 0% Cancer-associated malnutrition can result from local mass effects (such as dysphagia), systemic responses to tumors (such as the production of pro-inflammatory cytokines) and anticancer therapies such as chemotherapy or chemoradiotherapy, and other complications.7 In a study which enrolled 1000 screened patients from 17 centers in the US, it was observed that the weight loss was higher in the case of EC patients, with a 15.9% decrease in the baseline weight, followed by in pancreatic cancer and gastric cancer patients. Similarly, a Nutritional Risk Screening score (NRI) ≥3, which is required for nutrition assessment, was observed in a majority of EC patients.8 In a large survey of 5044 patients with EC, as part of the American College of Surgeons Patient Care Evaluation Study, in 1997; it was found that dysphagia (74%) and weight loss (57.3%) were the most common symptoms of EC.9 Statement 2: Various tools and scoring systems are available for the evaluation of the malnutrition risk in patients with esophageal cancer. The patient-generated suggestive global assessment (PG-SGA) is correlated with the performance status and prognosis. Evidence level: 2b Agreement: 96.7% Grade of recommendation: A: 56.7%, B: 43.3%, C: 0%, D: 0% There are no current standardized and widely accepted tools and scoring systems for the nutrition assessment of patients with EC; this may impair the proper assessment of malnutrition in academic study between groups. In order to be efficient, screening should be brief and inexpensive, and have high specificity. In clinical practice, a preferred alternative is the use of a single prognostic index, or perhaps a tool with a few indices to grade the severity of malnutrition, and a subjective assessment through questionnaires. In a previously conducted study, the PG-SGA scores comprised 2 sections that were completed by a patient or clinician.10 An Asian cross-sectional study was conducted to determine the nutrition assessment in patients with advanced EC, using the PG-SGA, and to examine the relationship between their performances through the Karnofsky performance score (KPS) or Eastern cooperative oncology group (ECOG) performance score. The PG-SGA was found to be strongly correlated with the KPS (r = −0.717) and ECOG score (r = 0.672).11 Statement 3: Nutrition assessment at the diagnosis, prior to definitive therapy, and a change of treatment strategy are suggested for esophageal cancer patients. Evidence level: 2b Agreement: 96.7% Grade of recommendation: A: 50%, B: 46.7%, C: 3.3%, D: 0% Regardless of the different treatment approaches, the goals of nutrition therapy are to prevent long-term malnutritional risk from the time of diagnosis, and to reduce treatment-related morbidity and mortality. With the assessment, we can also set treatment goals and simultaneously evaluate the effectiveness of nutrition therapy with relevant prognostic aspects such as changes in body weight, food intake, nutrition impact symptoms, and performance status.12 Maintaining lean body mass may protect the patient from complications during the treatment13 because muscle provides amino acids necessary for the repair of tissue and adequate functioning of the immune system. The nutrition therapy aimed to improve the intake of the patient toward 1.2–1.5 g protein per kilogram of body weight per day. The energy goal was calculated using the Harris–Benedict equation multiplied by 1.3–1.5 for intended weight gain. Nutritional goals on intake of protein, specific amino acids, energy and micronutrients in relation to preservation of lean body mass during treatment may not be specific for patients undergoing treatment for esophageal cancer, but are not less relevant. Assessment should be repeated at adequate intervals to judge the requirement and adjustment for nutrition intervention, and to monitor its effects. Twohundred and fifty-eight patients with advanced EC were randomly allocated to undergo definitive chemoradiotherapy in the SCOPE1, a randomized controlled phase II/III trial in the UK.14 Nutrition intervention improved survival if provided at the baseline, with a hazard ratio (HR) of 0.13 (P < 0.003), but a similar benefit was not observed if it was provided later in the treatment course. It was also found that ongoing nutrition assessments in patients receiving defined chemoradiation therapy significantly reduced weight loss and incidences of unplanned hospital admissions, and resulted in greater radiotherapy completion rates. In addition, it was suggested that early and regular nutrition assessments and interventions resulted in improved outcomes for EC patients.15 Statement 4: In esophageal cancer patients, the time interval for nutrition assessment can range from 2 weeks during treatment, to 1 month when stability is achieved after the completion of treatment. Evidence level: 2b Agreement: 93.3% Grade of recommendation: A: 36.7%, B: 63.3%, C: 0%, D: 0% Serial assessments, both in the inpatient and outpatient settings, may have some utility, provide prognostic information and decrease the chance of perioperative and postoperative complications in EC patients. Some studies supported the importance of dietary counseling as part of multimodal treatment including chemoradiotherapy14 and surgery in EC patients.16 In a prospective study on EC patients who underwent an esophagectomy, a more favorable outcome was observed in 28 patients who received intensive nutritional support intervention compared with controls.16 This study shows that dietician-delivered intensive nutritional support decreases severe postoperative complications in patients with esophageal cancer prior to treatment and during recovery after discharge. The program also resulted in a relative preoperative weight gain of +4.8% (P = 0.009, adjusted) if the intensive nutritional support was last at least for one a year, compared to the control group, in these neoadjuvant-treatment patients after surgery. Section II: Therapy Statement 5: Patients identified as having a high risk of malnutrition development should be considered for preoperative nutrition support (tube feeding) for at least 7–10 days. Evidence level: 2b Agreement: 83.3% Grade of recommendation: A: 26.7%, B: 53.3%, C: 20%, D: 0% Esophageal resection exerts enormous stress on EC patients and is associated with pain, asthenia, and anorexia. Postoperative malnutrition can have a negative effect on wound-healing, rehabilitation, postoperative adaptation, and infection rates, and can increase the rate of hospitalization.17 Patients are considered to be at a severe nutrition risk if at least 1 of the following criteria is fulfilled: weight loss of 10–15% of the body weight within 6 months, BMI < 18.5 kg/m2, Subjective Global Assessment Grade C or serum albumin level <30 g/L, according to ESPEN guidelines.6 For patients at a severe nutrition risk, major surgery should be postponed until the nutrition status has been corrected. The ESPEN 2016 guidelines on nutrition in cancer patients suggest that those with a severe nutrition risk benefit from nutrition support that is provided 10–14 days prior to major surgery, even if the surgery has to be delayed (Grade A). The evidences are adapted from 2 earlier randomized studies that suggested oral or nasogastric feeding for up to 10 days may reduce postoperative morbidity or mortality by up to 50% compared to the control group.18,19 Statement 6: Various routes of tube feeding are available for esophageal cancer patients, after esophagectomy, with similar nutrition support benefits. Evidence level: 2a Agreement: 100% Grade of recommendation: A: 56.7%, B: 43.3%, C: 0%, D: 0% For patients who have undergone an esophagectomy, access to the functional gastrointestinal tract, bypass the fresh anastomoses utilization instead of the early initiation of parenteral support can reduce postoperative infections and lengths of stay.20 A study supported the use of jejunal access during operation in 204 patients who underwent esophagectomy; 95% of these patients were successfully fed through this route and approximately 13% of them required jejunostomy tubes for more than 30 days.21 The placement of a nasojejunal tube is a simple option, but after 20 days, it is not well tolerated, with high rates of tube dislodgement and interruptions in feeding. For this reason, many surgeons favor the placement of jejunostomy tubes during the index operation.21,22 Five randomized control trials (RCTs) and 1 case-control trial, with 344 EC patients, were included in a systematic review.23 In the RCTs, no route was suggested to be superior to the other because there were no difference in complications and efficacy and it was hard to weight the risks and benefits among the various routes of tube feeding. There is a lack of strong direct evidence supporting the use of the single feeding access route in esophagectomy patients. If enteral feeding is chosen, the placement of jejunostomy feeding tubes may be superior to that of nasojejunal or duodenal tubes due to lower rates of tube dislodgement and interruptions in feeding with the former. Statement 7: Limited intrathoracic anastomotic leakage postesophagectomy can be managed with intravenous antibiotics and a self-expanding metal stent (SEMS) or jejunal tube. Evidence level: 2b Agreement: 100% Grade of recommendation: A: 46.7%, B: 53.3%, C: 0%, D: 0% Physiologically, enteral is preferable to ameliorate surgical stress such as higher serum bilirubin and C-reactive protein levels24 and more common catheter complications25 comparing with total parenteral nutrition (TPN). Cervical anastomotic insufficiencies occur in 25–45% of esophagectomy patients and a majority of them are due to intrathoracic leakages.1 When an anastomotic insufficiency or a leakage is suspected after esophagectomy, the primary goals are the determination of the leak's location and status of the conduit's perfusion, and the observation of the sepsis parameters. Endoscopy in combination with a contrast agent, bronchoscopy, CT, and laboratory parameters can be performed to guide the management. Intrathoracic anastomotic leaks are characterized by a small fistula, which can be sufficiently drained so the patient has no mediastinitis or sepsis. Treatment is conservative, with antibiotic treatment and jejunal tube nutrition.26 If intrathoracic anastomotic leaks are characterized by a large area leakage with a sufficient gastric tube perfusion and no signs of mediastinitis or sepsis, the treatment options are the placement of a covered, self-expanding esophageal stent in combination with antibiotic treatment, and temporary TPN.27 Parenteral nutrition should be considered only when other routes of administration are impractical or not feasible. Statement 8: Enteral nutrition in patients receiving preoperative chemotherapy or chemoradiation provides the benefits of weight maintenance, reduced toxicity, and the prevention of treatment interruption. Evidence level: 2b Agreement: 100% Grade of recommendation: A: 63.3%, B: 36.7%, C: 0%, D: 0% Preoperative chemoradiation improves survival among patients with potentially curable esophageal cancers.28 The side effects of chemotherapy or chemoradiation, including mucositis and gastrointestinal upset (appetite loss, nausea, and diarrhea), can worsen patients’ malnutrition status, leading to the interruption of neoadjuvant chemoradiation therapy. Perioperative enteral nutrition has been reported to reduce morbidity and mortality; however, for patients with EC, who undergo chemotherapy, the effect of EN during chemotherapy or chemoradiation has not been well established. A randomized study of 91 EC patients who received neoadjuvant chemotherapy (5-fluorouracil, cisplatin, and adriamycin) were enrolled to receive either EN (n = 47) or parenteral nutrition (PN) (n = 44). In that study, the incidences of grade 3–4 hematological side effects were significantly lower in the EN group than in the PN group (n = 44 and 47; leukopenia: 17% vs. 41%, P = 0.011; neutropenia: 36% vs. 66%, P = 0.005).29 A cohort study of 48 EC patients found that those in whom a nutrition pathway was followed, incorporating early and periodic nutrition assessment and support, during definite chemoradiation therapy, experienced lesser weight loss (mean weight change −4.2 ± 6.4 kg vs. −8.9 ± 5.9 kg, P = 0.03) and had greater radiotherapy completion rates (92% vs. 50%, P = 0.001), and fewer patients had an unplanned hospital admission (46% vs. 75%, P = 0.04); those that did, had a shorter length of stay (3.2 ± 5.4 days vs. 13.5 ± 14.1 days, P = 0.002).30 Statement 9: Tube feeding or self-expanding metal stents can offer nutrition support in patients with unresectable esophageal cancer, but self-expanding metal stents are not recommended for those with neoadjuvant chemoradiation before surgery. Evidence level: 1a Agreement: 96.7% Grade of recommendation: A: 60%, B: 36.7%, C: 3.3%, D: 0% In patients with unresectable EC, the restoration of body weight and maintenance of the ability to swallow represent the primary goals of supportive care. Enteral food intake should be ensured by the use of a percutaneous endoscopic gastrostomy (PEG) tube or jejunal catheter. Self-expandable metal stents (SEMS) can palliate malignant dysphagia to maintain oral intake. In this, the technical success rate was found to be high but chest pain and stent migration were common side effects.31,32 A review of 12 studies focusing on the efficacy and safety of esophageal stent placement in the neoadjuvant setting for EC found that up to 92.3% patients experienced chest pain, and, sometimes, stent removal or replacement was required.33 A meta-analysis also indicated a high incidence of complications, including 32% cases of stent migration and 51.4% cases of chest discomfort in the stent group, with similar increases in weight and serum albumin levels, compared to the nonstent group, during neoadjuvant chemotherapy.34 A multicenter European cohort study revealed that SEMS insertion was a predictor of poor prognosis (adjusted HR = 1.6; P = 0.038) and led to negative oncology outcomes.35 Therefore, the European Society of Gastrointestinal Endoscopy recently recommended against the use of esophageal stents as a bridge to surgery or prior to chemotherapy/chemoradiotherapy.32 Alternative ways of tube feeding such as nasogastric tube insertion, surgical gastrostomy or jejunostomy can provide similar nutrition support under lower costs.34 In patients with advanced EC and a short expected life-span, endoscopy-assisted nasogastric tube placement was shown to be effective and safe, in studies conducted in Taiwan.36,37 Section III: Formula Statement 10: Enteral immunonutrition may preserve the lean body mass and attenuate the stress response post esophagectomy compared to standard enteral nutrition. Evidence level: 1b Agreement: 96.7% Grade of recommendation: A: 50%, B: 46.7%, C: 3.3%, D: 0% Esophagectomy, including reconstruction, is defined as a major operation associated with a high incidence of complications and marked alterations in metabolism, immunology and physiology. There is a continued debate as to the effectiveness of immunonutrition in postesophagectomy patients. The results of this study should be interpreted in the context of its methodology and heterogeneity. Most of the studies included small size of patients, the duration and timing of administration of immunonutrition were also varied depending on the protocols. Heterogeneity may exist when the study enrolled a range of patients with varies preoperative nutritional status and medical comorbidities. Data from a randomized trial comprising 22 EC patients suggest that perioperative immunonutrition, namely supplementation with arginine, omega-3 fatty acids and nucleotides via jenunostomy, reduced infectious complications and lengths of stay compared to cases of standard enteral feeding.38 In a double-blind study, 53 patients were randomized to a standard EN or a formula enriched with 2.2 g eicosapentaenoic acid (EPA)/d, for 5 days preoperatively (orally), and 21 days postoperatively (via jejunostomy). In the EPA-rich formula group (n = 28) all the aspects of body composition were maintained postoperatively, whereas patients in the standard EN group (n = 25) lost significant amounts of fat-free mass (1.9 kg, P = 0.030) [leg (0.3 kg, P = 0.05), arm (0.17 kg, P = 0.01), and trunk (1.44 kg, P = 0.03)] in comparison. The EPA group had a significantly (P < 0.05) attenuated stress response to TNF-alpha, IL-10, and IL-8 compared to the standard group.39 Preoperative immunonutrition significantly reduced the incidence of postoperative infectious complications, but the optimal regimen of administration remains unclear. In a prospective nonrandomized study which included 20 EC patients who underwent an esophagectomy, immune EN of 500 mL/day (supplemented with arginine 12.8 g/L, n-3 fatty acids 4.1 g/L, and RNA 1.29 g/L) or 1000 mL/day, for 7 days, was administered before the operation. No difference was observed in the perioperative changes in the inflammatory, immunological and nutritional variables.40 Only three small RCTs have evaluated immunonutrition use in patients exclusively undergoing EC surgery, in a systemic review.39,41–43 Although there is evidence suggesting that immunonutrition improved nutrition-related endpoints such as the preservation of lean body mass and the attenuation of stress response, it was not determined if immunonutrition had an impact on clinical outcomes, in terms of the length of hospital stay or postoperative morbidity and mortality. Due to the heterogeneity of the available formulas, identifying the specific components responsible for the improved outcomes is difficult. Statement 11: Administration of glutamine may decrease the severity of chemotherapy-induced mucositis in esophageal cancer patients. Evidence level: 2a Agreement: 96.7% Grade of recommendation: A: 30%, B: 56.7%, C: 13.3%, D: 0% A systematic review of 15 studies conducted in cancer patients receiving chemotherapy or chemoradiation showed that oral glutamine was effective in 11 of the 15 studies. It significantly reduced the incidence of mucositis, and the maximum grade of mucositis. The rates of nausea, vomiting, dry mouth, and anorexia were similar in the glutamine and control groups.44 Thirty-two patients diagnosed with lung cancer were studied in a prospective study comprising 16 patients who received prophylactic oral glutamine powder with 10 g/8 h. Patients were then irradiated with 2 Gy per fraction, daily, 5 days a week. The grading of esophagitis at the end of each daily fraction was recorded until a cumulative dose of 50 Gy was reached. The toxicity grade, weight loss, serum cytokine levels, and esophageal transit times exhibited statistically significant improvement in the glutamine group.45 A small study enrolled 13 EC patients randomized to control or glutamine groups. Glutamine was administered orally in doses of 30 g/day at the start of mediastinal irradiation and chemotherapy, comprising 5-fluorouracil and cisplatin, for 28 days. Oral glutamine prevented a decline in the lymphocyte counts (control 567 ± 96/mm3 vs. glutamine 1007 ± 151/mm3, P < 0.05). The amount of phenolsulfonphthalein excretion in the urine decreased in the glutamine group, indicating a protective effect on the gut barrier function (control 15.4 ± 2.4% vs. glutamine 7.4 ± 1.2, P < 0.05).46 Statement 12: Enteral immunonutrition helps in the achievement of a better nutrition status or maintains the immune functions during concurrent chemoradiation for esophageal cancer. Evidence level: 1b Agreement: 90% Grade of recommendation: A: 36.7%, B: 63.3%, C: 0%, D: 0% Chemoradiation is a treatment option for localized EC, particularly in the case of squamous cell carcinoma or in patients with adenocarcinoma who are deemed unfit for surgery. Nearly half of these patients experience grade 3–4 gastrointestinal toxicities during treatment.47 In an RCT, 37 EC patients received either immune EN (including a polymeric formula enriched with arginine (13 g/L), eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) (EPA + DHA 3.4 g/L), and ribonucleotides (1.3 g/L)), or an isonitrogenous, isoenergetic standard, 5 days prior to and until the end of chemoradiation (5–7 weeks). A significant gain in the total body weight (+2.1 ± 3.1 kg), and the improvement of albuminemia and the nutritional risk index (NRI) were observed in patients who received immune EN. The plasma antioxidant capacity (+100 ± 13 μM EqTrolox), functional capacity, performance status, and Karnofsky index were also maintained in the immunonutrition group.48 In another randomized study, patients who received a combination of omega-3 fatty acids, glutamine, and arginine as part of immune EN were compared to the control group, which received a standard formula. In 71 locally advanced EC patients who were treated with 5-FU and cisplatin and radiation, it was found that the levels of C-reactive protein (P = 0.001) and tumor necrosis factor (P = 0.014) increased more in the control group than the treatment group, during treatment.49 These preliminary data show that immunonutrition can improve the nutrition status together with functional capacity by attenuating the inflammatory cytokine levels in EC patients undergoing chemoradiation. Notes Funding information: The conferences in which this work was performed were underwritten by unrestricted grants from the Gastroenterological Society of Taiwan. Specific author contributions: Ming-Jen Chen, Cheng-Hsin Chu, I-Chen Wu, and Yu-Jen Chen wrote the manuscript. Tsang-En Wang, Yi-Fang Chang, Chueh-Lien Yang, Wen-Chien Huang, Wei-Kuo Chang reviewed the literatures and statements. Bor-Shyang Sheu coordinated as the chairman of the Taiwan expert group to compose the draft of the manuscript. Ming-Shiang Wu served as the co-chairman, Jaw-Town Lin applied the funding for the expert meeting and critically reviewed the article. References 1 Palmes D , Brüwer M , Bader F G et al. German Advanced Surgical Treatment Study Group . Diagnostic evaluation, surgical technique, and perioperative management after esophagectomy: consensus statement of the German Advanced Surgical Treatment Study Group . Langenbecks Arch Surg 2011 ; 396 : 857 – 66 . 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Randomized study of antiinflammatory and immune-modulatory effects of enteral immunonutrition during concurrent chemoradiotherapy for esophageal cancer . Nutr Cancer 2014 ; 66 : 1 – 5 . Google Scholar CrossRef Search ADS PubMed © The Authors 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Diseases of the EsophagusOxford University Press

Published: Aug 1, 2018

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