Nutritional optimization during neoadjuvant therapy prior to surgical resection of esophageal cancer—a narrative review

Nutritional optimization during neoadjuvant therapy prior to surgical resection of esophageal... Summary This narrative review aims to evaluate the evidence for the different nutritional approaches employed during neoadjuvant therapy in patients with locoregional esophageal cancer. Patients with esophageal cancer are often malnourished and difficult to optimize nutritionally. While evidence suggests that neoadjuvant therapy can offer a survival advantage, associated toxicity can exacerbate poor nutritional status. There is currently no accepted standard of care regarding optimal nutritional approach. A systematic literature search was undertaken. Studies describing the utilization of an additional nutritional intervention in patients with esophageal cancer receiving neoadjuvant therapy prior to esophagectomy were included. Primary outcome measure was 30-day postoperative mortality after esophagectomy. Secondary outcome measures were loss of weight during neoadjuvant therapy, completion rate of intended neoadjuvant therapy, complications from nutritional intervention, 30-day postoperative morbidity after esophagectomy and quality of life during neoadjuvant treatment. Given the heterogeneity of retrieved articles results was presented as a narrative review. Twenty-five studies were included of which 16 evaluated esophageal stenting, four feeding jejunostomy, three gastrostomy, one nasogastric feeding, and one comparative study of esophageal stenting to feeding jejunostomy. 30-day postoperative mortality was only reported in two of the 26 included studies limiting comparison between nutritional strategies. All studies of esophageal stents reported improvements in dysphagia with reported weight change ranging from −5.4 to +6 kg and one study reported 30-day postoperative mortality after esophagectomy (10%). In patients undergoing esophageal stenting for their neoadjuvant treatment overall migration rate was 29.9%. Studies of laparoscopically inserted jejunostomy were all retrospective reviews that demonstrated an increase in weight ranging from 0.4 to 11.8 kg and similarly no study reported 30-day postoperative mortality. Only one comparative study was included that compared esophageal stents to jejunostomy. This study reported no significant difference between the two groups in respect to complication rates (stents 22% vs. jejunostomy 4%, P = 0.11) or increase in weight (stents 4.4 kg vs. jejunostomy 4.2 kg, P = 0.59). Quality of life was also poorly reported. This review demonstrates the uncertainty on the optimal nutritional approach for patients with resectable esophageal cancer undergoing neoadjuvant treatment prior to esophagectomy. A prospective, multicenter, observational cohort study is needed to determine current practice and inform a prospective clinical trial. INTRODUCTION Patients with esophageal cancer have complex nutritional needs. At the time of diagnosis, most are malnourished due to local tumor effects with dysphagia, anorexia, and cancer cachexia in addition to psychological factors that negatively influence adequate dietary intake. Meta-analyses and randomized controlled trials have demonstrated improved survival benefit of neoadjuvant therapy prior to esophagectomy compared to surgery alone for patients with locoregional esophageal cancer.1–6 Treatment toxicities during neoadjuvant therapy contribute to further weight loss and nutritional deficiencies.7 Malnutrition during neoadjuvant therapy is associated with negative outcomes including poor tumor response, poor treatment tolerance, increased neoadjuvant treatment related morbidity, and reduced of life (QOL).8,9 Early identification of malnutrition and appropriate nutritional support leads to improved nutritional status and QOL.10–17 Furthermore, malnutrition is associated with adverse postoperative outcomes including immune suppression, increased infection rate, increased morbidity including pulmonary complications, delayed wound healing, muscle wasting, prolonged in-hospital stay, and increased healthcare costs.8,18–22 During medical anticancer treatment, The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommend, ‘enteral or, if this is not sufficient or possible, parenteral nutrition If oral food intake is inadequate despite counselling and oral nutritional supplements.’11,23 Further guidelines by Allum et al. recommend preoperative nutritional support for 10–14 days for malnourished patients with esophageal and gastric cancer,24 and patients with severe nutritional risk for 10–14 days prior to any major surgery.11 Specialist esophagogastric dietitians are ideally placed to assess and manage the complex nutritional problems encountered in this patient group. Within the UK, there is a requirement for a specialist dietitian to be a core member of the cancer tumor board. Several approaches have been employed to optimize nutrition prior to and during neoadjuvant therapy including esophageal stenting, feeding jejunostomy or gastrostomy, and nasogastric or nasojejunal feeding.25–27 However, there is no accepted standard of care or level 1 evidence to guide the optimal nutritional approach. Treatment decisions differ according to regional practice, physician, and patient preference. The aim of this review article is to evaluate the evidence in support of these different nutritional approaches during neoadjuvant therapy for esophageal cancer. MATERIALS AND METHODS A systematic electronic literature search was undertaken using Embase, Medline, Web of Science, and Cochrane library databases up to December 2016. The search terms: ‘esophagectomy’, ‘esophageal cancer’, ‘neoadjuvant therapy’, ‘nutrition’, ‘malnutrition’, ‘jejunostomy’, ‘gastrostomy’, ‘esophageal stent’, ‘nasoenteric feeding’ and the Medical Subject Headings (MeSH), ‘esophageal neoplasms’, ‘esophagectomy’, ‘neoadjuvant therapy’, ‘nutritional status’, ‘malnutrition’, ‘jejunostomy’, ‘gastrostomy’, ‘stents’, and ‘enteral nutrition’ were used in combination with the Boolean operators AND or OR. The electronic search was supplemented by a hand search of published abstracts from meetings of the Society of Academic and Research Surgery, Digestive Disease Week, the Association of Upper Gastro-Intestinal Surgeons of Great Britain and Ireland, and the American Society of Clinical Oncology 2005 to 2015. The reference lists of articles obtained were also searched to identify further relevant citations; as was the Current Controlled Trials Register (http://www.controlled-trials.com). The quality of evidence provided by each study was evaluated using the Oxford levels of evidence-based medicine scoring system28 and the Newcastle–Ottawa Score.29 Publications were included if they met the following criteria: Studies where the primary research population included patients with locoregional esophageal cancer receiving neoadjuvant therapy prior to curatively intended esophagectomy. Studies that included nutritional assessment before commencing neoadjuvant therapy. Studies that evaluated the utilization of an additional nutritional strategy, including feeding jejunostomy, gastrostomy, esophageal stenting, and nasoenteric feeding during neoadjuvant therapy. Publications were excluded if they met any of the following criteria: Studies not concerning the management of esophageal cancer. Studies in which the pretreatment nutritional status of patients was not assessed or poorly defined. Review articles Outcome measures for this review The primary outcome measure was 30-day postoperative mortality. Secondary outcome measures were loss of weight during neoadjuvant therapy, completion rate of intended neoadjuvant therapy, nutritional intervention-related complications including mortality, 30-day postoperative morbidity, and health-related QOL (assessed by European Organisation for Research and Treatment of Cancer questionnaires prior to and postnutritional intervention). RESULTS The search strategy used yielded a total of 3489 articles. Following the removal of duplications, all articles were subsequently selected on title, abstract and full text based on the inclusion and exclusion criteria. Twenty-five studies were selected for inclusion (Fig. 1). Of these, 16 original articles evaluated the use of esophageal stenting,30–45 four25,46–48 feeding jejunostomy, three26,49,50 gastrostomy, and one nasogastric feeding.51 One article52 directly compared esophageal stenting to feeding jejunostomy. Fig. 1 View largeDownload slide PRISMA flow diagram of literature search. Fig. 1 View largeDownload slide PRISMA flow diagram of literature search. Esophageal stenting Sixteen articles30–45 evaluated the use of esophageal stenting and included 383 patients. There were nine prospective studies and seven retrospective studies. The study characteristics are described in Table 1 and outcomes in Table 2. All studies recruited patients with grade 2 dysphagia or more (able to swallow only semisolid foods).53 Fifteen studies reported improvement in dysphagia scores. Eleven studies reported technical success rate ranging from 83–100%, with the seven most recent studies all reporting 100% success rates. Postoperative mortality was reported in five studies30,31,33,34,41 and ranged from 4% to13.2%, while only one of these studies specified 30-day postoperative mortality (10%). Seven studies reported weight change, of which six reported weight loss, ranging from −5.4 to +6 kg. Completion of neoadjuvant therapy was reported in eight studies and ranged from 52.6% to 100%. Fourteen studies reported migration rates and included 321 patients with an overall incidence of migration seen in 96 patients (29.9%). Other complications were reported in 15 studies of 331 patients of chest pain (n = 50 (15.6%)), tumor ingrowth (n = 7 (2.2%)), esophagobronchial or tracheal fistula (n = 6 (1.9%)), esophageal perforation (n = 5 (1.5%)), requirement for extra support (n = 7 (2.2%)), food bolus obstruction (n = 2 (0.6%)), stent dysfunction secondary to inflammation (n = 2 (0.6%)), erosion of aortic wall (n = 1 (0.3%)), small bowel perforation (n = 1 (0.3%)), endoleak (n = 1 (0.3%)), small bowel obstruction (n = 1 (0.3%)), significant acid reflux (n = 1 (0.3%)), and hematemesis (n = 1 (0.3%)). Table 1 Study characteristics of included studies evaluating the use of esophageal stenting during neoadjuvant treatment Author and Year  Type of study  Evidence level  N-O Score (max = 9)  Outcomes assessed  n  Age  Male  Success rate  Siddiqui et al. 45  Retrospective  IV  5  Efficacy of treatment, stent-related complications and changes in nutritional status of the patient  6  62.5 (47–82)  4 (66.7%)  83%  Martin et al. 44  Retrospective  IV  5  Dysphagia score and outcome  5  63 (50–82)  3 (60%)  Not stated (only stented patients included)  Bower et al. 30  Retrospective  IV  5  Complications, dysphagia score, nutritional changes (albumin and body weight), progression to surgery  25  64 (48–82)  21 (84%)  Not stated (only stented patients included)  Adler et al. 32  Prospective  III  5  Dysphagia scores and patient weights  13  63.3 ± 12.3  13 (100%)  11 (85%) (2 (15%) initial placement was suboptimal and therefore replaced in same procedure)  Langer et al. 31  Prospective  III  5  Success of insertion, complications, change in dysphagia score, change in albumin  38  66 (30.3–88.2)  26  97.4  Lopes et al. 38  Retrospective  IV  5  Dysphagia scores, complications, tissue reaction, ease of removal  11  60.5  10 (90.9%)  90.9%  Brown et al. 33  Prospective  III  5  Esophageal cancer patients undergoing neoadjuvant therapy prior to resection  32  61 (39–82)  26 (81%)  100%  Pellen et al. 34  Retrospective  IV  6  Patients with esophageal cancer recommended for neoadjuvant treatment with endoscopically significant stenosis or dysphagia score of 3 or more  16  63 (53–76)  9 (56%)  100%  Siddiqui et al. 35  Retrospective  IV  5  Patients with locally advanced esophageal cancer  55  65.8 ± 11.1  43  100%  Krokidis et al. 36  Prospective  III  5  Patients undergoing neoadjuvant treatment or radical radiotherapy after stent insertion  11  64.9 ± 7.5  9  100%  Laquière et al. 37  Prospective  III  5  Patients undergoing neoadjuvant chemoradiotherapy for advanced esophageal cancer with grade 2 dysphagia or more  20  61.5 (43–82)  15 (75%)  100%  Martin et al. 39  Prospective  III  5  Esophageal cancer patients undergoing neoadjuvant treatment prior to esophagectomy  52  61 (39–82)  42 (81%)  Not stated  Van den Berg et al. 40  Prospective  III  4  Consecutive patients with esophageal cancer scheduled for neoadjuvant therapy and complaining of dysphagia (grade 2 or more)  10  68 ± 7.7  7 (70%)  100%  Mariette et al. 41  Retrospective  IV  5  Patients who had undergone esophagectomy with curative intent and had undergone insertion of self-expanding metallic stent as a bridge to surgery (60.5% had neoadjuvant treatment)  38  64.5 (34–81)  33 (86.8%)  Not stated  Philips et al. 42  Prospective  III  5  Patients with stage 2/3 junctional adenocarcinoma undergoing neoadjuvant therapy and who underwent stenting for symptoms of gastroesophageal reflux  40  62 (47–83)  32 (80%)  Not stated  Mão-de-Ferro et al43  Properspective  III  5  Nutritional status and dysphagia  11  64 (56–75)  10 (91%)  100%  Author and Year  Type of study  Evidence level  N-O Score (max = 9)  Outcomes assessed  n  Age  Male  Success rate  Siddiqui et al. 45  Retrospective  IV  5  Efficacy of treatment, stent-related complications and changes in nutritional status of the patient  6  62.5 (47–82)  4 (66.7%)  83%  Martin et al. 44  Retrospective  IV  5  Dysphagia score and outcome  5  63 (50–82)  3 (60%)  Not stated (only stented patients included)  Bower et al. 30  Retrospective  IV  5  Complications, dysphagia score, nutritional changes (albumin and body weight), progression to surgery  25  64 (48–82)  21 (84%)  Not stated (only stented patients included)  Adler et al. 32  Prospective  III  5  Dysphagia scores and patient weights  13  63.3 ± 12.3  13 (100%)  11 (85%) (2 (15%) initial placement was suboptimal and therefore replaced in same procedure)  Langer et al. 31  Prospective  III  5  Success of insertion, complications, change in dysphagia score, change in albumin  38  66 (30.3–88.2)  26  97.4  Lopes et al. 38  Retrospective  IV  5  Dysphagia scores, complications, tissue reaction, ease of removal  11  60.5  10 (90.9%)  90.9%  Brown et al. 33  Prospective  III  5  Esophageal cancer patients undergoing neoadjuvant therapy prior to resection  32  61 (39–82)  26 (81%)  100%  Pellen et al. 34  Retrospective  IV  6  Patients with esophageal cancer recommended for neoadjuvant treatment with endoscopically significant stenosis or dysphagia score of 3 or more  16  63 (53–76)  9 (56%)  100%  Siddiqui et al. 35  Retrospective  IV  5  Patients with locally advanced esophageal cancer  55  65.8 ± 11.1  43  100%  Krokidis et al. 36  Prospective  III  5  Patients undergoing neoadjuvant treatment or radical radiotherapy after stent insertion  11  64.9 ± 7.5  9  100%  Laquière et al. 37  Prospective  III  5  Patients undergoing neoadjuvant chemoradiotherapy for advanced esophageal cancer with grade 2 dysphagia or more  20  61.5 (43–82)  15 (75%)  100%  Martin et al. 39  Prospective  III  5  Esophageal cancer patients undergoing neoadjuvant treatment prior to esophagectomy  52  61 (39–82)  42 (81%)  Not stated  Van den Berg et al. 40  Prospective  III  4  Consecutive patients with esophageal cancer scheduled for neoadjuvant therapy and complaining of dysphagia (grade 2 or more)  10  68 ± 7.7  7 (70%)  100%  Mariette et al. 41  Retrospective  IV  5  Patients who had undergone esophagectomy with curative intent and had undergone insertion of self-expanding metallic stent as a bridge to surgery (60.5% had neoadjuvant treatment)  38  64.5 (34–81)  33 (86.8%)  Not stated  Philips et al. 42  Prospective  III  5  Patients with stage 2/3 junctional adenocarcinoma undergoing neoadjuvant therapy and who underwent stenting for symptoms of gastroesophageal reflux  40  62 (47–83)  32 (80%)  Not stated  Mão-de-Ferro et al43  Properspective  III  5  Nutritional status and dysphagia  11  64 (56–75)  10 (91%)  100%  View Large Table 2 Study outcomes of included studies evaluating the use of esophageal stenting during neoadjuvant treatment Author and Year  Mean weight change  Quality of life  Improvement in dysphagia score  Completion of neoadjuvant treatment  Number preceeding to surgery  Migration  Complications (n)  Post-operative mortality   Siddiqui et al.45  +6 kg  Not assessed  Yes  Not stated  6 (100%)  1 (20%)  0  Not stated  Martin et al.44  Not assessed  Not assessed  Yes  5 (100%)  Not stated  1 (20%)  0  Not stated  Bower et al.30  −1.5%  Not assessed  Yes  23 (92%)  14 (56%)  6 (24%)  Extra support required via nasoduodenal tube 2 (8%)  0 (postoperative)                Chest pain 1 (4%)    Adler et al.32  Not stated  Not assessed  Yes  Not stated  3 (23%)  6 (46%)  Chest pain 12 (92.3%)  Not stated                Requirement for PEG tube–2 (15%)    Langer et al.31  Not stated  Not assessed  Yes  20 (52.6%)  26 (68.4%)  12 (46%)  Erosion of aortic wall −1  1 (4%) (Post-operative mortality)                Small bowel perforation −1                  Esophago-tracheo-bronchial fistula −2                  Perforation at stent placement −1    Lopes et al.38  Not stated  Not assessed  Yes  10 (100%)  2 (20%)  2 (20%)  Chest pain −3 (30%)  Not stated                Tracheoesophageal fistula −1    Brown et al.33  −7.3 kg  Not assessed  Yes  Not stated  20  8 (25%)  Chest pain −2 (6.3%)  0 (peri-operative mortality)                Endoleak −1 (3.1%)    Pellen et al.34  −2.2 kg  Not assessed  Yes  Not stated  10 (62.5%)  7 (43.8%)  Food bolus obstruction −2 (12.5%)  1 (10%) (30-day mortality)                Small bowel obstruction −1 (6.3%)                  Tumor ingrowth −1 (6.3%)    Siddiqui et al.35  +1.8 kg  Not assessed  Yes  Not stated  8 (15%)  17 (31%)  Chest pain −8 (15%)  Not stated                Significant acid reflux −1 (2%)                  Odynophagia −1 (2%)                  Food impaction 1 (2%)                  Esophageal perforation 1(2%)    Krokidis et al.36  Not stated  Not assessed  Yes  Not stated  1 (9%)  1 (9%)  Aspiration and hematemesis −1 (9%)  Not stated            (3 (27% awaiting surgery))    Tracheobronchial aspiration and tracheoesophageal fistula −1 (9%)                  Aspiration pneumonia and fistula with the bronchial tree −1 (9%)                  Stent dysfunction from tumor growth −3 (27%)                  Stent dysfunction from inflammation −2 (18%)    Laquiere et al.37  Not stated  QLQ-ES18 scores revealed an improvement of both dysphagia and alimentary parameters following stent placement No difference in parameters for pain, swallowing disorders, anorexia and anosmia  Yes  100%  3 (20%)  3 (15%)  Chest pain −13 (65%)  Not stated                Perforation −1 (5%)                  Orotracheal fistula −1 (5%)                  Tumor overgrowth −2 (10%)    Martin et al.39  −3.2 kg  Statistically significant improvements in terms of dysphagia, eating restriction, and pain and discomfort  Yes  Chemotherapy −34 (93%)  Not stated  3 (5.8%)  Not stated  Not stated      No change in social quality of life    Radiotherapy −27 (75%)              Worsening of physical QOL during patients’ neoadjuvant therapy (not significant)                  Worsening of emotional quality of life at week 3 but returned to baseline by completion of treatment              Van den Berg et al.40  −5.4 kg (range 0.2 −11) (−6.5%)  Not assessed  Yes  9 (90%)  6 (60%)  Not stated  Chest pain −6 (60%)  Not stated                Stent obstruction from tumor in growth −1 (10%)    Mariette et al.41  Not assessed  Not assessed  Not stated  Not applicable  38 (100%) (This was part of inclusion criteria)  Not stated  Tumor perforation at insertion −2  5 (13.2%) (post-operative in-hospital mortality)  Phillips et al.42  Not assessed  Significantly improved and sustained swallowing quality of life from 2 weeks up to 10 weeks postinsertion. Reflux symptoms QOL was similar at 2 weeks but improved after this point.  Yes  95%  Not assessed  25 (62.5%)  Chest pain −5 (12.5%)  Not stated  Mão-de-Ferro et al.43  Not assessed  Not assessed  Yes  Not stated  4 (36%)  4 (36%)  Esophageal perforation −1 (9%)  Not stated                Requirement for nasogastric feeding - 3 (27%)    Author and Year  Mean weight change  Quality of life  Improvement in dysphagia score  Completion of neoadjuvant treatment  Number preceeding to surgery  Migration  Complications (n)  Post-operative mortality   Siddiqui et al.45  +6 kg  Not assessed  Yes  Not stated  6 (100%)  1 (20%)  0  Not stated  Martin et al.44  Not assessed  Not assessed  Yes  5 (100%)  Not stated  1 (20%)  0  Not stated  Bower et al.30  −1.5%  Not assessed  Yes  23 (92%)  14 (56%)  6 (24%)  Extra support required via nasoduodenal tube 2 (8%)  0 (postoperative)                Chest pain 1 (4%)    Adler et al.32  Not stated  Not assessed  Yes  Not stated  3 (23%)  6 (46%)  Chest pain 12 (92.3%)  Not stated                Requirement for PEG tube–2 (15%)    Langer et al.31  Not stated  Not assessed  Yes  20 (52.6%)  26 (68.4%)  12 (46%)  Erosion of aortic wall −1  1 (4%) (Post-operative mortality)                Small bowel perforation −1                  Esophago-tracheo-bronchial fistula −2                  Perforation at stent placement −1    Lopes et al.38  Not stated  Not assessed  Yes  10 (100%)  2 (20%)  2 (20%)  Chest pain −3 (30%)  Not stated                Tracheoesophageal fistula −1    Brown et al.33  −7.3 kg  Not assessed  Yes  Not stated  20  8 (25%)  Chest pain −2 (6.3%)  0 (peri-operative mortality)                Endoleak −1 (3.1%)    Pellen et al.34  −2.2 kg  Not assessed  Yes  Not stated  10 (62.5%)  7 (43.8%)  Food bolus obstruction −2 (12.5%)  1 (10%) (30-day mortality)                Small bowel obstruction −1 (6.3%)                  Tumor ingrowth −1 (6.3%)    Siddiqui et al.35  +1.8 kg  Not assessed  Yes  Not stated  8 (15%)  17 (31%)  Chest pain −8 (15%)  Not stated                Significant acid reflux −1 (2%)                  Odynophagia −1 (2%)                  Food impaction 1 (2%)                  Esophageal perforation 1(2%)    Krokidis et al.36  Not stated  Not assessed  Yes  Not stated  1 (9%)  1 (9%)  Aspiration and hematemesis −1 (9%)  Not stated            (3 (27% awaiting surgery))    Tracheobronchial aspiration and tracheoesophageal fistula −1 (9%)                  Aspiration pneumonia and fistula with the bronchial tree −1 (9%)                  Stent dysfunction from tumor growth −3 (27%)                  Stent dysfunction from inflammation −2 (18%)    Laquiere et al.37  Not stated  QLQ-ES18 scores revealed an improvement of both dysphagia and alimentary parameters following stent placement No difference in parameters for pain, swallowing disorders, anorexia and anosmia  Yes  100%  3 (20%)  3 (15%)  Chest pain −13 (65%)  Not stated                Perforation −1 (5%)                  Orotracheal fistula −1 (5%)                  Tumor overgrowth −2 (10%)    Martin et al.39  −3.2 kg  Statistically significant improvements in terms of dysphagia, eating restriction, and pain and discomfort  Yes  Chemotherapy −34 (93%)  Not stated  3 (5.8%)  Not stated  Not stated      No change in social quality of life    Radiotherapy −27 (75%)              Worsening of physical QOL during patients’ neoadjuvant therapy (not significant)                  Worsening of emotional quality of life at week 3 but returned to baseline by completion of treatment              Van den Berg et al.40  −5.4 kg (range 0.2 −11) (−6.5%)  Not assessed  Yes  9 (90%)  6 (60%)  Not stated  Chest pain −6 (60%)  Not stated                Stent obstruction from tumor in growth −1 (10%)    Mariette et al.41  Not assessed  Not assessed  Not stated  Not applicable  38 (100%) (This was part of inclusion criteria)  Not stated  Tumor perforation at insertion −2  5 (13.2%) (post-operative in-hospital mortality)  Phillips et al.42  Not assessed  Significantly improved and sustained swallowing quality of life from 2 weeks up to 10 weeks postinsertion. Reflux symptoms QOL was similar at 2 weeks but improved after this point.  Yes  95%  Not assessed  25 (62.5%)  Chest pain −5 (12.5%)  Not stated  Mão-de-Ferro et al.43  Not assessed  Not assessed  Yes  Not stated  4 (36%)  4 (36%)  Esophageal perforation −1 (9%)  Not stated                Requirement for nasogastric feeding - 3 (27%)    View Large Three studies reported health-related QOL. All three of these used European Organisation for Research and Treatment of Cancer (EORTC)54 questionnaires including QLQ-C30, QLQ-OG25, and QLQ-ES18. In addition two studies used the Functional Assessment of Cancer Therapy (FACT)55 questionnaires including FACT-General, FACT-Esophageal, and FACT-Anorexia. All three of these studies demonstrated improvement in some of the measured symptom specific QOL metrics including dysphagia, eating restriction, and quality of oral feeding. Health-related QOL outcomes from these studies are summarized in Table 2. One study reported a reduction in physical QOL but the neoadjuvant therapy is a confounder to these assessments. Feeding jejunostomy Four studies25,46–48 reported an evaluation of laparoscopically inserted feeding jejunostomy in 236 patients. All were retrospective reviews of patients who underwent laparoscopic feeding jejunostomy insertion at staging laparoscopy prior to neoadjuvant therapy. The study characteristics are described in Table 3 and outcomes in Table 4. No studies reported 30-day postprocedural mortality. Three studies reported change in patient weights with all demonstrating an increase in weight ranging from 0.4 to 11.8 kg. One study reported completion of neoadjuvant therapy in greater than 90% of patients. All studies reported complications including tube blockage (n = 11 (4.6%)), dislodgement (n = 9 (3.8%)), wound infection (n = 7 (3%)), leakage (n = 5 (2.1%)), diarrhea (n = 3 (1.3%)), connector breakage (n = 2 (0.8%)), and kinked tube (n = 1 (0.4%)). 30-day postoperative mortality after esophagectomy and health-related QOL was not reported in any study. Table 3 Study characteristics of included studies evaluating feeding jejunostomy during neoadjuvant treatment Author and Year  Type of study  Evidence Level  N-O Score (max = 9)  n  Age  Male  Grondona et al. 47  Retrospective  IV  3  18  63 (53–73)  11  Jenkinson et al. 25  Retrospective  IV  3  43  66 (42–82)  30  Ben-David et al. 46  Retrospective  IV  5  153  63  115  Tsujimoto et al. 48  Retrospective  IV  5  22 (9 patients with esophageal cancer undergoing neoadjuvant therapy)  69.4 ± 6.0 (range 48–79)  22  Author and Year  Type of study  Evidence Level  N-O Score (max = 9)  n  Age  Male  Grondona et al. 47  Retrospective  IV  3  18  63 (53–73)  11  Jenkinson et al. 25  Retrospective  IV  3  43  66 (42–82)  30  Ben-David et al. 46  Retrospective  IV  5  153  63  115  Tsujimoto et al. 48  Retrospective  IV  5  22 (9 patients with esophageal cancer undergoing neoadjuvant therapy)  69.4 ± 6.0 (range 48–79)  22  View Large Table 4 Study outcomes of included studies evaluating feeding jejunostomy during neoadjuvant treatment Author and Year  Mean weight loss  Number of patients who required jejunostomy feeding  Median duration of feeding through jejunostomy  Completion of neoadjuvant treatment  Number preceeding to surgery  Complications (n)  Mortality  Grondona et al.47  Not assessed  14  30 days  Not stated  5  Leakage and wound infection −1  Not stated              Wound infection −1                Kinked tube requiring removal −1                Accidental displacement −1    Jenkinson et al.25  +1.1 kg  20  Not stated  Not stated  100% (inclusion criteria)  Dislodgement −6 (20%)  Not stated              Blockage −4 (13%)                Connector breakage −2 (7%)    Ben-David et al.46  +11.8 kg  All  Approximately a 10-week course of supplementary nutrition  >90%   86%  Dislodgement −2  Mortality rate in patients having laparoscopic jejunostomy and esophagectomy was 1%              Leak −4                Clogging −5                Superficial wound infection −4    Tsujimoto et al.48  +0.4 kg  Not stated  Not stated  Not stated  9 (100%)  Diarrhoea −3 (13.6%)  Not stated              Tube obstruction −2 (9%)    Author and Year  Mean weight loss  Number of patients who required jejunostomy feeding  Median duration of feeding through jejunostomy  Completion of neoadjuvant treatment  Number preceeding to surgery  Complications (n)  Mortality  Grondona et al.47  Not assessed  14  30 days  Not stated  5  Leakage and wound infection −1  Not stated              Wound infection −1                Kinked tube requiring removal −1                Accidental displacement −1    Jenkinson et al.25  +1.1 kg  20  Not stated  Not stated  100% (inclusion criteria)  Dislodgement −6 (20%)  Not stated              Blockage −4 (13%)                Connector breakage −2 (7%)    Ben-David et al.46  +11.8 kg  All  Approximately a 10-week course of supplementary nutrition  >90%   86%  Dislodgement −2  Mortality rate in patients having laparoscopic jejunostomy and esophagectomy was 1%              Leak −4                Clogging −5                Superficial wound infection −4    Tsujimoto et al.48  +0.4 kg  Not stated  Not stated  Not stated  9 (100%)  Diarrhoea −3 (13.6%)  Not stated              Tube obstruction −2 (9%)    View Large Gastrostomy Three studies26,49,50 evaluated the use percutaneous gastrostomy (two percutaneous endoscopic gastrostomy and one percutaneous radiological gastrostomy). All were retrospective reviews of single center experiences. The study characteristics are described in Table 5 and outcomes in Table 6. Only one study discussed the contra-indications to gastrostomy placement of portal hypertension, coagulopathy, and abundant ascites. All studies highlighted concerns including the risks of traversing esophageal tumors, rendering the stomach unsuitable for gastric conduit, tumor seeding at the site of gastrostomy and injury to the right gastroepiploic artery. Two studies reported success rates of gastrostomy insertion of 87%–96.3%. Gastrostomy related complications occurred in ranging from 3.4% to 4% including failure, suppurative wound infection, protracted ileus, persistent gastric leakage, hemoperitoneum, peritonitis, small bowel obstruction, abdominal pain, fever, failure and accidental dislodgement. One study reported minor complications in 12%, most frequently cellulitis requiring antibiotics. Two studies reported mean weight loss through neoadjuvant therapy, with one reporting a significant improvement in mean weight loss before and after neoadjuvant therapy (14.3% ± 6.9 and 10.7% ± 7.8, respectively P = 0.011) and the other reporting a gradual decline in weight loss during chemoradiation with a mean weight loss of patients undergoing surgery of 3.8% (range: 0%–9%). Completion rates of neoadjuvant treatment ranged from 70% to 95%. Table 5 Study characteristics of included studies evaluating gastrostomy during neoadjuvant treatment Author and Year  Type of study  Evidence Level  N-O Score (max = 9)  n  Age  Male  Guidance  Success rate  Margolis et al. 49  Retrospective  IV  5  179  61.4 (38–81)    Endoscopic  103/119 (87%)  Tessier et al.26  Retrospective  IV  5  269 (139 of whom were pre-operative and 130 were having CRT treatment alone)  60.5  6.3:1  Radiological  259 (96.3%)  Wright et al.50  Retrospective  IV  3  15  58  73%  Endoscopic  Not stated  Author and Year  Type of study  Evidence Level  N-O Score (max = 9)  n  Age  Male  Guidance  Success rate  Margolis et al. 49  Retrospective  IV  5  179  61.4 (38–81)    Endoscopic  103/119 (87%)  Tessier et al.26  Retrospective  IV  5  269 (139 of whom were pre-operative and 130 were having CRT treatment alone)  60.5  6.3:1  Radiological  259 (96.3%)  Wright et al.50  Retrospective  IV  3  15  58  73%  Endoscopic  Not stated  View Large Table 6 Study outcomes of included studies evaluating gastrostomy during neoadjuvant treatment Author and Year  Mean weight loss  Median duration of feeding through gastrostomy  Completion of neoadjuvant treatment  Number preceding to surgery  Removal rate  Complications (n)  Mortality  Margolis et al.49  3.8% (0–9)  15 weeks (3 days to 10 months)  71 (70%)  61  4 (4%)  Major 4 (4%)  13.5% (30 day mortality, 0% PEG related)              Suppurative wound infections –2                Protracted Ileus −1                Persistent leakage −1                Minor 12 (12%)    Tessier et al.26  10.7% ± 7.8  14.5 weeks (1–53)  93.7% in CRT group and 95% on chemotherapy group  83  5 (1.9%)  9 (3.4%)  0% (procedure related mortality)              Hemoperitoneum–1                Peritonitis −2                Small bowel obstruction −1                Abdominal pain and fever (normal laparoscopy) −1                Failure requiring laparotomy and surgical jejunostomy −1                Accidental dislodgement −1    Wright et al.50  Not stated  Not stated  Not stated  15 (100%) (was part of study inclusion criteria)  Not stated  Not stated  7% (90 day mortality)  Author and Year  Mean weight loss  Median duration of feeding through gastrostomy  Completion of neoadjuvant treatment  Number preceding to surgery  Removal rate  Complications (n)  Mortality  Margolis et al.49  3.8% (0–9)  15 weeks (3 days to 10 months)  71 (70%)  61  4 (4%)  Major 4 (4%)  13.5% (30 day mortality, 0% PEG related)              Suppurative wound infections –2                Protracted Ileus −1                Persistent leakage −1                Minor 12 (12%)    Tessier et al.26  10.7% ± 7.8  14.5 weeks (1–53)  93.7% in CRT group and 95% on chemotherapy group  83  5 (1.9%)  9 (3.4%)  0% (procedure related mortality)              Hemoperitoneum–1                Peritonitis −2                Small bowel obstruction −1                Abdominal pain and fever (normal laparoscopy) −1                Failure requiring laparotomy and surgical jejunostomy −1                Accidental dislodgement −1    Wright et al.50  Not stated  Not stated  Not stated  15 (100%) (was part of study inclusion criteria)  Not stated  Not stated  7% (90 day mortality)  View Large No study reported 30-day mortality after esophagectomy. One study49 reported a 30-day postgastrostomy mortality of 13.5% (none being gastrostomy related); one study26 reported 60-day postgastrostomy mortality of 0%; and the third study50 reported a 90-day postesophagectomy mortality of 3%. All included studies described the suture closing of gastrostomy site at the time of esophagectomy and in all cases where gastric conduit formation was planned the stomach provided a suitable esophageal substitute. Two studies reported a nonsignificant increase in operative time in the gastrostomy group (16–43 minute increase). None of the included studies assessed health-related QOL. Nasogastric feeding tubes One retrospective study of 16 patients evaluated the use of nasogastric feeding tubes (Dobhoff tubes) during neoadjuvant therapy.51 Four patients required at least one intervention to replace or unblock the tubing, while a further four patients required more than one intervention, two of whom required percutaneous endoscopic gastrostomy. Comparative studies One study compared the efficacy of self-expanding esophageal stenting (SES) (n = 12) versus feeding jejunostomy (n = 24) during neoadjuvant therapy.52 Success rates for SES placement and jejunostomy tube were 83.3 and 100%, respectively. In the SES group, eight (72%) experienced postprocedural chest pain and four stent migration (36%). All patients with successful stent deployment had immediate and sustained improvement in dysphagia score and these was used as a surrogate for QOL. In the feeding jejunostomy group, two wound infection requiring antibiotics and one minor leak were reported. Both cohorts gained weight during neoadjuvant treatment (SES mean weight increase from 60.5 to 65 kg, p < 0.001 versus feeding jejunostomy mean weight gain 72.2 to 76 kg, P ≤ 0.05). Thirty-day postesophagectomy and 30-day postprocedural mortality were not reported. DISCUSSION Published evidence suggests that the optimal treatment for resectable advanced locoregional esophageal cancer is neoadjuvant therapy followed by esophagectomy.1–6 The CROSS trial demonstrated improved locoregional control and distant metastases-free survival with neoadjuvant chemoradiotherapy and surgery versus surgery alone.2,56 In addition, a recent network meta-analysis has provided evidence of a survival advantage of neoadjuvant chemoradiotherapy compared to neoadjuvant chemotherapy, adjuvant chemotherapy, adjuvant chemoradiotherapy, or surgery alone.57 Neoadjuvant chemoradiotherapy or neoadjuvant chemotherapy is the accepted standard of care in the USA and UK, respectively.3 With increasing use of neoadjuvant chemoradiotherapy protocols for nutritional optimization during neoadjuvant therapy should be prioritized to enable completion of prescribed treatment cycles, improve treatment response rates, and reduce treatment-related toxicity. Importantly, optimizing nutritional status during neoadjuvant treatment has a causal link to improved surgical outcome.8,18–22 However, the uncertainty regarding the optimal nutritional approach has led to regional variability in nutritional strategies in patients with locoregional disease receiving neoadjuvant therapy. This systematic review clearly demonstrates the paucity of evidence to define the optimal nutritional approach. The evidence is limited to case series with few prospective, multicenter or comparative studies. No randomized controlled trials or cost-effectiveness studies were identified. Evaluation is mostly limited to studies that are insufficiently powered to report objective nutritional outcomes, QOL, and mortality. Study outcomes relied on weight change with no additional measures of nutritional status such as grip strength. Furthermore, the primary endpoint of 30-day postoperative mortality was particularly poorly reported in the included studies. Therefore, based on the limited poor quality data available, this systematic review cannot clearly identify the optimal strategy to improve nutrition in this patient cohort. Esophageal stenting was the most frequently reported intervention in 15 studies. The majority used improvement in dysphagia as the primary outcome measure with all studies demonstrating improvement without a corresponding consistent improvement in nutritional parameters including weight. The reported complication rate was low but included life-threatening aortic erosion and tracheoesophageal fistula and variable stent migration rates of 9%–65%30–39,42,44,45 while the proportion of patients proceeding to esophagectomy ranged from 15%–100%. Although some centers have published good outcomes following esophageal stenting as a bridge to esophagectomy30,42,45 a recent systematic review58 concluded that stent insertion before neoadjuvant therapy could not be supported given the lack of evidence to demonstrate a consistent benefit to weight or nutritional markers, the required extra interventions due to pain or migration, variation in the numbers of patients proceeding to surgery and life-threatening complications. Feeding jejunostomy insertion at esophagectomy is a common practice in many centers. Earlier insertion at the time of staging laparoscopy is increasingly performed in patients with significant dysphagia and malnutrition. In three of the four studies reporting feeding jejunostomy use rates of progression to surgery were high at >85% although only one study reported weight gain. Reported complication rates are comparable to esophageal stenting and less severe although the Clavien–Dindo scoring59 was not documented in the majority. One study investigating gastrostomy reportedly had a post gastrostomy 30-day mortality of 13.5%. This is exceeding high and not consistent with the other included studies, no reason for this high figure was provided. Huerter et al. report their experience of 127 patients undergoing neoadjuvant treatment for esophageal cancer,60 of whom 61 (48%) received enteral feeding access following nutritional assessment. This included 49 patients who underwent laparoscopic feeding jejunostomy and the remaining 12 patients having percutaneous endoscopic gastrostomy. Their results demonstrated a 36% incidence of adverse events for tube placement including bleeding, infection, dislodgement, and tube site problems. While multivariate regression did demonstrate that enteral access was associated with nutritional stability during neoadjuvant therapy, all patients proceeded to esophagectomy with outcomes similar between the enteral access and no enteral access groups. However, this study is retrospective and it is therefore not known if those patients who had supplementary feeding would have been able to complete their neoadjuvant therapy and proceed to surgery without it. This study was not included in the analysis as it was not possible to separate the patients who had jejunostomy or PEG placement. Also 27.9% of patients who had enteral access tubes placed did not use it consistently or at all during their neoadjuvant treatment. A recent review61 of 299 consecutive laparoscopic feeding jejunostomies reported low complication rates and a 30-day mortality of 4% in keeping with the findings of this current review. QOL was reported poorly. Only three studies, all evaluating esophageal stenting, reported QOL. These demonstrated improvement in some of the scores measured but in the main these were symptom specific rather than global QOL evaluations. The physical, psychological, and emotional consequences for patients of living with different nutritional interventions and associated feeding regimes are unknown. Validated esophageal cancer-specific QOL questionnaires do allow the differentiation of specific symptoms including dysphagia, eating restrictions, pain, and discomfort. Studies are required to investigate the impact of the differing nutritional approaches on patient-reported outcome measures including QOL in addition to clinical outcomes. This narrative review has limitations. The primary outcome of 30-day postoperative mortality was poorly reported and therefore the optimal nutritional strategy to improve survival could not be determined. 30-day postoperative mortality was selected as the primary outcome in keeping with the recommendation of the Esophagectomy Complications Consensus Group who agreed that 30-day mortality should be recorded as a quality and outcome measure following esophagectomy.62 We recognize that the review is heavily weighted by studies of stent placement (16/26 studies with 383 patients). Eleven of these studies evaluated dysphagia scores as a primary outcome and we acknowledge that dysphagia does necessarily equate to malnutrition. We have not presented health economic data as evaluation of the cost effectiveness of stent placement and reintervention was not the remit of this systematic review. Data on unplanned hospital admissions and emergency department visits for dehydration and/or complications for the nutritional approaches were lacking. These limitations further support the need for a prospective, well designed, multicenter, randomized controlled trial to compare the effectiveness of the current approaches for nutritional optimization in patients undergoing neoadjuvant chemotherapy prior to esophagectomy, and their impact on survival and health-related QOL benefits. This review highlights the lack of an accepted standard of care or level 1 evidence to guide management plan in determining the optimal nutritional approach in patients with resectable locoregional esophageal cancer undergoing neoadjuvant therapy. Prior to designing and undertaking such a trial a prospective, multicenter, observational cohort study will be needed to determine the number of patients who may be potentailly eligible and to collect evidence of current multidisciplinary team treatment decision making for this group of patients. Notes Funding source: Sheraz R. Markar is supported by the National Institute of Health Research. Conflict of interest: Fiona M. S. Huddy has previously received a one off honorarium from Lilly for presentation at an advisory board. The authors have no other conflicts of interest. Specific author contributions: Jeremy R. Huddy participated in the literature search, data collection, analysis and interpretation of findings. Fiona M. S. Huddy participated in the analysis and interpretation of findings. Sheraz R. Markar participated in the study design, literature search, data collection, analysis, and interpretation of findings. 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Ann Thorac Surg  2003; 76( 5): 1694-7-8. 50 Wright G P, Foster S M, Chung M H. Esophagectomy in patients with prior percutaneous endoscopic gastrostomy tube placement. Am J Surg  2014; 207( 3): 361-5-5. 51 Starr B, Davis S, Ayala-Peacock D, Blackstock W A, Levine E A. Reassessment of the role of enteral tube feedings for patients with esophageal cancer. Am Surg  2014; 80: 752– 8. Google Scholar PubMed  52 Siddiqui A A, Glynn C, Loren D, Kowalski T. Self-expanding plastic esophageal stents versus jejunostomy tubes for the maintenance of nutrition during neoadjuvant chemoradiation therapy in patients with esophageal cancer: a retrospective study. Dis Esophagus  2009; 22: 216– 22. Google Scholar CrossRef Search ADS PubMed  53 Ogilvie A L, Dronfield M W, Ferguson R, Atkinson M. Palliative intubation of oesophagogastric neoplasms at fibreoptic endoscopy. Gut  1982; 23( 12): 1060– 7. Google Scholar CrossRef Search ADS PubMed  54 EORTC. [cited 1 Feb 2017]. Available from: http://groups.eortc.be/qol/. 55 FACIT.org Home. [cited 10 Apr 2017]. Available from: http://www.facit.org/FACITOrg. 56 MAGIC vs. CROSS Upper GI. ICORG 10–14, V3 - Full Text View - ClinicalTrials.gov . Available from: https://clinicaltrials.gov/ct2/show/study/NCT01726452#contacts. 57 Pasquali S, Yim G, Vohra R S et al.   Survival after neoadjuvant and adjuvant treatments compared to surgery alone for resectable esophageal carcinoma: a network meta-analysis. Ann Surg  2016; Available from: http://www.ncbi.nlm.nih.gov/pubmed/27429017. 58 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  59 Dindo D, Demartines N, Clavien P A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg  2004; 240( 2): 205– 13. Google Scholar CrossRef Search ADS PubMed  60 Huerter M E, Charles E J, Downs E A et al.   Enteral access is not required for esophageal cancer patients undergoing neoadjuvant therapy. Ann Thorac Surg  2016; 102: 948– 54. Google Scholar CrossRef Search ADS   61 Young M T, Troung H, Gebhart A, Shih A, Nguyen N T. Outcomes of laparoscopic feeding jejunostomy tube placement in 299 patients. Surg Endosc  2016; 30( 1): 126– 31. Google Scholar CrossRef Search ADS PubMed  62 Low D E, Alderson D, Cecconello I et al.   International consensus on standardization of data collection for complications associated with esophagectomy. Ann Surg  2015; 262( 2): 286– 94. Google Scholar CrossRef Search ADS PubMed  © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Nutritional optimization during neoadjuvant therapy prior to surgical resection of esophageal cancer—a narrative review

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The International Society for Diseases of the Esophagus
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© The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
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1120-8694
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1442-2050
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10.1093/dote/dox110
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Abstract

Summary This narrative review aims to evaluate the evidence for the different nutritional approaches employed during neoadjuvant therapy in patients with locoregional esophageal cancer. Patients with esophageal cancer are often malnourished and difficult to optimize nutritionally. While evidence suggests that neoadjuvant therapy can offer a survival advantage, associated toxicity can exacerbate poor nutritional status. There is currently no accepted standard of care regarding optimal nutritional approach. A systematic literature search was undertaken. Studies describing the utilization of an additional nutritional intervention in patients with esophageal cancer receiving neoadjuvant therapy prior to esophagectomy were included. Primary outcome measure was 30-day postoperative mortality after esophagectomy. Secondary outcome measures were loss of weight during neoadjuvant therapy, completion rate of intended neoadjuvant therapy, complications from nutritional intervention, 30-day postoperative morbidity after esophagectomy and quality of life during neoadjuvant treatment. Given the heterogeneity of retrieved articles results was presented as a narrative review. Twenty-five studies were included of which 16 evaluated esophageal stenting, four feeding jejunostomy, three gastrostomy, one nasogastric feeding, and one comparative study of esophageal stenting to feeding jejunostomy. 30-day postoperative mortality was only reported in two of the 26 included studies limiting comparison between nutritional strategies. All studies of esophageal stents reported improvements in dysphagia with reported weight change ranging from −5.4 to +6 kg and one study reported 30-day postoperative mortality after esophagectomy (10%). In patients undergoing esophageal stenting for their neoadjuvant treatment overall migration rate was 29.9%. Studies of laparoscopically inserted jejunostomy were all retrospective reviews that demonstrated an increase in weight ranging from 0.4 to 11.8 kg and similarly no study reported 30-day postoperative mortality. Only one comparative study was included that compared esophageal stents to jejunostomy. This study reported no significant difference between the two groups in respect to complication rates (stents 22% vs. jejunostomy 4%, P = 0.11) or increase in weight (stents 4.4 kg vs. jejunostomy 4.2 kg, P = 0.59). Quality of life was also poorly reported. This review demonstrates the uncertainty on the optimal nutritional approach for patients with resectable esophageal cancer undergoing neoadjuvant treatment prior to esophagectomy. A prospective, multicenter, observational cohort study is needed to determine current practice and inform a prospective clinical trial. INTRODUCTION Patients with esophageal cancer have complex nutritional needs. At the time of diagnosis, most are malnourished due to local tumor effects with dysphagia, anorexia, and cancer cachexia in addition to psychological factors that negatively influence adequate dietary intake. Meta-analyses and randomized controlled trials have demonstrated improved survival benefit of neoadjuvant therapy prior to esophagectomy compared to surgery alone for patients with locoregional esophageal cancer.1–6 Treatment toxicities during neoadjuvant therapy contribute to further weight loss and nutritional deficiencies.7 Malnutrition during neoadjuvant therapy is associated with negative outcomes including poor tumor response, poor treatment tolerance, increased neoadjuvant treatment related morbidity, and reduced of life (QOL).8,9 Early identification of malnutrition and appropriate nutritional support leads to improved nutritional status and QOL.10–17 Furthermore, malnutrition is associated with adverse postoperative outcomes including immune suppression, increased infection rate, increased morbidity including pulmonary complications, delayed wound healing, muscle wasting, prolonged in-hospital stay, and increased healthcare costs.8,18–22 During medical anticancer treatment, The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommend, ‘enteral or, if this is not sufficient or possible, parenteral nutrition If oral food intake is inadequate despite counselling and oral nutritional supplements.’11,23 Further guidelines by Allum et al. recommend preoperative nutritional support for 10–14 days for malnourished patients with esophageal and gastric cancer,24 and patients with severe nutritional risk for 10–14 days prior to any major surgery.11 Specialist esophagogastric dietitians are ideally placed to assess and manage the complex nutritional problems encountered in this patient group. Within the UK, there is a requirement for a specialist dietitian to be a core member of the cancer tumor board. Several approaches have been employed to optimize nutrition prior to and during neoadjuvant therapy including esophageal stenting, feeding jejunostomy or gastrostomy, and nasogastric or nasojejunal feeding.25–27 However, there is no accepted standard of care or level 1 evidence to guide the optimal nutritional approach. Treatment decisions differ according to regional practice, physician, and patient preference. The aim of this review article is to evaluate the evidence in support of these different nutritional approaches during neoadjuvant therapy for esophageal cancer. MATERIALS AND METHODS A systematic electronic literature search was undertaken using Embase, Medline, Web of Science, and Cochrane library databases up to December 2016. The search terms: ‘esophagectomy’, ‘esophageal cancer’, ‘neoadjuvant therapy’, ‘nutrition’, ‘malnutrition’, ‘jejunostomy’, ‘gastrostomy’, ‘esophageal stent’, ‘nasoenteric feeding’ and the Medical Subject Headings (MeSH), ‘esophageal neoplasms’, ‘esophagectomy’, ‘neoadjuvant therapy’, ‘nutritional status’, ‘malnutrition’, ‘jejunostomy’, ‘gastrostomy’, ‘stents’, and ‘enteral nutrition’ were used in combination with the Boolean operators AND or OR. The electronic search was supplemented by a hand search of published abstracts from meetings of the Society of Academic and Research Surgery, Digestive Disease Week, the Association of Upper Gastro-Intestinal Surgeons of Great Britain and Ireland, and the American Society of Clinical Oncology 2005 to 2015. The reference lists of articles obtained were also searched to identify further relevant citations; as was the Current Controlled Trials Register (http://www.controlled-trials.com). The quality of evidence provided by each study was evaluated using the Oxford levels of evidence-based medicine scoring system28 and the Newcastle–Ottawa Score.29 Publications were included if they met the following criteria: Studies where the primary research population included patients with locoregional esophageal cancer receiving neoadjuvant therapy prior to curatively intended esophagectomy. Studies that included nutritional assessment before commencing neoadjuvant therapy. Studies that evaluated the utilization of an additional nutritional strategy, including feeding jejunostomy, gastrostomy, esophageal stenting, and nasoenteric feeding during neoadjuvant therapy. Publications were excluded if they met any of the following criteria: Studies not concerning the management of esophageal cancer. Studies in which the pretreatment nutritional status of patients was not assessed or poorly defined. Review articles Outcome measures for this review The primary outcome measure was 30-day postoperative mortality. Secondary outcome measures were loss of weight during neoadjuvant therapy, completion rate of intended neoadjuvant therapy, nutritional intervention-related complications including mortality, 30-day postoperative morbidity, and health-related QOL (assessed by European Organisation for Research and Treatment of Cancer questionnaires prior to and postnutritional intervention). RESULTS The search strategy used yielded a total of 3489 articles. Following the removal of duplications, all articles were subsequently selected on title, abstract and full text based on the inclusion and exclusion criteria. Twenty-five studies were selected for inclusion (Fig. 1). Of these, 16 original articles evaluated the use of esophageal stenting,30–45 four25,46–48 feeding jejunostomy, three26,49,50 gastrostomy, and one nasogastric feeding.51 One article52 directly compared esophageal stenting to feeding jejunostomy. Fig. 1 View largeDownload slide PRISMA flow diagram of literature search. Fig. 1 View largeDownload slide PRISMA flow diagram of literature search. Esophageal stenting Sixteen articles30–45 evaluated the use of esophageal stenting and included 383 patients. There were nine prospective studies and seven retrospective studies. The study characteristics are described in Table 1 and outcomes in Table 2. All studies recruited patients with grade 2 dysphagia or more (able to swallow only semisolid foods).53 Fifteen studies reported improvement in dysphagia scores. Eleven studies reported technical success rate ranging from 83–100%, with the seven most recent studies all reporting 100% success rates. Postoperative mortality was reported in five studies30,31,33,34,41 and ranged from 4% to13.2%, while only one of these studies specified 30-day postoperative mortality (10%). Seven studies reported weight change, of which six reported weight loss, ranging from −5.4 to +6 kg. Completion of neoadjuvant therapy was reported in eight studies and ranged from 52.6% to 100%. Fourteen studies reported migration rates and included 321 patients with an overall incidence of migration seen in 96 patients (29.9%). Other complications were reported in 15 studies of 331 patients of chest pain (n = 50 (15.6%)), tumor ingrowth (n = 7 (2.2%)), esophagobronchial or tracheal fistula (n = 6 (1.9%)), esophageal perforation (n = 5 (1.5%)), requirement for extra support (n = 7 (2.2%)), food bolus obstruction (n = 2 (0.6%)), stent dysfunction secondary to inflammation (n = 2 (0.6%)), erosion of aortic wall (n = 1 (0.3%)), small bowel perforation (n = 1 (0.3%)), endoleak (n = 1 (0.3%)), small bowel obstruction (n = 1 (0.3%)), significant acid reflux (n = 1 (0.3%)), and hematemesis (n = 1 (0.3%)). Table 1 Study characteristics of included studies evaluating the use of esophageal stenting during neoadjuvant treatment Author and Year  Type of study  Evidence level  N-O Score (max = 9)  Outcomes assessed  n  Age  Male  Success rate  Siddiqui et al. 45  Retrospective  IV  5  Efficacy of treatment, stent-related complications and changes in nutritional status of the patient  6  62.5 (47–82)  4 (66.7%)  83%  Martin et al. 44  Retrospective  IV  5  Dysphagia score and outcome  5  63 (50–82)  3 (60%)  Not stated (only stented patients included)  Bower et al. 30  Retrospective  IV  5  Complications, dysphagia score, nutritional changes (albumin and body weight), progression to surgery  25  64 (48–82)  21 (84%)  Not stated (only stented patients included)  Adler et al. 32  Prospective  III  5  Dysphagia scores and patient weights  13  63.3 ± 12.3  13 (100%)  11 (85%) (2 (15%) initial placement was suboptimal and therefore replaced in same procedure)  Langer et al. 31  Prospective  III  5  Success of insertion, complications, change in dysphagia score, change in albumin  38  66 (30.3–88.2)  26  97.4  Lopes et al. 38  Retrospective  IV  5  Dysphagia scores, complications, tissue reaction, ease of removal  11  60.5  10 (90.9%)  90.9%  Brown et al. 33  Prospective  III  5  Esophageal cancer patients undergoing neoadjuvant therapy prior to resection  32  61 (39–82)  26 (81%)  100%  Pellen et al. 34  Retrospective  IV  6  Patients with esophageal cancer recommended for neoadjuvant treatment with endoscopically significant stenosis or dysphagia score of 3 or more  16  63 (53–76)  9 (56%)  100%  Siddiqui et al. 35  Retrospective  IV  5  Patients with locally advanced esophageal cancer  55  65.8 ± 11.1  43  100%  Krokidis et al. 36  Prospective  III  5  Patients undergoing neoadjuvant treatment or radical radiotherapy after stent insertion  11  64.9 ± 7.5  9  100%  Laquière et al. 37  Prospective  III  5  Patients undergoing neoadjuvant chemoradiotherapy for advanced esophageal cancer with grade 2 dysphagia or more  20  61.5 (43–82)  15 (75%)  100%  Martin et al. 39  Prospective  III  5  Esophageal cancer patients undergoing neoadjuvant treatment prior to esophagectomy  52  61 (39–82)  42 (81%)  Not stated  Van den Berg et al. 40  Prospective  III  4  Consecutive patients with esophageal cancer scheduled for neoadjuvant therapy and complaining of dysphagia (grade 2 or more)  10  68 ± 7.7  7 (70%)  100%  Mariette et al. 41  Retrospective  IV  5  Patients who had undergone esophagectomy with curative intent and had undergone insertion of self-expanding metallic stent as a bridge to surgery (60.5% had neoadjuvant treatment)  38  64.5 (34–81)  33 (86.8%)  Not stated  Philips et al. 42  Prospective  III  5  Patients with stage 2/3 junctional adenocarcinoma undergoing neoadjuvant therapy and who underwent stenting for symptoms of gastroesophageal reflux  40  62 (47–83)  32 (80%)  Not stated  Mão-de-Ferro et al43  Properspective  III  5  Nutritional status and dysphagia  11  64 (56–75)  10 (91%)  100%  Author and Year  Type of study  Evidence level  N-O Score (max = 9)  Outcomes assessed  n  Age  Male  Success rate  Siddiqui et al. 45  Retrospective  IV  5  Efficacy of treatment, stent-related complications and changes in nutritional status of the patient  6  62.5 (47–82)  4 (66.7%)  83%  Martin et al. 44  Retrospective  IV  5  Dysphagia score and outcome  5  63 (50–82)  3 (60%)  Not stated (only stented patients included)  Bower et al. 30  Retrospective  IV  5  Complications, dysphagia score, nutritional changes (albumin and body weight), progression to surgery  25  64 (48–82)  21 (84%)  Not stated (only stented patients included)  Adler et al. 32  Prospective  III  5  Dysphagia scores and patient weights  13  63.3 ± 12.3  13 (100%)  11 (85%) (2 (15%) initial placement was suboptimal and therefore replaced in same procedure)  Langer et al. 31  Prospective  III  5  Success of insertion, complications, change in dysphagia score, change in albumin  38  66 (30.3–88.2)  26  97.4  Lopes et al. 38  Retrospective  IV  5  Dysphagia scores, complications, tissue reaction, ease of removal  11  60.5  10 (90.9%)  90.9%  Brown et al. 33  Prospective  III  5  Esophageal cancer patients undergoing neoadjuvant therapy prior to resection  32  61 (39–82)  26 (81%)  100%  Pellen et al. 34  Retrospective  IV  6  Patients with esophageal cancer recommended for neoadjuvant treatment with endoscopically significant stenosis or dysphagia score of 3 or more  16  63 (53–76)  9 (56%)  100%  Siddiqui et al. 35  Retrospective  IV  5  Patients with locally advanced esophageal cancer  55  65.8 ± 11.1  43  100%  Krokidis et al. 36  Prospective  III  5  Patients undergoing neoadjuvant treatment or radical radiotherapy after stent insertion  11  64.9 ± 7.5  9  100%  Laquière et al. 37  Prospective  III  5  Patients undergoing neoadjuvant chemoradiotherapy for advanced esophageal cancer with grade 2 dysphagia or more  20  61.5 (43–82)  15 (75%)  100%  Martin et al. 39  Prospective  III  5  Esophageal cancer patients undergoing neoadjuvant treatment prior to esophagectomy  52  61 (39–82)  42 (81%)  Not stated  Van den Berg et al. 40  Prospective  III  4  Consecutive patients with esophageal cancer scheduled for neoadjuvant therapy and complaining of dysphagia (grade 2 or more)  10  68 ± 7.7  7 (70%)  100%  Mariette et al. 41  Retrospective  IV  5  Patients who had undergone esophagectomy with curative intent and had undergone insertion of self-expanding metallic stent as a bridge to surgery (60.5% had neoadjuvant treatment)  38  64.5 (34–81)  33 (86.8%)  Not stated  Philips et al. 42  Prospective  III  5  Patients with stage 2/3 junctional adenocarcinoma undergoing neoadjuvant therapy and who underwent stenting for symptoms of gastroesophageal reflux  40  62 (47–83)  32 (80%)  Not stated  Mão-de-Ferro et al43  Properspective  III  5  Nutritional status and dysphagia  11  64 (56–75)  10 (91%)  100%  View Large Table 2 Study outcomes of included studies evaluating the use of esophageal stenting during neoadjuvant treatment Author and Year  Mean weight change  Quality of life  Improvement in dysphagia score  Completion of neoadjuvant treatment  Number preceeding to surgery  Migration  Complications (n)  Post-operative mortality   Siddiqui et al.45  +6 kg  Not assessed  Yes  Not stated  6 (100%)  1 (20%)  0  Not stated  Martin et al.44  Not assessed  Not assessed  Yes  5 (100%)  Not stated  1 (20%)  0  Not stated  Bower et al.30  −1.5%  Not assessed  Yes  23 (92%)  14 (56%)  6 (24%)  Extra support required via nasoduodenal tube 2 (8%)  0 (postoperative)                Chest pain 1 (4%)    Adler et al.32  Not stated  Not assessed  Yes  Not stated  3 (23%)  6 (46%)  Chest pain 12 (92.3%)  Not stated                Requirement for PEG tube–2 (15%)    Langer et al.31  Not stated  Not assessed  Yes  20 (52.6%)  26 (68.4%)  12 (46%)  Erosion of aortic wall −1  1 (4%) (Post-operative mortality)                Small bowel perforation −1                  Esophago-tracheo-bronchial fistula −2                  Perforation at stent placement −1    Lopes et al.38  Not stated  Not assessed  Yes  10 (100%)  2 (20%)  2 (20%)  Chest pain −3 (30%)  Not stated                Tracheoesophageal fistula −1    Brown et al.33  −7.3 kg  Not assessed  Yes  Not stated  20  8 (25%)  Chest pain −2 (6.3%)  0 (peri-operative mortality)                Endoleak −1 (3.1%)    Pellen et al.34  −2.2 kg  Not assessed  Yes  Not stated  10 (62.5%)  7 (43.8%)  Food bolus obstruction −2 (12.5%)  1 (10%) (30-day mortality)                Small bowel obstruction −1 (6.3%)                  Tumor ingrowth −1 (6.3%)    Siddiqui et al.35  +1.8 kg  Not assessed  Yes  Not stated  8 (15%)  17 (31%)  Chest pain −8 (15%)  Not stated                Significant acid reflux −1 (2%)                  Odynophagia −1 (2%)                  Food impaction 1 (2%)                  Esophageal perforation 1(2%)    Krokidis et al.36  Not stated  Not assessed  Yes  Not stated  1 (9%)  1 (9%)  Aspiration and hematemesis −1 (9%)  Not stated            (3 (27% awaiting surgery))    Tracheobronchial aspiration and tracheoesophageal fistula −1 (9%)                  Aspiration pneumonia and fistula with the bronchial tree −1 (9%)                  Stent dysfunction from tumor growth −3 (27%)                  Stent dysfunction from inflammation −2 (18%)    Laquiere et al.37  Not stated  QLQ-ES18 scores revealed an improvement of both dysphagia and alimentary parameters following stent placement No difference in parameters for pain, swallowing disorders, anorexia and anosmia  Yes  100%  3 (20%)  3 (15%)  Chest pain −13 (65%)  Not stated                Perforation −1 (5%)                  Orotracheal fistula −1 (5%)                  Tumor overgrowth −2 (10%)    Martin et al.39  −3.2 kg  Statistically significant improvements in terms of dysphagia, eating restriction, and pain and discomfort  Yes  Chemotherapy −34 (93%)  Not stated  3 (5.8%)  Not stated  Not stated      No change in social quality of life    Radiotherapy −27 (75%)              Worsening of physical QOL during patients’ neoadjuvant therapy (not significant)                  Worsening of emotional quality of life at week 3 but returned to baseline by completion of treatment              Van den Berg et al.40  −5.4 kg (range 0.2 −11) (−6.5%)  Not assessed  Yes  9 (90%)  6 (60%)  Not stated  Chest pain −6 (60%)  Not stated                Stent obstruction from tumor in growth −1 (10%)    Mariette et al.41  Not assessed  Not assessed  Not stated  Not applicable  38 (100%) (This was part of inclusion criteria)  Not stated  Tumor perforation at insertion −2  5 (13.2%) (post-operative in-hospital mortality)  Phillips et al.42  Not assessed  Significantly improved and sustained swallowing quality of life from 2 weeks up to 10 weeks postinsertion. Reflux symptoms QOL was similar at 2 weeks but improved after this point.  Yes  95%  Not assessed  25 (62.5%)  Chest pain −5 (12.5%)  Not stated  Mão-de-Ferro et al.43  Not assessed  Not assessed  Yes  Not stated  4 (36%)  4 (36%)  Esophageal perforation −1 (9%)  Not stated                Requirement for nasogastric feeding - 3 (27%)    Author and Year  Mean weight change  Quality of life  Improvement in dysphagia score  Completion of neoadjuvant treatment  Number preceeding to surgery  Migration  Complications (n)  Post-operative mortality   Siddiqui et al.45  +6 kg  Not assessed  Yes  Not stated  6 (100%)  1 (20%)  0  Not stated  Martin et al.44  Not assessed  Not assessed  Yes  5 (100%)  Not stated  1 (20%)  0  Not stated  Bower et al.30  −1.5%  Not assessed  Yes  23 (92%)  14 (56%)  6 (24%)  Extra support required via nasoduodenal tube 2 (8%)  0 (postoperative)                Chest pain 1 (4%)    Adler et al.32  Not stated  Not assessed  Yes  Not stated  3 (23%)  6 (46%)  Chest pain 12 (92.3%)  Not stated                Requirement for PEG tube–2 (15%)    Langer et al.31  Not stated  Not assessed  Yes  20 (52.6%)  26 (68.4%)  12 (46%)  Erosion of aortic wall −1  1 (4%) (Post-operative mortality)                Small bowel perforation −1                  Esophago-tracheo-bronchial fistula −2                  Perforation at stent placement −1    Lopes et al.38  Not stated  Not assessed  Yes  10 (100%)  2 (20%)  2 (20%)  Chest pain −3 (30%)  Not stated                Tracheoesophageal fistula −1    Brown et al.33  −7.3 kg  Not assessed  Yes  Not stated  20  8 (25%)  Chest pain −2 (6.3%)  0 (peri-operative mortality)                Endoleak −1 (3.1%)    Pellen et al.34  −2.2 kg  Not assessed  Yes  Not stated  10 (62.5%)  7 (43.8%)  Food bolus obstruction −2 (12.5%)  1 (10%) (30-day mortality)                Small bowel obstruction −1 (6.3%)                  Tumor ingrowth −1 (6.3%)    Siddiqui et al.35  +1.8 kg  Not assessed  Yes  Not stated  8 (15%)  17 (31%)  Chest pain −8 (15%)  Not stated                Significant acid reflux −1 (2%)                  Odynophagia −1 (2%)                  Food impaction 1 (2%)                  Esophageal perforation 1(2%)    Krokidis et al.36  Not stated  Not assessed  Yes  Not stated  1 (9%)  1 (9%)  Aspiration and hematemesis −1 (9%)  Not stated            (3 (27% awaiting surgery))    Tracheobronchial aspiration and tracheoesophageal fistula −1 (9%)                  Aspiration pneumonia and fistula with the bronchial tree −1 (9%)                  Stent dysfunction from tumor growth −3 (27%)                  Stent dysfunction from inflammation −2 (18%)    Laquiere et al.37  Not stated  QLQ-ES18 scores revealed an improvement of both dysphagia and alimentary parameters following stent placement No difference in parameters for pain, swallowing disorders, anorexia and anosmia  Yes  100%  3 (20%)  3 (15%)  Chest pain −13 (65%)  Not stated                Perforation −1 (5%)                  Orotracheal fistula −1 (5%)                  Tumor overgrowth −2 (10%)    Martin et al.39  −3.2 kg  Statistically significant improvements in terms of dysphagia, eating restriction, and pain and discomfort  Yes  Chemotherapy −34 (93%)  Not stated  3 (5.8%)  Not stated  Not stated      No change in social quality of life    Radiotherapy −27 (75%)              Worsening of physical QOL during patients’ neoadjuvant therapy (not significant)                  Worsening of emotional quality of life at week 3 but returned to baseline by completion of treatment              Van den Berg et al.40  −5.4 kg (range 0.2 −11) (−6.5%)  Not assessed  Yes  9 (90%)  6 (60%)  Not stated  Chest pain −6 (60%)  Not stated                Stent obstruction from tumor in growth −1 (10%)    Mariette et al.41  Not assessed  Not assessed  Not stated  Not applicable  38 (100%) (This was part of inclusion criteria)  Not stated  Tumor perforation at insertion −2  5 (13.2%) (post-operative in-hospital mortality)  Phillips et al.42  Not assessed  Significantly improved and sustained swallowing quality of life from 2 weeks up to 10 weeks postinsertion. Reflux symptoms QOL was similar at 2 weeks but improved after this point.  Yes  95%  Not assessed  25 (62.5%)  Chest pain −5 (12.5%)  Not stated  Mão-de-Ferro et al.43  Not assessed  Not assessed  Yes  Not stated  4 (36%)  4 (36%)  Esophageal perforation −1 (9%)  Not stated                Requirement for nasogastric feeding - 3 (27%)    View Large Three studies reported health-related QOL. All three of these used European Organisation for Research and Treatment of Cancer (EORTC)54 questionnaires including QLQ-C30, QLQ-OG25, and QLQ-ES18. In addition two studies used the Functional Assessment of Cancer Therapy (FACT)55 questionnaires including FACT-General, FACT-Esophageal, and FACT-Anorexia. All three of these studies demonstrated improvement in some of the measured symptom specific QOL metrics including dysphagia, eating restriction, and quality of oral feeding. Health-related QOL outcomes from these studies are summarized in Table 2. One study reported a reduction in physical QOL but the neoadjuvant therapy is a confounder to these assessments. Feeding jejunostomy Four studies25,46–48 reported an evaluation of laparoscopically inserted feeding jejunostomy in 236 patients. All were retrospective reviews of patients who underwent laparoscopic feeding jejunostomy insertion at staging laparoscopy prior to neoadjuvant therapy. The study characteristics are described in Table 3 and outcomes in Table 4. No studies reported 30-day postprocedural mortality. Three studies reported change in patient weights with all demonstrating an increase in weight ranging from 0.4 to 11.8 kg. One study reported completion of neoadjuvant therapy in greater than 90% of patients. All studies reported complications including tube blockage (n = 11 (4.6%)), dislodgement (n = 9 (3.8%)), wound infection (n = 7 (3%)), leakage (n = 5 (2.1%)), diarrhea (n = 3 (1.3%)), connector breakage (n = 2 (0.8%)), and kinked tube (n = 1 (0.4%)). 30-day postoperative mortality after esophagectomy and health-related QOL was not reported in any study. Table 3 Study characteristics of included studies evaluating feeding jejunostomy during neoadjuvant treatment Author and Year  Type of study  Evidence Level  N-O Score (max = 9)  n  Age  Male  Grondona et al. 47  Retrospective  IV  3  18  63 (53–73)  11  Jenkinson et al. 25  Retrospective  IV  3  43  66 (42–82)  30  Ben-David et al. 46  Retrospective  IV  5  153  63  115  Tsujimoto et al. 48  Retrospective  IV  5  22 (9 patients with esophageal cancer undergoing neoadjuvant therapy)  69.4 ± 6.0 (range 48–79)  22  Author and Year  Type of study  Evidence Level  N-O Score (max = 9)  n  Age  Male  Grondona et al. 47  Retrospective  IV  3  18  63 (53–73)  11  Jenkinson et al. 25  Retrospective  IV  3  43  66 (42–82)  30  Ben-David et al. 46  Retrospective  IV  5  153  63  115  Tsujimoto et al. 48  Retrospective  IV  5  22 (9 patients with esophageal cancer undergoing neoadjuvant therapy)  69.4 ± 6.0 (range 48–79)  22  View Large Table 4 Study outcomes of included studies evaluating feeding jejunostomy during neoadjuvant treatment Author and Year  Mean weight loss  Number of patients who required jejunostomy feeding  Median duration of feeding through jejunostomy  Completion of neoadjuvant treatment  Number preceeding to surgery  Complications (n)  Mortality  Grondona et al.47  Not assessed  14  30 days  Not stated  5  Leakage and wound infection −1  Not stated              Wound infection −1                Kinked tube requiring removal −1                Accidental displacement −1    Jenkinson et al.25  +1.1 kg  20  Not stated  Not stated  100% (inclusion criteria)  Dislodgement −6 (20%)  Not stated              Blockage −4 (13%)                Connector breakage −2 (7%)    Ben-David et al.46  +11.8 kg  All  Approximately a 10-week course of supplementary nutrition  >90%   86%  Dislodgement −2  Mortality rate in patients having laparoscopic jejunostomy and esophagectomy was 1%              Leak −4                Clogging −5                Superficial wound infection −4    Tsujimoto et al.48  +0.4 kg  Not stated  Not stated  Not stated  9 (100%)  Diarrhoea −3 (13.6%)  Not stated              Tube obstruction −2 (9%)    Author and Year  Mean weight loss  Number of patients who required jejunostomy feeding  Median duration of feeding through jejunostomy  Completion of neoadjuvant treatment  Number preceeding to surgery  Complications (n)  Mortality  Grondona et al.47  Not assessed  14  30 days  Not stated  5  Leakage and wound infection −1  Not stated              Wound infection −1                Kinked tube requiring removal −1                Accidental displacement −1    Jenkinson et al.25  +1.1 kg  20  Not stated  Not stated  100% (inclusion criteria)  Dislodgement −6 (20%)  Not stated              Blockage −4 (13%)                Connector breakage −2 (7%)    Ben-David et al.46  +11.8 kg  All  Approximately a 10-week course of supplementary nutrition  >90%   86%  Dislodgement −2  Mortality rate in patients having laparoscopic jejunostomy and esophagectomy was 1%              Leak −4                Clogging −5                Superficial wound infection −4    Tsujimoto et al.48  +0.4 kg  Not stated  Not stated  Not stated  9 (100%)  Diarrhoea −3 (13.6%)  Not stated              Tube obstruction −2 (9%)    View Large Gastrostomy Three studies26,49,50 evaluated the use percutaneous gastrostomy (two percutaneous endoscopic gastrostomy and one percutaneous radiological gastrostomy). All were retrospective reviews of single center experiences. The study characteristics are described in Table 5 and outcomes in Table 6. Only one study discussed the contra-indications to gastrostomy placement of portal hypertension, coagulopathy, and abundant ascites. All studies highlighted concerns including the risks of traversing esophageal tumors, rendering the stomach unsuitable for gastric conduit, tumor seeding at the site of gastrostomy and injury to the right gastroepiploic artery. Two studies reported success rates of gastrostomy insertion of 87%–96.3%. Gastrostomy related complications occurred in ranging from 3.4% to 4% including failure, suppurative wound infection, protracted ileus, persistent gastric leakage, hemoperitoneum, peritonitis, small bowel obstruction, abdominal pain, fever, failure and accidental dislodgement. One study reported minor complications in 12%, most frequently cellulitis requiring antibiotics. Two studies reported mean weight loss through neoadjuvant therapy, with one reporting a significant improvement in mean weight loss before and after neoadjuvant therapy (14.3% ± 6.9 and 10.7% ± 7.8, respectively P = 0.011) and the other reporting a gradual decline in weight loss during chemoradiation with a mean weight loss of patients undergoing surgery of 3.8% (range: 0%–9%). Completion rates of neoadjuvant treatment ranged from 70% to 95%. Table 5 Study characteristics of included studies evaluating gastrostomy during neoadjuvant treatment Author and Year  Type of study  Evidence Level  N-O Score (max = 9)  n  Age  Male  Guidance  Success rate  Margolis et al. 49  Retrospective  IV  5  179  61.4 (38–81)    Endoscopic  103/119 (87%)  Tessier et al.26  Retrospective  IV  5  269 (139 of whom were pre-operative and 130 were having CRT treatment alone)  60.5  6.3:1  Radiological  259 (96.3%)  Wright et al.50  Retrospective  IV  3  15  58  73%  Endoscopic  Not stated  Author and Year  Type of study  Evidence Level  N-O Score (max = 9)  n  Age  Male  Guidance  Success rate  Margolis et al. 49  Retrospective  IV  5  179  61.4 (38–81)    Endoscopic  103/119 (87%)  Tessier et al.26  Retrospective  IV  5  269 (139 of whom were pre-operative and 130 were having CRT treatment alone)  60.5  6.3:1  Radiological  259 (96.3%)  Wright et al.50  Retrospective  IV  3  15  58  73%  Endoscopic  Not stated  View Large Table 6 Study outcomes of included studies evaluating gastrostomy during neoadjuvant treatment Author and Year  Mean weight loss  Median duration of feeding through gastrostomy  Completion of neoadjuvant treatment  Number preceding to surgery  Removal rate  Complications (n)  Mortality  Margolis et al.49  3.8% (0–9)  15 weeks (3 days to 10 months)  71 (70%)  61  4 (4%)  Major 4 (4%)  13.5% (30 day mortality, 0% PEG related)              Suppurative wound infections –2                Protracted Ileus −1                Persistent leakage −1                Minor 12 (12%)    Tessier et al.26  10.7% ± 7.8  14.5 weeks (1–53)  93.7% in CRT group and 95% on chemotherapy group  83  5 (1.9%)  9 (3.4%)  0% (procedure related mortality)              Hemoperitoneum–1                Peritonitis −2                Small bowel obstruction −1                Abdominal pain and fever (normal laparoscopy) −1                Failure requiring laparotomy and surgical jejunostomy −1                Accidental dislodgement −1    Wright et al.50  Not stated  Not stated  Not stated  15 (100%) (was part of study inclusion criteria)  Not stated  Not stated  7% (90 day mortality)  Author and Year  Mean weight loss  Median duration of feeding through gastrostomy  Completion of neoadjuvant treatment  Number preceding to surgery  Removal rate  Complications (n)  Mortality  Margolis et al.49  3.8% (0–9)  15 weeks (3 days to 10 months)  71 (70%)  61  4 (4%)  Major 4 (4%)  13.5% (30 day mortality, 0% PEG related)              Suppurative wound infections –2                Protracted Ileus −1                Persistent leakage −1                Minor 12 (12%)    Tessier et al.26  10.7% ± 7.8  14.5 weeks (1–53)  93.7% in CRT group and 95% on chemotherapy group  83  5 (1.9%)  9 (3.4%)  0% (procedure related mortality)              Hemoperitoneum–1                Peritonitis −2                Small bowel obstruction −1                Abdominal pain and fever (normal laparoscopy) −1                Failure requiring laparotomy and surgical jejunostomy −1                Accidental dislodgement −1    Wright et al.50  Not stated  Not stated  Not stated  15 (100%) (was part of study inclusion criteria)  Not stated  Not stated  7% (90 day mortality)  View Large No study reported 30-day mortality after esophagectomy. One study49 reported a 30-day postgastrostomy mortality of 13.5% (none being gastrostomy related); one study26 reported 60-day postgastrostomy mortality of 0%; and the third study50 reported a 90-day postesophagectomy mortality of 3%. All included studies described the suture closing of gastrostomy site at the time of esophagectomy and in all cases where gastric conduit formation was planned the stomach provided a suitable esophageal substitute. Two studies reported a nonsignificant increase in operative time in the gastrostomy group (16–43 minute increase). None of the included studies assessed health-related QOL. Nasogastric feeding tubes One retrospective study of 16 patients evaluated the use of nasogastric feeding tubes (Dobhoff tubes) during neoadjuvant therapy.51 Four patients required at least one intervention to replace or unblock the tubing, while a further four patients required more than one intervention, two of whom required percutaneous endoscopic gastrostomy. Comparative studies One study compared the efficacy of self-expanding esophageal stenting (SES) (n = 12) versus feeding jejunostomy (n = 24) during neoadjuvant therapy.52 Success rates for SES placement and jejunostomy tube were 83.3 and 100%, respectively. In the SES group, eight (72%) experienced postprocedural chest pain and four stent migration (36%). All patients with successful stent deployment had immediate and sustained improvement in dysphagia score and these was used as a surrogate for QOL. In the feeding jejunostomy group, two wound infection requiring antibiotics and one minor leak were reported. Both cohorts gained weight during neoadjuvant treatment (SES mean weight increase from 60.5 to 65 kg, p < 0.001 versus feeding jejunostomy mean weight gain 72.2 to 76 kg, P ≤ 0.05). Thirty-day postesophagectomy and 30-day postprocedural mortality were not reported. DISCUSSION Published evidence suggests that the optimal treatment for resectable advanced locoregional esophageal cancer is neoadjuvant therapy followed by esophagectomy.1–6 The CROSS trial demonstrated improved locoregional control and distant metastases-free survival with neoadjuvant chemoradiotherapy and surgery versus surgery alone.2,56 In addition, a recent network meta-analysis has provided evidence of a survival advantage of neoadjuvant chemoradiotherapy compared to neoadjuvant chemotherapy, adjuvant chemotherapy, adjuvant chemoradiotherapy, or surgery alone.57 Neoadjuvant chemoradiotherapy or neoadjuvant chemotherapy is the accepted standard of care in the USA and UK, respectively.3 With increasing use of neoadjuvant chemoradiotherapy protocols for nutritional optimization during neoadjuvant therapy should be prioritized to enable completion of prescribed treatment cycles, improve treatment response rates, and reduce treatment-related toxicity. Importantly, optimizing nutritional status during neoadjuvant treatment has a causal link to improved surgical outcome.8,18–22 However, the uncertainty regarding the optimal nutritional approach has led to regional variability in nutritional strategies in patients with locoregional disease receiving neoadjuvant therapy. This systematic review clearly demonstrates the paucity of evidence to define the optimal nutritional approach. The evidence is limited to case series with few prospective, multicenter or comparative studies. No randomized controlled trials or cost-effectiveness studies were identified. Evaluation is mostly limited to studies that are insufficiently powered to report objective nutritional outcomes, QOL, and mortality. Study outcomes relied on weight change with no additional measures of nutritional status such as grip strength. Furthermore, the primary endpoint of 30-day postoperative mortality was particularly poorly reported in the included studies. Therefore, based on the limited poor quality data available, this systematic review cannot clearly identify the optimal strategy to improve nutrition in this patient cohort. Esophageal stenting was the most frequently reported intervention in 15 studies. The majority used improvement in dysphagia as the primary outcome measure with all studies demonstrating improvement without a corresponding consistent improvement in nutritional parameters including weight. The reported complication rate was low but included life-threatening aortic erosion and tracheoesophageal fistula and variable stent migration rates of 9%–65%30–39,42,44,45 while the proportion of patients proceeding to esophagectomy ranged from 15%–100%. Although some centers have published good outcomes following esophageal stenting as a bridge to esophagectomy30,42,45 a recent systematic review58 concluded that stent insertion before neoadjuvant therapy could not be supported given the lack of evidence to demonstrate a consistent benefit to weight or nutritional markers, the required extra interventions due to pain or migration, variation in the numbers of patients proceeding to surgery and life-threatening complications. Feeding jejunostomy insertion at esophagectomy is a common practice in many centers. Earlier insertion at the time of staging laparoscopy is increasingly performed in patients with significant dysphagia and malnutrition. In three of the four studies reporting feeding jejunostomy use rates of progression to surgery were high at >85% although only one study reported weight gain. Reported complication rates are comparable to esophageal stenting and less severe although the Clavien–Dindo scoring59 was not documented in the majority. One study investigating gastrostomy reportedly had a post gastrostomy 30-day mortality of 13.5%. This is exceeding high and not consistent with the other included studies, no reason for this high figure was provided. Huerter et al. report their experience of 127 patients undergoing neoadjuvant treatment for esophageal cancer,60 of whom 61 (48%) received enteral feeding access following nutritional assessment. This included 49 patients who underwent laparoscopic feeding jejunostomy and the remaining 12 patients having percutaneous endoscopic gastrostomy. Their results demonstrated a 36% incidence of adverse events for tube placement including bleeding, infection, dislodgement, and tube site problems. While multivariate regression did demonstrate that enteral access was associated with nutritional stability during neoadjuvant therapy, all patients proceeded to esophagectomy with outcomes similar between the enteral access and no enteral access groups. However, this study is retrospective and it is therefore not known if those patients who had supplementary feeding would have been able to complete their neoadjuvant therapy and proceed to surgery without it. This study was not included in the analysis as it was not possible to separate the patients who had jejunostomy or PEG placement. Also 27.9% of patients who had enteral access tubes placed did not use it consistently or at all during their neoadjuvant treatment. A recent review61 of 299 consecutive laparoscopic feeding jejunostomies reported low complication rates and a 30-day mortality of 4% in keeping with the findings of this current review. QOL was reported poorly. Only three studies, all evaluating esophageal stenting, reported QOL. These demonstrated improvement in some of the scores measured but in the main these were symptom specific rather than global QOL evaluations. The physical, psychological, and emotional consequences for patients of living with different nutritional interventions and associated feeding regimes are unknown. Validated esophageal cancer-specific QOL questionnaires do allow the differentiation of specific symptoms including dysphagia, eating restrictions, pain, and discomfort. Studies are required to investigate the impact of the differing nutritional approaches on patient-reported outcome measures including QOL in addition to clinical outcomes. This narrative review has limitations. The primary outcome of 30-day postoperative mortality was poorly reported and therefore the optimal nutritional strategy to improve survival could not be determined. 30-day postoperative mortality was selected as the primary outcome in keeping with the recommendation of the Esophagectomy Complications Consensus Group who agreed that 30-day mortality should be recorded as a quality and outcome measure following esophagectomy.62 We recognize that the review is heavily weighted by studies of stent placement (16/26 studies with 383 patients). Eleven of these studies evaluated dysphagia scores as a primary outcome and we acknowledge that dysphagia does necessarily equate to malnutrition. We have not presented health economic data as evaluation of the cost effectiveness of stent placement and reintervention was not the remit of this systematic review. Data on unplanned hospital admissions and emergency department visits for dehydration and/or complications for the nutritional approaches were lacking. These limitations further support the need for a prospective, well designed, multicenter, randomized controlled trial to compare the effectiveness of the current approaches for nutritional optimization in patients undergoing neoadjuvant chemotherapy prior to esophagectomy, and their impact on survival and health-related QOL benefits. This review highlights the lack of an accepted standard of care or level 1 evidence to guide management plan in determining the optimal nutritional approach in patients with resectable locoregional esophageal cancer undergoing neoadjuvant therapy. Prior to designing and undertaking such a trial a prospective, multicenter, observational cohort study will be needed to determine the number of patients who may be potentailly eligible and to collect evidence of current multidisciplinary team treatment decision making for this group of patients. Notes Funding source: Sheraz R. Markar is supported by the National Institute of Health Research. Conflict of interest: Fiona M. S. Huddy has previously received a one off honorarium from Lilly for presentation at an advisory board. The authors have no other conflicts of interest. Specific author contributions: Jeremy R. Huddy participated in the literature search, data collection, analysis and interpretation of findings. Fiona M. S. Huddy participated in the analysis and interpretation of findings. Sheraz R. Markar participated in the study design, literature search, data collection, analysis, and interpretation of findings. 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Diseases of the EsophagusOxford University Press

Published: Jan 1, 2018

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