Long-Term Survival Associated with Direct Oral Feeding Following Minimally Invasive Esophagectomy: Results from a Randomized Controlled Trial (NUTRIENT II).

Advancements in perioperative care have improved postoperative morbidity and recovery after esophagectomy. The direct start of oral intake can also enhance short-term outcomes following minimally invasive Ivor Lewis esophagectomy (MIE-IL). Subsequently, short-term outcomes may affect long-term survival. This planned sub-study of the NUTRIENT II trial, a multicenter randomized controlled trial, investigated the long-term survival of direct versus delayed oral feeding following MIE-IL. The outcomes included 3- and 5-year overall survival (OS) and disease-free survival (DFS), and the influence of complications and caloric intake on OS. After excluding cases of 90-day mortality, 145 participants were analyzed. Of these, 63 patients (43.4%) received direct oral feeding. At 3 years, OS was significantly better in the direct oral feeding group (p = 0.027), but not at 5 years (p = 0.115). Moreover, 5-year DFS was significantly better in the direct oral feeding group (p = 0.047) and a trend towards improved DFS was shown at 3 years (p = 0.079). Postoperative complications and caloric intake on day 5 did not impact OS. The results of this study show a tendency of improved 3-year OS and 5-year DFS, suggesting a potential long-term survival benefit in patients receiving direct oral feeding after esophagectomy. However, the findings should be further explored in larger future trials.

The Effect of Postoperative Complications After Minimally Invasive Esophagectomy on Long-term Survival: An International Multicenter Cohort Study.

BACKGROUND: Esophagectomy is a technically challenging procedure, associated with significant morbidity. The introduction of minimally invasive esophagectomy (MIE) has reduced postoperative morbidity. OBJECTIVE: Although the short-term effect on complications is increasingly being recognized, the impact on long-term survival remains unclear. This study aims to investigate the association between postoperative complications following MIE and long-term survival. METHODS: Data were collected from the EsoBenchmark Collaborative composed by 13 high-volume, expert centers routinely performing MIE. Patients operated between June 1, 2011 and May 31, 2016 were included. Complications were graded using the Clavien-Dindo (CD) classification. To correct for short-term effects of postoperative complications on mortality, patients who died within 90 days postoperative were excluded. Primary endpoint was 5-year overall survival. RESULTS: A total of 915 patients were included with a mean follow-up time of 30.8 months (standard deviation 17.9). Complications occurred in 542 patients (59.2%) of which 50.2% had a CD grade ≥III complication [ie, (re)intervention, organ dysfunction, or death]. The incidence of anastomotic leakage (AL) was 135 of 915 patients (14.8%) of which 84 patients were classified as a CD grade ≥III. Multivariable analysis showed a significantly deteriorated long-term survival in all patients with AL [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.25-2.24]. This inverse relation was most distinct when AL was scored as a CD grade ≥III (HR 1.83, 95% CI 1.30-2.58). For all other complications, no significant association with long-term survival was found. CONCLUSION: The occurrence and severity of AL, but not overall complications, after MIE negatively affect long-term survival of esophageal cancer patients.

Feeding protocol deviation after esophagectomy: A retrospective multicenter study.

BACKGROUND: Esophagectomy is associated with high postoperative morbidity rates, which can result in decreased quality of life and impaired recovery. Implementation of enhanced recovery after surgery (ERAS) protocols have made a great impact in optimizing postoperative recovery. However, the best timing to start oral intake is still unclear. Conservative feeding protocols have been developed with a nil-by-mouth period in the first postoperative days to reduce postoperative complication rates (e.g. anastomotic leakage and pneumonia). This study aimed to evaluate adherence to the feeding protocol following minimal invasive esophagectomy and identify reasons for protocol deviation. METHODS: All consecutive patients who underwent an esophagectomy with gastric tube reconstruction between 2014 and 2016 in two high-volume hospitals in the Netherlands were retrospectively analyzed. All patients were planned to receive enteral tube feeding via jejunostomy directly after surgery. Data regarding postoperative feeding related symptoms (e.g. nausea, vomiting, regurgitation) and adherence to the postoperative feeding protocol were gathered. RESULTS: A total of 186 patients were included. Feeding protocol deviation was observed in 109 patients (59%) and was significantly more common in patients with anastomotic leakage, chyle leakage, and acute respiratory distress. Postoperative feeding related symptoms were present in 107 patients (58%) and were significantly more common in female patients and patients with a cervical anastomosis. CONCLUSION: In this study, more than half of the patients deviated from the intended feeding protocol after esophagectomy. Postoperative complications appeared to be the main reason for feeding protocol deviation. This study shows that a predefined feeding protocol including an oral fasting period is often violated because of complications.

Direct Oral Feeding Following Minimally Invasive Esophagectomy (NUTRIENT II trial): An International, Multicenter, Open-label Randomized Controlled Trial.

OBJECTIVE: Patients undergoing an esophagectomy are often kept nil-by-mouth postoperatively out of fear for increasing anastomotic leakage and pulmonary complications. This study investigates the effect of direct start of oral feeding following minimally invasive esophagectomy (MIE) compared with standard of care. BACKGROUND: Elements of enhanced recovery after surgery (ERAS) protocols have been successfully introduced in patients undergoing an esophagectomy. However, start of oral intake, which is an essential part of the ERAS protocols, remains a matter of debate. METHODS: Patients in this multicenter, international randomized controlled trial were randomized to directly start oral feeding (intervention) after a MIE with intrathoracic anastomosis or to receive nil-by-mouth and tube feeding for 5 days postoperative (control group). Primary outcome was time to functional recovery. Secondary outcome parameters included anastomotic leakage, pneumonia rate, and other surgical complications scored by predefined definitions. RESULTS: Baseline characteristics were similar in the intervention (n = 65) and control (n = 67) group. Functional recovery was 7 days for patients receiving direct oral feeding compared with 8 days in the control group (P = 0.436). Anastomotic leakage rate did not differ in the intervention (18.5%) and control group (16.4%, P = 0.757). Pneumonia rates were comparable between the intervention (24.6%) and control group (34.3%, P = 0.221). Other morbidity rates were similar, except for chyle leakage, which was more prevalent in the standard of care group (P = 0.032). CONCLUSION: Direct oral feeding after an esophagectomy does not affect functional recovery and did not increase incidence or severity of postoperative complications.

Learning Curve and Associated Morbidity of Minimally Invasive Esophagectomy: A Retrospective Multicenter Study.

OBJECTIVE: To investigate the morbidity that is associated with the learning curve of minimally invasive esophagectomy. BACKGROUND: Although learning curves have been described, it is currently unknown how much extra morbidity is associated with the learning curve of technically challenging surgical procedures. METHODS: Prospectively collected data were retrospectively analyzed of all consecutive patients undergoing minimally invasive Ivor Lewis esophagectomy in 4 European expert centers. The primary outcome parameter was anastomotic leakage. Secondary outcome parameters were operative time and textbook outcome ("optimal outcome"). Learning curves were plotted using weighted moving average and CUSUM analysis was used to determine after how many cases the plateau was reached. Learning associated morbidity was calculated with area under the curve analysis. RESULTS: This study included 646 patients. Three of the 4 hospitals reached the plateau of 8% anastomotic leakage. The length of the learning curve was 119 cases. The mean incidence of anastomotic leakage decreased from 18.8% during the learning phase to 4.5% after the plateau had been reached (P < 0.001). Thirty-six extra patients (10.1% of all patients operated on during the learning curve) experienced learning associated anastomotic leakage, that could have been avoided if patients were operated by surgeons who had completed the learning curve. The incidence of textbook outcome increased from 28% to 53% and the mean operative time decreased from 344 minutes to 270 minutes. CONCLUSIONS: A considerable number of 36 extra patients (10.1%) experienced learning associated anastomotic leakage. More research is urgently needed to investigate how learning associated morbidity can be reduced to increase patient safety during learning curves.

Nasogastric decompression following esophagectomy: a systematic literature review and meta-analysis.

Routine use of nasogastric tubes for gastric decompression has been abolished in nearly all types of gastro-intestinal surgery after introduction of enhanced recovery after surgery programs. However, in esophagectomy the routine use of nasogastric decompression is still a matter of debate. To determine the effects of routine nasogastric decompression following esophagectomy compared with early or peroperative removal of the nasogastric tube on pulmonary complications, anastomotic leakage, mortality, and postoperative recovery. A systematic literature review and meta-analysis of studies comparing early or peroperative versus late removal of nasogastric tubes. A total of seven comparative studies were included (n = 608). In two randomized trials, and one retrospective cohort study, peroperative removal of the nasogastric tube was compared with routine nasogastric decompression. In one randomized trial early removal of the nasogastric tube (on postoperative day 2) was compared with removal of the nasogastric tube on the 6th-10th postoperative day. In the remaining three trials a fast-track protocol without a nasogastric tube was compared with conventional care with a nasogastric tube during the first postoperative days. Peroperative or early removal of the nasogastric tube did not result in a significantly different rate of anastomotic leakage, pulmonary complications or mortality in individual studies, nor in the meta-analysis. In the meta-analysis, hospital stay was significantly shorter with peroperative or early removal of the nasogastric tube when all studies were included, but not when the meta-analysis was limited to randomized trials. This systematic review did not find a difference in adverse outcomes between nasogastric decompression or no nasogastric decompression following esophagectomy.

Nutritional route in oesophageal resection trial II (NUTRIENT II): study protocol for a multicentre open-label randomised controlled trial.

INTRODUCTION: Early start of an oral diet is safe and beneficial in most types of gastrointestinal surgery and is a crucial part of fast track or enhanced recovery protocols. However, the feasibility and safety of oral intake directly following oesophagectomy remain unclear. The aim of this study is to investigate the effects of early versus delayed start of oral intake on postoperative recovery following oesophagectomy. METHODS AND ANALYSIS: This is an open-label multicentre randomised controlled trial. Patients undergoing elective minimally invasive or hybrid oesophagectomy for cancer are eligible. Further inclusion criteria are intrathoracic anastomosis, written informed consent and age 18 years or older. Inability for oral intake, inability to place a feeding jejunostomy, inability to provide written consent, swallowing disorder, achalasia, Karnofsky Performance Status <80 and malnutrition are exclusion criteria. Patients will be randomised using online randomisation software. The intervention group (direct oral feeding) will receive a liquid oral diet for 2 weeks with gradually expanding daily maximums. The control group (delayed oral feeding) will receive enteral feeding via a jejunostomy during 5 days and then start the same liquid oral diet. The primary outcome measure is functional recovery. Secondary outcome measures are 30-day surgical complications; nutritional status; need for artificial nutrition; need for additional interventions; health-related quality of life. We aim to recruit 148 patients. Statistical analysis will be performed according to an intention to treat principle. Results are presented as risk ratios with corresponding 95% CIs. A two-tailed p<0.05 is considered statistically significant. ETHICS AND DISSEMINATION: Our study protocol has received ethical approval from the Medical research Ethics Committees United (MEC-U). This study is conducted according to the principles of Good Clinical Practice. Verbal and written informed consent is required before randomisation. All data will be collected using an online database with adequate security measures. TRIAL REGISTRATION NUMBERS: NCT02378948 and Dutch trial registry: NTR4972; Pre-results.

Immediate Postoperative Oral Nutrition Following Esophagectomy: A Multicenter Clinical Trial.

BACKGROUND: Immediate start of oral intake is beneficial following colorectal surgery. However, following esophagectomy the safety and feasibility of immediate oral intake is unclear, thus these patients are still kept nil by mouth. This study therefore aimed to determine the feasibility and safety of oral nutrition immediately after esophagectomy. METHODS: A multicenter, prospective trial was conducted in 3 referral centers between August 2013 and May 2014, including 50 patients undergoing a minimally invasive esophagectomy. Oral nutrition was started postoperatively immediately (clear liquids on postoperative day [POD] 0, liquid nutrition on POD 1 to 6, solid food from POD 7). Nonoral enteral nutrition was started when <50% of caloric need was met on postoperative day POD 5 or when oral intake was impossible. A comparison was made with a retrospective cohort (n = 50) with a per-protocol delayed start of oral intake until POD 4 to 7. RESULTS: The median caloric intake at POD 5 was 58% of required. In 38% of the patients nonoral nutrition was started, mainly due to complications (36%). The pneumonia rate was 28% following immediate oral intake and 40% following delayed oral intake (p = 0.202). The aspiration pneumonia rate was 4% in both groups. The anastomotic leakage rate was 14% after immediate oral intake versus 24% following delayed oral intake (p = 0.202). The 90-day mortality rate was 2% in both groups. Hospital stay and intensive care unit stay were significantly shorter following immediate oral intake. CONCLUSIONS: Immediate start of oral nutrition following esophagectomy seems to be feasible and does not increase complications compared to a retrospective cohort and literature. However, if complications arise an alternative nutritional route is required. This explorative study shows that a randomized controlled trial is needed.

Diagnostic value of drain amylase for detecting intrathoracic leakage after esophagectomy.

AIM: To investigate the value of elevated drain amylase concentrations for detecting anastomotic leakage (AL) after minimally invasive Ivor-Lewis esophagectomy (MI-ILE). METHODS: This was a retrospective analysis of prospectively collected data in two hospitals in the Netherlands. Consecutive patients undergoing MI-ILE were included. A Jackson-Pratt drain next to the dorsal side of the anastomosis and bilateral chest drains were placed at the end of the thoracoscopic procedure. Amylase levels in drain fluid were determined in all patients during at least the first four postoperative days. Contrast computed tomography scans and/or endoscopic imaging were performed in cases of a clinically suspected AL. Anastomotic leakage was defined as any sign of leakage of the esophago-gastric anastomosis on endoscopy, re-operation, radiographic investigations, post mortal examination or when gastro-intestinal contents were found in drain fluid. Receiver operator characteristic curves were used to determine the cut-off values. Sensitivity, specificity, positive predictive value, negative predictive value, risk ratio and overall test accuracy were calculated for elevated drain amylase concentrations. RESULTS: A total of 89 patients were included between March 2013 and August 2014. No differences in group characteristics were observed between patients with and without AL, except for age. Patients with AL were older than were patients without AL (P = 0.01). One patient (1.1%) without AL died within 30 d after surgery due to pneumonia and acute respiratory distress syndrome. Anastomotic leakage that required any intervention occurred in 15 patients (16.9%). Patients with proven anastomotic leakage had higher drain amylase levels than patients without anastomotic leakage [median 384 IU/L (IQR 34-6263) vs median 37 IU/L (IQR 26-66), P = 0.003]. Optimal cut-off values on postoperative days 1, 2, and 3 were 350 IU/L, 200 IU/L and 160 IU/L, respectively. An elevated amylase level was found in 9 of the 15 patients with AL. Five of these 9 patients had early elevations of their amylase levels, with a median of 2 d (IQR 2-5) before signs and symptoms occurred. CONCLUSION: Measurement of drain amylase levels is an inexpensive and easy tool that may be used to screen for anastomotic leakage soon after MI-ILE. However, clinical validation of this marker is necessary.

Routes for early enteral nutrition after esophagectomy. A systematic review.

BACKGROUND: Early enteral feeding following surgery can be given orally, via a jejunostomy or via a nasojejunal tube. However, the best feeding route following esophagectomy is unclear. OBJECTIVES: To determine the best route for enteral nutrition following esophagectomy regarding anastomotic leakage, pneumonia, percentage meeting the nutritional requirements, weight loss, complications of tube feeding, mortality, patient satisfaction and length of hospital stay. DESIGN: A systematic literature review following PRISMA and MOOSE guidelines. RESULTS: There were 17 eligible studies on early oral intake, jejunostomy or nasojejunal tube feeding. Only one nonrandomized study (N = 133) investigated early oral feeding specifically following esophagectomy. Early oral feeding was associated with a reduced length of stay with delayed oral feeding, without increased complication rates. Postoperative nasojejunal tube feeding was not significantly different from jejunostomy tube feeding regarding complications or catheter efficacy in the only randomised trial on this subject (N = 150). Jejunostomy tube feeding outcome was reported in 12 non-comparative studies (N = 3293). It was effective in meeting short-term nutritional requirements, but major tube-related complications necessitated relaparotomy in 0-2.9% of patients. In three non-comparative studies (N = 135) on nasojejunal tube feeding only minor complications were reported, data on nutritional outcome was lacking. Data on patient satisfaction and long-term nutritional outcome were not found for any of the feeding routes investigated. CONCLUSION: It is unclear what the best route for early enteral nutrition is after esophagectomy. Especially data regarding early oral intake are scarce, and phase 2 trials are needed for further investigation. REGISTRATION: International prospective register of systematic reviews, CRD42013004032.