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The standard of care (SoC) in our department consists of enteral nutritional support of maximum 1000 kilocalories (kCal) through a peroperatively placed jejunostomy feeding tube started at POD 1. Oral caloric intake is resumed at POD 4.

As study intervention (INT), a period of caloric restriction is set by starting the enteral nutritional support later, at POD 5. Oral caloric intake is resumed at POD 4, similarly as in the control group. This intervention results in a relative caloric defect of more than 4.000 kCal in the immediate postoperative course.

instead of caloric suppletion, participants will receive mls of water over the jejunostomy feeding tube daily equivalent to the rate of increase of infusion of the control group as to preserve the same amount of fluid administration through the GI route as the control group.

This is continued until POD5 12.00h when enteral feeding is started according to the incremental regimen as defined for the SOC group. During the intervention, water is used as to maximize stimulation of the enteral route, however without giving nutritional support and need to prolong iv-infusion for maintaining the fluid balance in the participants. Also subjects in this interventional arm will end up with a caloric suppletion of 1.000kCal/24h by the end of postoperative day 7.

delayed start enteral support @ POD5

Hans GL Van Veer, MD

Johnny Moons, MscN

Celine Rihon, RN

Philippe Nafteux, MD, PhD

Lieven P Depypere, MD, PhD

Michaël Casaer, MD, PhD

The surgical stress of an esophagectomy causes a detrimental impact on the physiological response of the body. In this perspective, one could question whether the current feeding regimens of starting early nutritional support at postoperative day (POD) 1 have a similar negative impact on the muscle mass as documented in critically ill patients.

This study will introduce relative starvation in the early days following esophagectomy compared to the current regimen of early enteral nutritional support.

The research team aims to investigate whether the negative impact on muscle mass and muscle function might be reduced, which should result in enhanced postoperative recovery. The final result of the study will be a well-documented and scientifically substantiated nutritional regimen for patients who underwent an esophagectomy for cancer.

Patients suffering from oesophageal cancer are known to suffer from important weight loss preoperatively, due to dysphagia attributed to the growing tumour. Postoperatively, the challenge of maintaining weight is even more important given the new way of eating through the gastric conduit that replaces the oesophagus. They often also need to tackle dysphagia caused by an anastomotic stricture and overcome the physiological stress of the operation. As a consequence, almost all patients are confronted with postoperative weight loss. Obviously, patients with a low preoperative weight do not have a lot of reserve and are thus even more at risk of becoming anorectic in the postoperative setting.

This postoperative weight loss has a direct relationship with impaired survival. Therefore, reversing or at least stabilizing the postoperative weight loss might improve survival. The link between weight loss and impaired survival is found in the concept of sarcopenia, the breakdown of muscle fibers. Indeed, by losing muscle strength, patients become too weak for general tasks like bathing, putting clothes on or shopping. In a more pronounced stage, loss of muscle mass is responsible for impaired recovery and eg. the inability to fight against respiratory infections due to lack of cough power.

A logical reaction would therefore be to maximize caloric intake in the peri- and postoperative setting. One could therefore implement extra caloric intake as early as possible in the postoperative track in order to improve recovery. This has been up to now been advocated by scientific organisations like ESPEN (European Society for Clinical Nutrition and Metabolism) by spreading their guidelines on postoperative nutrition.

In contrast, within the field of intensive care and nutrition, discussion has risen about timing of feeding. The focus here shifted in the direction of postponing nutrition to a later stage in the recovery of a sick patient, rather than initiate feeding too soon. Through fundamental research, the concept of impaired autophagy at muscular level in case of early feeding was put forward as underlying mechanism. Muscle cells get swollen and their interlinking structure gets disturbed, resulting in decreased function. The muscle loss itself is triggered by the initial inflammatory storm that these patients go through when their lives are at stake at admission on the ICU. Early energy suppletion seems to aggravate this process even more. This cascade negatively influences recovery. This finding led in our own institution to postpone feeding of patients at the ICU until one week after admission, in order to minimize muscle tissue loss.

The investigators consider the experience in ICU patients as a proof of concept of the postoperative aggravation of sarcopenia in esophageal cancer patients. As patients following esophagectomy are also confronted with a similar catecholamin storm and insulin resistance, they could also be considered to suffer from similar processes that inhibit recovery as patients at the ICU.

The main research hypothesis is therefore that relative energy restriction following surgery would result in better qualitative muscle tissue, in comparison to patients that receive early enteral nutritional support. By doing so, the researchers assume to minimize autophagy at muscular level, resulting in better function and ultimately also in better postoperative recovery. Ultimately, this limitation of muscle loss most likely will have a beneficial effect on survival.

The primary outcome parameter, improvement of muscle function, will be assessed by means of a 6 minute walk test. Apart from this test, several side measurements will be performed - a nutrition diary, activity assessment by means of a MoveMonitor sensor, bio-impedance measurement, quantitive evaluation of muscle mass by CT, qualitative evaluation of muscle quality by muscle biopsy, quality-of-life-questionnaires and continous monitoring of glucose levels during enteral feeding will give the researchers more insight in the underliying mechanisms.

Single blinded (for outcome), open label, prospective, randomized, controlled, parallel-group designed interventional study

The study is single blinded at the level of outcome assessment. As in the postoperative setting it will be clear which subject is in the delayed enteral feeding group, masking cannot be performed for participants, care providers and the investigators. Therefore the study is considered to be open label, but single blinded for the primary outcome analysis.

Assessing Timing of Enteral Feeding Support in Esophageal Cancer Patients on Muscle functTion and Survival

Assessing the Influence of Timing of Enteral Feeding Support in Esophageal Cancer Patients on Muscle functTion and Survival

number of readmissions following primary discharge

Changes in 6-minute walked distances at further time points than the primary parameter

status dead or alive following surgery, after ongoing follow-up for one year

complications as defined by the Esophagectomy Complications Consensus Group (ECCG)

duration of admission, from day of operation until discharge, expressed in days

Reasons for readmissions following primary discharge, based on the complications list as defined by the Esophagectomy Complications Consensus Group (ECCG)

quality of life, assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30, probing quality of life in cancer patients by means of 30 questions - Likert Scales \[range 1 to 4, lower is better\]

quality of life, assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-OES18, probing quality of life in oesaphageal cancer patients by means of 18 questions, being more disease specific than the QLQ-C30 questionnaire - Likert Scales \[range 1 to 4, lower is better\]

monitored by means of a Dynaport® accelerometer; duration per assessment period a subject has performed physical activity with a Metabolic Equivalent of Tasks (MET) greater than \>3.

MET is a measure for energy expenditure with MET \>3 corresponding to activity more than sedentary state (MET 0 to 3); higher scores means more active.

monitored by means of a Dynaport® accelerometer, expressed in kCal

analysis of body composition by means of Seca Body Composition Analyzer 515. Assessed parameter: skeletal muscle mass, expressed in percentage of body weight

analysis of body composition by means of Seca Body Composition Analyzer 515. Assessed parameter: total body water, expressed in percentage of body weight

analysis of body composition by means of Seca Body Composition Analyzer 515. Assessed parameter: total body fat, expressed in percentage of body weight

analysis of body composition by means of Seca Body Composition Analyzer 515. Assessed parameter: phase angle, expressed in ° (degrees)

effect of permissive caloric restriction in the intervention group (detection of eventual hypoglycaemia) and the effect of nocturnal enteral nutrition on the glucose homeostasis in the whole patient cohort - by means of a flash glucose monitoring system (Freestyle, Abbott).

• total time of 'glycaemia level in range', defined as time with (interstitial) glycaemia level between 70mg/dl and 180mg/dl, expressed in total time (minutes/24h)

effect of permissive caloric restriction in the intervention group (detection of eventual hypoglycaemia) and the effect of nocturnal enteral nutrition on the glucose homeostasis in the whole patient cohort - by means of a flash glucose monitoring system (Freestyle, Abbott).

• total time of hypoglycaemia, defined as time with interstitial glycaemia level \< 70mg/dl, expressed in total time (minutes/24h);

effect of permissive caloric restriction in the intervention group (detection of eventual hypoglycaemia) and the effect of nocturnal enteral nutrition on the glucose homeostasis in the whole patient cohort - by means of a flash glucose monitoring system (Freestyle, Abbott).

• total time of hyperglycaemia, defined as time with interstitial glycaemia level \> 250mg/dl) during nocturnal enteral feeding between 08 pm and 08 am, expressed in total time (minutes/12h)

estimation of muscle quantity/sarcopenia via pre- and postoperative available CT-imaging, in comparing mm² of muscle surface area on L3-level image slice

microscopic evaluation and assessment of muscle tissue through muscle biopsy; for seperate consented participants only

recording of infections, luxations, blockages and reasons for reintervention/replacement/reinsertion

weight and height will be combined to report BMI in kg/m\^2

recording of total caloric intake, proteins and fat (oral intake and administered enteral nutritional support though feeding tube), expressed in kCal, g proteins, g fats, based on feeding diaries (home) and food platter pictures (hospital)

Level of variation of satiety hormones between groups, which could influence appetite and weight loss, expressed in pmol/l

Assessment of blood glycaemic profile over the course of the study, at sober state of participant, expressed in mg/dl

Assessment of HbA1c profile over the course of the study, at sober state of participant, expressed in percent

detect a difference in walked distance evaluated by means of a 6-minute walk test

number of days alive outside hospital from randomisation until POD90, divided by the number of postoperative days excludng admission days for perioperative chemotherapy (max: 90 days)

General Health Related Quality of Life evaluated by means of participant responses on the European Organisation for Research on the Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer QLQ-C30 (generic cancer questionnaire) and Quality of Life Questionnaire QLQ-OES18 (oesophageal cancer disease-specific questionnaire, as an adjoint to the more generic cancer cancer questionnaire).

Scores are expressed in 4-point Likert scales from 1 to 4; higher score equals worser outcomes.

Research Foundation Flanders

Kom Op Tegen Kanker

KU Leuven

University Hospital, Gasthuisberg

MD, FEBS-OGS

Central Nervous System Depressants

All Drugs and Chemicals

Other Dietary Supplements

Benzocaine

Tannic Acid

Start oral feeding 5-7 days after esophagectomy and discharge with soft blended diet as major energy source

Start clear liquid fluid diet 5-7 days after esophagectomy and discharge with jejunostomy feeding as the major energy source. Start oral feeding at postoperative 1st visit

Maintain jejunostomy feeding till postoperative 1st visit after esophagectomy in delayed feeding group

Jejunostomy feeding

Comparison of nutritional and early surgical outcome between early and delayed oral feeding after esophagectomy for esophageal cancer

Esophageal cancer is a highly aggressive malignancy that metastasizes to the lymph nodes and is associated with a poor prognosis. The 5-year overall survival rate is 40.0 % and the 30-day mortality rate is 1.7 %. Surgical resection is the most effective treatment for localized esophageal cancer; however, esophagectomy is extremely invasive and is associated with high morbidity and mortality rates.

Nutrition is one of the most important factors to consider after esophagectomy in order to reduce surgical mortality. The European Society for Parenteral and Enteral Nutrition guidelines recommend early tube feeding after major gastrointestinal surgery for cancer. Several studies have shown that enteral nutrition is more effective than parenteral nutrition in reducing postoperative complications in postesophagectomy patients. It has been reported that 5 to 7 days are required for anastomosis site healing. Therefore, many centers start oral feeding after esophagectomy on postoperative 7 days after anastomosis site evaluation, and enteral feeding via jejunostomy are maintained for nutritional support. However, the optimal timing for oral feeding after esophagectomy is still under debate.

In our center, the investigators routinely place jejunostomy tube for sufficient enteral feeding after esophagectomy. Before 2014, the investigators started oral feeding 5 to 7 days after esophagectomy and patients were discharged with soft blended diet. After 2014, the investigators changed our postoperative management protocols: 1) the investigators started only liquid diet 5 to 7 days after esophagectomy and maintained this feeding regimen until the first postoperative clinic visit with supplement of enteral feeding by jejunostomy tube. However, no studies have been conducted showing the optimal timing for oral feeding for esophagectomy patients for nutritional support and postoperative care.

The investigators hypothesized that delayed oral feeding after esophagectomy with jejunostomy feeding is superior to conventional oral feeding for nutritional support and early clinical outcome.

Conventional Oral Intake vs Delayed Oral Intake With Jejunostomy Feeding After Esophagectomy (JNS Study)

Comparison of Clinical Outcomes and Nutritional Status Between Conventional Oral Intake and Delayed Oral Intake With Jejunostomy Feeding After Esophagectomy: An Open Labeled Randomized Controlled Trial

Percentage of body weight loss from preoperative body weight

Complication related to jejunostomy feeding

GLIM criteria for malnutrition, handgrip strength, serum albumin, serum prealbumin

Postoperative daily total calorie intake (kcal/day)

Postoperative daily protein intake (g/day)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Assessing Timing of Enteral Feeding Support in Esophageal Cancer Patients on Muscle functTion and Survival	NCT03676478	Esophageal Canc... Nutrition Aspec... Postoperative C... Muscle Weakness Sarcopenia Jejunostomy; Co...	delayed start e...	18 Years - 90 Years	University Hospital, Gasthuisberg
Conventional Oral Intake vs Delayed Oral Intake With Jejunostomy Feeding After Esophagectomy (JNS Study)	NCT05318404	Esophageal Canc... Surgery Jejunostomy; Co... Nutrition Relat...	Jejunostomy fee...	19 Years - 75 Years	Seoul National University Hospital
Conventional Oral Intake vs Delayed Oral Intake With Jejunostomy Feeding After Esophagectomy (JNS Study)	NCT05318404	Esophageal Canc... Surgery Jejunostomy; Co... Nutrition Relat...	Jejunostomy fee...	19 Years - 75 Years	Seoul National University Hospital

Spots Global Cancer Trial Database for jejunostomy; complications