halted prematurely on the occasion of a planned sample size reestimation after 200 randomised patients during which an unexpected futility finding was demonstrated

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.

Inclusion Criteria:

• Candidates for surgical resection with a curative intent, admitted to our Department.
• Able to understand the study information in Dutch or French and tasks related to the study measurements provided by the researchers.
• Able to consent.
• Patients with cancer of the gastroesophageal junction (GEJ), distal, mid- and proximal thoracic esophagus.
• Patients with early as well as advanced clinical stage esophageal cancer: from clinical stages cT1N0 over cT2+ N+ or cT3 Nx after neo-adjuvant therapy or at the time of staging as a candidate for primary surgery.
• Histology preop: Squamous or adenocarcinoma.
• Patients must undergo at least two-field lymphadenectomy; three-field lymphadenectomy if deemed necessary by the clinical team is not a contraindication for inclusion.
• All access: (robotic assisted) minimal invasive (thoracoscopy & laparoscopy) approach, left thoraco-abdominal incision, hybrid esophageal resection or R thoracotomy + laparotomy
• Partial or subtotal esophagectomy.
• Reconstruction by gastric conduit.
• All anastomoses (intrathoracic or cervical).
• Women of child bearing age with esophageal cancer can be included.

Exclusion Criteria:

• Patients in a definitive chemoradiation protocol, or undergoing rescue resection following definitive chemoradiotherapy.
• Patients expected to die within 12 hours (=moribund patients).
• Patients transferred from another institute after esophageal resection with an established nutritional therapy.
• Patients with a cT4b tumor after neo-adjuvant therapy.
• Patients who are at the time of surgery deemed unresectable or found to be unresectable during surgery.
• Patients with a R2-resection.
• Patients with metastasis at the time of clinical staging.
• Patients undergoing transhiatal resection of the esophagus.
• Patients undergoing total gastrectomy
• Patients undergoing an esophageal resection or esophageal bypass as palliative treatment
• Patients with tumors in the cervical esophagus with a distance less than 3cm from the cricopharyngeal sphincter.
• Patients with pharyngeal cancer undergoing (laryngo-)pharyngectomy with gastric pull-up
• Need for colonic or jejunal interposition
• Patients with a second synchronous malignancy
• Patients with inflammatory bowel disease (as this might interfere with caloric uptake in the small bowel)
• Patients with contra-indications for enteral nutrition.
• Patients already participating in a study with a nutritional intervention.

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.