**3. Perioperative nutritional care**

#### **3.1. Enteral versus parenteral nutrition**

avoid foods that worsen symptoms leading to inadequate intake of calories. The surgical pro‐ cedure often causes deficiencies in macronutrients and micronutrients, with the most prevail‐ ing side effects being postprandial dumping syndrome, dysphagia, anorexia, reflux, and early satiety [53–55]. Furthermore, chemotherapy affects rapidly proliferating cells preferentially and, consequently, affects the cells of the gastrointestinal tract. Chemotherapy‐related causes of reduced food intake include nausea, vomiting, diarrhea, mucositis, and decreased appetite. Radiotherapy also contributes to malnutrition, and combined with chemotherapy exacerbates patients' nutritional status. Common side effects of radiotherapy include mucositis, esopha‐ gitis, odynophagia, mouth and throat soreness, and hypogeusia [56]. Tumor‐related causes of malnutrition are also of great significance, but the mechanisms involved are still under inves‐ tigation. Cancer‐induced anorexia may result from circulating factors produced by the tumor or by the host in response to the tumor. For instance, cytokines, such as interleukins (IL) and tumor necrosis factor‐alpha (TNF‐α) cause anorexia [57], whereas other tumor‐secreted fac‐ tors promote central‐ and peripheral‐mediated cancer cachexia. Tumor growth results in the secretion of pro‐inflammatory factors that promote cachexia by signaling anorexia, muscle wasting, and white adipose tissue atrophy. Tumors also secrete both the proteolysis‐inducing factor and activin, which promote skeletal muscle degradation and sarcopenia [58, 59].

**Figure 1.** Example of CT scan analysis by the Slice‐O‐Matic software. Lumbar vertebrae 3 slice with Hounsfield units used to measure area of skeletal muscle, subcutaneous fat and visceral fat. White outer ring, subcutaneous fat; Light grey

inner ring, muscle; Dark grey central area, visceral fat. Reproduced from Gibson et al. [42].

94 Esophageal Abnormalities

Even though the mechanisms behind muscle wasting have been widely studied, less is known about the factors implicated in adipose tissue loss in cancer cachectic patients, such as lipid‐ mobilizing factor, as well as about the derangement in the neuroendocrine regulation of food intake and anorexia [60]. Additionally, changes in carbohydrate, lipid, and protein metabo‐ lism account for altered substrate metabolism. Changes in resting energy expenditure (REE) are considered one of the causes of nutritional depletion in cancer. In particular, measured REE by indirect calorimetry (IC) was elevated in patients with newly detected esophageal Esophagectomy is one of the most invasive and time‐consuming operations among gastro‐ intestinal surgical procedures. It induces a strong stress response in the human body [66]. Consequently, patients' nutritional status is deteriorated after surgery, making postoperative nutritional care very important. The use of enteral nutrition (EN) postoperatively is a matter of debate, while scientific research attempts to define the role of enteral and parenteral nutri‐ tion (PN) on the clinical outcome of patients undergoing esophagectomy. Enteral feeding is considered the method of choice for the nutritional support of cancer patients with function‐ ing gastrointestinal tract. Enteral nutrition is advantageous over parenteral nutrition for the following reasons: it provides all the necessary micro‐ and macronutrients in a more intact form, maintains gut mucosal integrity, inhibits the cytokine response, reduces the secretion of stress hormones, inhibits bacterial translocation, has a decreased risk of complications, and is less expensive [67]. Nevertheless, enteral nutrition is often avoided in order to minimize strain to the anastomoses, and reduce the risk of postoperatively impaired gastrointestinal motility. Another concern involves the return of gut motility or peristalsis and the ability of the gut to absorb nutrients. Surgical advances have increased the integrity of all anastomoses, making early oral enteral feeding after surgery a feasible option.

A randomized control trial investigated the outcomes of PN or EN after thoracoscopic esoph‐ agectomy. The rate of weight loss at postoperative day (POD) 14 was significantly lower in the EN group than in the PN group. Prealbumin levels at POD 10 showed no differences between the two groups. However, the incidence of postoperative pneumonia was higher in the PN group than in the EN group [68]. The results of another randomized clinical trial showed that there was no significant difference between EN and PN groups in terms of postoperative serum albumin, prealbumin, or transferrin. However, complement component 3 (C3) and 4 (C4) levels were significantly higher in the EN group compared with the PN group, while C‐reactive protein level was significantly lower in the enteral feeding group. Bowel move‐ ments were restored sooner and costs of treatment were lower in the EN group. Postoperative complications did not differ significantly between the two groups [69]. Results from a recent meta‐analysis of 10 randomized controlled trials concerning cancer patients following esoph‐ agectomy indicated that early postoperative enteral nutrition could significantly decrease pulmonary complications and anastomotic leakage compared with parenteral nutrition. On the eighth postoperative day, the EN group had higher levels of albumin and prealbumin compared with the PN group, suggesting that postoperative EN support is more effective in maintaining patients' nutritional status than PN support. No difference was observed in digestive complications between these two approaches. However, this meta‐analysis is char‐ acterized by heterogeneity issues, especially regarding the postoperative nutritional status [70]. Furthermore, others suggest that combination of enteral and parenteral feeding is more beneficial, since total parenteral nutrition (TPN) could lead to hyperglycemia in stressed patients. A combination of EN and TPN might have some benefits when compared to TPN alone, such as improvement of intestinal integrity and stimulation of incretin production con‐ tributing to improved glucose control in patients undergoing esophagectomy [71]. Moreover, supplemental parenteral nutrition after esophagectomy contributes to better coverage of patients' calorie requirements, since large amounts of enteral nutrition are not usually toler‐ ated in the first postoperative days [72].

The European Society for Parenteral and Enteral Nutrition (ESPEN) guidelines for nutritional support recommend that interruption of nutritional intake is unnecessary after surgery in most patients and in patients who require postoperative artificial nutrition, enteral feeding, or a combination of enteral and supplementary parenteral feeding is the first choice. Also this combination should be considered in patients in whom more than 60% of energy needs cannot be met via the enteral route. Postoperative parenteral nutrition is beneficial in under‐ nourished patients in whom enteral nutrition is not feasible or not tolerated. In addition, postoperative parenteral nutrition is beneficial in patients with postoperative complications impairing gastrointestinal function that are unable to receive and absorb adequate amounts of oral/enteral feeding for at least 7 days [28]. Moreover, the American Society for Parenteral and Enteral Nutrition (ASPEN) guidelines for critically ill patients recommends that patients who have undergone major upper gastrointestinal tract surgery and EN is not feasible, PN should be initiated (only if the duration of therapy is anticipated to be more than 7 days). Unless the patient is at high nutrition risk, PN should not be started in the immediate postoperative period, but should be delayed for 5–7 days [73]. In conclusion, although enteral nutrition seems to be a safe and feasible option postoperatively in terms of immunological parameters and postoperative complications, no firm conclusion can be drawn regarding postoperative nutritional markers that reflect patients' nutritional status.

#### **3.2. Time of feeding**

#### *3.2.1. Early enteral nutrition*

The initiation of enteral feeding after esophagectomy remains a controversial topic and many studies examine whether or not early enteral feeding affects negatively or positively the post‐ operative outcome. One study that investigated early enteral feeding after esophagectomy included 208 patients who received enteral nutrition postoperatively and were divided into three groups (Group 1, 2, and 3) based on whether they received EN within 48 h, 48–72 h or more than 72 h, respectively. The postoperative complications, length of hospital (LOH) stay, days for first fecal passage, cost of hospitalization, and the difference in serum albumin values pre‐ and postoperatively were all recorded. Group 1 had the lowest thoracic drainage volume, the earliest first fecal passage, and the lowest LOH and hospitalization expenses of all the three groups. The incidence of pneumonia was higher in Group 3. Finally, all postop‐ erative outcomes of nutritional status were worst in Group 3 [74]. Similarly, one systematic review demonstrated that early oral EN was associated with reduced length of stay and did not increase complication rates [75]. More randomized clinical trials are required to confirm the results from retrospective studies that indicated that early EN promotes early recovery of intestinal movement and better recovery from systemic inflammation [66]. In addition, current literature is inconclusive with respect to the right time of EN administration postoperatively, that is, EN initiation within 24 h versus EN initiation during 24–72 h [76, 77].

#### *3.2.2. Enhanced recovery after surgery (ERAS)*

pulmonary complications and anastomotic leakage compared with parenteral nutrition. On the eighth postoperative day, the EN group had higher levels of albumin and prealbumin compared with the PN group, suggesting that postoperative EN support is more effective in maintaining patients' nutritional status than PN support. No difference was observed in digestive complications between these two approaches. However, this meta‐analysis is char‐ acterized by heterogeneity issues, especially regarding the postoperative nutritional status [70]. Furthermore, others suggest that combination of enteral and parenteral feeding is more beneficial, since total parenteral nutrition (TPN) could lead to hyperglycemia in stressed patients. A combination of EN and TPN might have some benefits when compared to TPN alone, such as improvement of intestinal integrity and stimulation of incretin production con‐ tributing to improved glucose control in patients undergoing esophagectomy [71]. Moreover, supplemental parenteral nutrition after esophagectomy contributes to better coverage of patients' calorie requirements, since large amounts of enteral nutrition are not usually toler‐

The European Society for Parenteral and Enteral Nutrition (ESPEN) guidelines for nutritional support recommend that interruption of nutritional intake is unnecessary after surgery in most patients and in patients who require postoperative artificial nutrition, enteral feeding, or a combination of enteral and supplementary parenteral feeding is the first choice. Also this combination should be considered in patients in whom more than 60% of energy needs cannot be met via the enteral route. Postoperative parenteral nutrition is beneficial in under‐ nourished patients in whom enteral nutrition is not feasible or not tolerated. In addition, postoperative parenteral nutrition is beneficial in patients with postoperative complications impairing gastrointestinal function that are unable to receive and absorb adequate amounts of oral/enteral feeding for at least 7 days [28]. Moreover, the American Society for Parenteral and Enteral Nutrition (ASPEN) guidelines for critically ill patients recommends that patients who have undergone major upper gastrointestinal tract surgery and EN is not feasible, PN should be initiated (only if the duration of therapy is anticipated to be more than 7 days). Unless the patient is at high nutrition risk, PN should not be started in the immediate postoperative period, but should be delayed for 5–7 days [73]. In conclusion, although enteral nutrition seems to be a safe and feasible option postoperatively in terms of immunological parameters and postoperative complications, no firm conclusion can be drawn regarding postoperative

The initiation of enteral feeding after esophagectomy remains a controversial topic and many studies examine whether or not early enteral feeding affects negatively or positively the post‐ operative outcome. One study that investigated early enteral feeding after esophagectomy included 208 patients who received enteral nutrition postoperatively and were divided into three groups (Group 1, 2, and 3) based on whether they received EN within 48 h, 48–72 h or more than 72 h, respectively. The postoperative complications, length of hospital (LOH) stay, days for first fecal passage, cost of hospitalization, and the difference in serum albumin values pre‐ and postoperatively were all recorded. Group 1 had the lowest thoracic drainage

ated in the first postoperative days [72].

96 Esophageal Abnormalities

nutritional markers that reflect patients' nutritional status.

**3.2. Time of feeding**

*3.2.1. Early enteral nutrition*

Early enteral nutrition is an essential part of fast‐track surgery protocols in order to maximize the effects of enhanced recovery. Fast‐track programs incorporate new methods regarding anes‐ thesia, nutritional care, pain control, and surgical techniques in the preoperative, intraopera‐ tive, and postoperative period, aiming to promote postoperative rehabilitation of patients [78]. ESPEN guidelines recommend that all cancer patients undergoing either curative or palliative surgery should be managed within an enhanced recovery program postoperatively; within this program every patient should be screened for malnutrition and if deemed at risk, given addi‐ tional nutritional support [79]. Nutritional aspects of ERAS could be summarized as follows: limitation of preoperative fasting, preoperative fluid and carbohydrate loading, and initiation of oral diet on the first postoperative day [80]. A recently published review demonstrated that utilization of enhanced recovery programs in esophageal cancer patients was associated with a reduction in the incidence of anastomotic leak, pulmonary complications, and length of hospi‐ tal stay, but no significant change was observed in postoperative mortality or readmission rate. Nevertheless, there was significant heterogeneity between the studies in terms of enhanced recovery protocols, surgical approach, and utilization of neoadjuvant therapies that should be taken into account [81]. Results from a randomized controlled clinical study showed that the implementation of a fast‐track protocol improved postoperative clinical recovery and cellular and humoral immunity of patients undergoing esophagectomy for esophageal cancer (**Table 2**) [82]. In this context, the implementation of fast‐track programs in esophagectomy patients is promising, but the majority of patients included in the studies are relatively healthy patients. More randomized controlled studies and evidence‐based research are required in order to jus‐ tify the routine use of fast‐track protocols in esophageal cancer patients [83].

#### **3.3. Perioperative immunonutrition**

Immunonutrition is one of the most debated topics in nutritional support of esophageal can‐ cer patients. The term immunonutrition includes formulas that contain immune‐modulating substances, such as arginine, glutamine, ribose nucleic acid, and omega‐3‐fatty acids. A recent review concluded that postoperative enteral immunonutrition could be promising in improv‐ ing humoral immunity in patients undergoing esophagogastric resection, but this improvement is not related to a reduced hospital stay, nor does it reduce the rate of infections. The authors reported that there is heterogeneity regarding the types of operations undertaken (two studies included patients undergoing esophagectomy, three studied patients undergoing gastrectomy,


**Table 2.** Daily guideline of postoperative care of patients with fast‐track surgery pathway.

and one had patients undergoing both operations). Additionally, the included randomized clinical trials used different formulations of enteral immunonutrition and standard enteral nutrition, further limiting the accuracy of the results. Moreover, not all studies reported the same outcomes as far as inflammatory and immunological markers are concerned. Therefore, the authors suggest that there is no convincing evidence in terms of routine immunonutrition in patients undergoing esophageal resection for cancer [84].

On the other hand, preoperative nutritional supplementation with immune‐enhancing for‐ mulas was associated with reduced infectious complications, duration of hospitalization, improved short‐term survival and less mortality in patients with esophageal cancer. These results highlight the possible need to provide immunonutrients before surgery to obtain suf‐ ficient levels at the time of surgical stress when there is an increased need for stimulation of the immune system [85]. One meta‐analysis that included studies with patients that under‐ went esophagectomy, gastrectomy and pancreatectomy, demonstrated that patients who received immunonutrition postoperatively, had a significantly lower risk of wound infec‐ tion and shorter length of hospital stay. No significant effect of immunonutrition on other postoperative morbidities and mortality was noticed [86]. The reduction in hospital stay and/ or in postoperative complications seems to compensate for the higher cost of immunonutri‐ tion compared to standard enteral feeding in a cost‐effectiveness analysis [87]. According to ESPEN guidelines on nutrition in cancer patients, upper gastrointestinal tract cancer patients undergoing surgical resection should receive oral/enteral immunonutrition in the context of traditional perioperative care [79]. Furthermore, ASPEN guidelines suggest the routine use of an immunemodulating formula (containing both arginine and fish oils) in the surgical inten‐ sive care unit for the postoperative patient who requires enteral nutrition therapy [73].

Synbiotics, which are a combination of prebiotics and probiotics, are speculated to have beneficial effects on human health, but little is known about their clinical value in patients who have undergone esophagectomy. Administration of synbiotics prevented postoperative deterioration of the intestinal microfloral environment and suppressed excessive inflamma‐ tory response, possibly by exerting immunomodulatory effects and by inhibiting bacterial translocation [88, 89]. Additionally, synbiotics led to decreased incidence of severe diarrhea and lower interruption or reduction of enteral nutrition. Passage of flatus postoperatively occurred significantly earlier in patients who received synbiotics than in the control group, suggesting that synbiotics maintain intestinal motility [88]. Taking all the aforementioned things into consideration, larger scale studies are needed in order to define whether or not immunonutrition has beneficial effects on the postoperative outcome of esophageal cancer patients. Future research should focus on the optimal dose of specific immunonutrients, on the timing (preoperatively and/or postoperatively) and duration of immunonutrition delivery and clarify which is the target group the intervention should be addressed to.

#### **3.4. Type of feeding**

**Day FTS pathway**

98 Esophageal Abnormalities

POD1 Jejunostomy tube feeding 500 ml (starting at 20 ml/h)

Physical therapy and nebulizers

Expand mobilization (>4 h out of bed) Continue physical therapy and nebulizers

Expand mobilization (>6 h out of bed) Continue physical therapy and nebulizers

If swallow shows no leak, advance patient to oral drink Jejunostomy tube feeding 1500 ml (60–80 ml/h) Continue physical therapy and nebulizers Education on aspiration precaution Education on chewing and swallowing

(>2 h out of bed)

Remove urine catheter Head of bed put at 30° Supply albumin Chest tube to suction Promoted to lung recruitment

POD2 Jejunostomy tube feeding 1000 ml (40 ml/h) Chest tube to suction

Continue supply albumin POD3 Jejunostomy tube feeding 1500 ml (60–80 ml/h) Remove chest tube Remove epidural catheter

Continue supply albumin POD4 Gastrograffin opacification of upper gastrointestine

POD5 Jejunostomy tube feeding 1500 ml (60–80 ml/h)

(500 or 1000 ml)

Full liquid diet

*Note:* FTS: Fast track surgery. Adapted from Chen et al. [82].

POD6 Increase liquid diet

POD7 Remove jejunostomy tube

Advance patient to a full liquid diet Continue aspiration precautions

Decrease jejunostomy tube feeding

Continue aspiration precautions

Continue aspiration precautions

Continue physical therapy and nebulizers

Continue physical therapy and nebulizers

Discharge home on soft diet and liquid diet

**Table 2.** Daily guideline of postoperative care of patients with fast‐track surgery pathway.

Early postoperative mobilization program

Enteral feeding postoperatively seems to be the method of choice for uncomplicated esopha‐ geal cancer patients. Enteral feeding options after surgery include mainly nasoenteric tubes and jejunostomy catheters, in order to bypass recently constructed anastomoses. However there is no general agreement regarding the best method for postoperative feeding, and the optimal access route remains questionable. Tube‐related complications include occlusion, catheter displacement and local cellulitis at the site of insertion. More severe complications include leakage into the peritoneal cavity resulting in peritonitis, volvulus at the point of fixation to the anterior abdominal wall, aspiration pneumonia, necrotizing fasciitis or jejunal necrosis at the site of catheter insertion and septicemia [90, 91].

A retrospective analysis of 90 patients who underwent esophagectomy demonstrated that early enteral nutrition can be administered using three different routes (nasojejunal tube, jejunostomy tube, and pharyngostomy tube) with similar results regarding tube‐related complications, length of stay, and 30‐day morbidity [92]. Another study of esophageal can‐ cer patients with dysphagia examined the effects of jejunostomy feeding on weight loss and treatment outcomes. The palliative group of patients was able to maintain a stable weight despite the presence of cancer cachexia. This was also evident in the esophagectomy group of patients despite the catabolic effect of the operation, indicating the effectiveness of the jeju‐ nostomy feeding catheter as a means of nutritional support. The feeding catheter was well tolerated by the majority of patients (86.8%) and the most frequently occurred complications included catheter clogging (10.1% of the study population) and catheter dislodgement (3.1% of the study population) [93]. A randomized clinical study that compared nasoenteric tubes to jejunostomy feeding in upper gastrointestinal tract cancer patients showed that the length of enteral feeding use was less in the nasoenteric group and parenteral feeding was required more frequently than in jejunostomy feeding group. Complications related to the different feeding routes were similar between the two groups [94]. A recent review investigated the best route for enteral nutrition following esophagectomy (oral intake, jejunostomy, or naso‐ jejunal tube feeding) in terms of postoperative complication rates, percentage of patients meeting their nutritional needs, weight loss, tube feeding complications, mortality, patient satisfaction, and length of hospital stay. Complications and catheter efficacy did not differ between postoperative nasojejunal tube feeding and jejunostomy tube feeding. Moreover, jejunostomy feeding patients were able to meet their short‐term nutritional requirements, but data concerning long‐term outcomes and patients satisfaction were scarce. This review concluded that the best route for the delivery of early enteral nutrition postoperatively is still unclear [75].

ESPEN guidelines on enteral nutrition in surgical patients recommends that tube feed‐ ing should be applied in patients who cannot start early oral nutrition, including those undergoing gastrointestinal surgery for cancer and patients with obvious undernutrition at the time of surgery, in whom oral intake will be inadequate (<60%) for more than 10 days. Initiation of tube feeding should start within 24 h after surgery with a low flow rate (i.e. 10–20 ml/h) due to limited intestinal tolerance. Placement of a needle catheter jejunos‐ tomy or nasojejunal tube is recommended for all candidates for tube feeding undergoing major abdominal surgery. When anastomoses of the proximal gastrointestinal tract have been performed, enteral nutrition should be delivered via a tube placed distally to the anastomosis [95].

Postoperative nutritional management of esophageal cancer patients can be summarized as in **Figure 2**.

**Figure 2.** Postoperative nutritional management of esophageal cancer patients.
