**4. Nutritional care during chemoradiotherapy**

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

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

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

Postoperative nutritional management of esophageal cancer patients can be summarized as

necrosis at the site of catheter insertion and septicemia [90, 91].

still unclear [75].

100 Esophageal Abnormalities

anastomosis [95].

in **Figure 2**.

#### **4.1. Nutrition issues during chemotherapy and radiotherapy**

Currently, perioperative chemotherapy is frequently administered for the treatment of resectable advanced esophageal cancer. The neoadjuvant administration of chemother‐ apy or chemoradiotherapy preoperatively results in reduced tumor size before surgery. Perioperative chemotherapy improves significantly disease‐free survival and overall survival rates compared to surgery alone. However, a great percentage of these patients are not able to complete the planned postoperative chemotherapeutic regimens. This is mainly caused because of postoperative complications and impaired nutritional and physical status [96–98]. Gastrointestinal disorders caused by chemotherapy itself, including nausea, vomiting, diar‐ rhea, and anorexia, negatively affect patients' quality of life and make completion of chemo‐ therapy difficult. Neoadjuvant chemotherapy induces changes in body composition which, in turn have negative impact on clinical outcomes. Results from a small cohort of esophageal cancer patients showed that 26% of patients were sarcopenic before the initiation of neoad‐ juvant chemotherapy and this percentage increased to 43% after its completion. There was a significant loss of fat mass and skeletal muscle mass which was associated with risk of circumferential resection margin positivity [50]. In another study, sarcopenia was present in 56 and 67% of patients before and after neoadjuvant chemoradiotherapy, respectively. This decrease in muscle mass was predictive of postoperative mortality in the stage III–IV sub‐ group of patients [99]. Furthermore, most of the radiotherapy‐related toxicities are strongly associated with patient's nutritional status. Esophagitis is the main toxicity during radio‐ therapy in esophageal cancer patients. These patients often suffer from pain and difficulties in swallowing [100]. One study in patients receiving concurrent chemoradiotherapy revealed that malnutrition was observed in 83.8% of patients, while 68.8% of patients developed severe dysphagia. Malnourished patients developed more treatment‐related toxicities compared to those without malnutrition. Patients with impaired nutritional status presented severe dys‐ phagia, anorexia, severe nausea/vomiting, and severe hematologic toxicities more frequently than those in a good nutrition status [17]. Although nutritionally related side effects occur fre‐ quently, nutritional assessment of patients with cancer receiving chemoradiotherapy is often omitted in the clinical setting. Scientific research has to focus on nutritional interventions during neoadjuvant chemoradiotherapy or postoperative adjuvant therapy that seems to improve patients' nutritional status, alleviate symptoms and increase tolerance to therapies.

#### **4.2. Nutritional interventions during chemoradiotherapy**

The type and timing of nutritional interventions during chemoradiotherapy challenge the caregivers, since a multidisciplinary approach seems more effective in managing treatment's side effects. Current literature emphasizes mainly on the immunomodulatory effects of some nutrients, on the impact of oral/tube administration of high‐energy, and/or high protein sup‐ plements on the clinical outcome and on patients education about selecting an enriched diet. In cancer patients, it has been shown that the use of supplemental formulas and *n*‐3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can improve body composition, preserve muscle mass, and possibly reverse or stop the development of cancer cachexia [101]. A controlled, randomized prospective, double‐blind, multicenter study investigated the impact of enteral nutrition (via percutaneous endoscopic gastrostomy (PEG)) enriched with EPA and DHA on body composition, nutritional and functional status of esophageal and head and neck cancer patients undergoing concurrent chemoradiotherapy. There was a tendency toward improvement regarding loss of body cell mass and body weight following chemoradiotherapy, but did not reach statistical significance. However, Karnofsky score and subjective parameters, such as the NRS 2002 and the SGA score were significantly improved in the experimental group compared with the control group, indicating improved nutritional and functional status [102]. Similar results reported by another randomized dou‐ ble‐blind clinical trial showed that administration of immunonutrition during chemoradio‐ therapy in head and neck and esophageal cancer patients was advantageous over standard enteral nutrition in terms of body weight, lean body mass, serum albumin levels, NRI assess‐ ment, plasma antioxidant capacity, and functional capacity [103].

Moreover, immunonutrition can modulate the immunological and inflammatory systems, thus reducing the risks of concurrent chemoradiotherapy. One randomized clinical trial examined the effects of immunonutrition on serum cytokine and inflammatory markers, and cellular immunity in locally advanced esophageal cancer patients undergoing chemoradio‐ therapy. The levels of C‐Reactive Protein (CRP) and TNF increased more during treatment in the control group (standard enteral nutrition) than in the treatment group, whereas all other markers did not differ significantly between the two groups [104]. In addition, the impact of immunonutrients on immune system of head and neck and esophageal cancer patients during chemoradiotherapy was examined in another randomized clinical trial. Immune cells metabolism and functions were assessed at the initiation and at the completion of treatment. The experimental group had better adaptation to the systematic inflammation and oxida‐ tive stress, as indicated by CD4<sup>+</sup> /CD8<sup>+</sup> T‐lymphocyte counts ratio, CD3 membrane expression, polymorphonuclear cells CD62L and CD15 densities, reactive oxygen species (ROS) produc‐ tion, and peripheral blood mononuclear cells production of pro‐inflammatory prostaglandin‐ E2 [105].

a significant loss of fat mass and skeletal muscle mass which was associated with risk of circumferential resection margin positivity [50]. In another study, sarcopenia was present in 56 and 67% of patients before and after neoadjuvant chemoradiotherapy, respectively. This decrease in muscle mass was predictive of postoperative mortality in the stage III–IV sub‐ group of patients [99]. Furthermore, most of the radiotherapy‐related toxicities are strongly associated with patient's nutritional status. Esophagitis is the main toxicity during radio‐ therapy in esophageal cancer patients. These patients often suffer from pain and difficulties in swallowing [100]. One study in patients receiving concurrent chemoradiotherapy revealed that malnutrition was observed in 83.8% of patients, while 68.8% of patients developed severe dysphagia. Malnourished patients developed more treatment‐related toxicities compared to those without malnutrition. Patients with impaired nutritional status presented severe dys‐ phagia, anorexia, severe nausea/vomiting, and severe hematologic toxicities more frequently than those in a good nutrition status [17]. Although nutritionally related side effects occur fre‐ quently, nutritional assessment of patients with cancer receiving chemoradiotherapy is often omitted in the clinical setting. Scientific research has to focus on nutritional interventions during neoadjuvant chemoradiotherapy or postoperative adjuvant therapy that seems to improve patients' nutritional status, alleviate symptoms and increase tolerance to therapies.

The type and timing of nutritional interventions during chemoradiotherapy challenge the caregivers, since a multidisciplinary approach seems more effective in managing treatment's side effects. Current literature emphasizes mainly on the immunomodulatory effects of some nutrients, on the impact of oral/tube administration of high‐energy, and/or high protein sup‐ plements on the clinical outcome and on patients education about selecting an enriched diet. In cancer patients, it has been shown that the use of supplemental formulas and *n*‐3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can improve body composition, preserve muscle mass, and possibly reverse or stop the development of cancer cachexia [101]. A controlled, randomized prospective, double‐blind, multicenter study investigated the impact of enteral nutrition (via percutaneous endoscopic gastrostomy (PEG)) enriched with EPA and DHA on body composition, nutritional and functional status of esophageal and head and neck cancer patients undergoing concurrent chemoradiotherapy. There was a tendency toward improvement regarding loss of body cell mass and body weight following chemoradiotherapy, but did not reach statistical significance. However, Karnofsky score and subjective parameters, such as the NRS 2002 and the SGA score were significantly improved in the experimental group compared with the control group, indicating improved nutritional and functional status [102]. Similar results reported by another randomized dou‐ ble‐blind clinical trial showed that administration of immunonutrition during chemoradio‐ therapy in head and neck and esophageal cancer patients was advantageous over standard enteral nutrition in terms of body weight, lean body mass, serum albumin levels, NRI assess‐

Moreover, immunonutrition can modulate the immunological and inflammatory systems, thus reducing the risks of concurrent chemoradiotherapy. One randomized clinical trial

**4.2. Nutritional interventions during chemoradiotherapy**

102 Esophageal Abnormalities

ment, plasma antioxidant capacity, and functional capacity [103].

Another role of immunonutrition is the potential protection against chemotherapy‐induced toxicities. Miyata et al. compared the effects between enteral nutrition rich in *n*‐3 fatty acids (900 mg/d) and enteral nutrition poor in *n*‐3 fatty acids (250 mg/d) on chemotherapy‐related adverse events and inflammatory markers during neoadjuvant chemotherapy in esoph‐ ageal cancer patients. This randomized control trial showed no significant difference in the incidence of grade 3/4 leukopenia and neutropenia, but stomatitis was observed less frequently in the *n*‐3‐rich group, than in the *n*‐3‐poor group. Grade 3/4 diarrhea was also observed less frequently in the *n*‐3‐rich group than in the *n*‐3‐poor group, but this was not statistically significant. Moreover, *n*‐3‐rich enteral nutrition seems to have hepatoprotec‐ tive properties by preventing an increase of aspartate aminotransferase and alanine amino‐ transferase values [106].

Synbiotics seem also to mitigate chemotherapy‐related side effects through adjustments to the intestinal microbiota. A randomized clinical trial investigated the effects of synbiotics in esophageal cancer patients undergoing neoadjuvant chemotherapy, on the intestinal microbi‐ ota, and the adverse events of treatment. Severe lymphopenia and diarrhea were less frequent in patients who received synbiotics than in the control group. Furthermore, febrile neutrope‐ nia occurred less in the synbiotics group compared to the control group [107]. Chemotherapy may disturb the intestinal microbiota, leading to reduced production of organic acids in the bowel, impaired mucosal integrity, and increased harmful bacteria. These, in turn, may induce chemotherapy‐related toxicities, such as diarrhea and infectious complications [108]. Administration of synbiotics results in increased concentrations of short‐chain fatty acids, such as acetate and propionate. These fatty acids are an important energy source of entero‐ cytes, maintain intestinal environment acidity and intestinal motility. Synbiotics also maintain the number of beneficial bacteria and inhibit the overgrowth of possible diarrheal pathogens, thus reducing the incidence of diarrhea [109].

ESPEN guidelines on nutrition in cancer patients recommend the supplementation with long‐ chain *n*‐3 fatty acids or fish oil to stabilize or improve appetite, food intake, lean body mass, and body weight in patients with advanced cancer undergoing chemotherapy and at risk of weight loss or malnourished [79]. It is therefore evident that immunonutrition enhances immune system and exerts anti‐inflammatory properties, but the promising effects on clini‐ cal outcome during chemoradiotherapy in esophageal cancer are still under investigation. Additional clinical trials are needed to determine the preferred type, timing and duration of immunonutrition required to reduce inflammation and chemotherapy‐induced toxicities, and maintain muscle mass.

Nutritional interventions, other than that examining the impact of specific immunonutrients on chemoradiotherapy‐related outcomes, include nutritional counseling and/or enteral sup‐ plements in order to maintain stable body weight and cope with feeding difficulties (**Table 3**). A recent randomized controlled trial compared the effects of a walk‐and‐eat intervention versus conventional medical care for patients with esophageal cancer undergoing neoadju‐ vant chemoradiotherapy. This intervention consisted of a structured walking protocol and weekly nutritional advice including weight and intake evaluation, counseling to overcome feeding difficulties, supplementation, if necessary, with enteral formulas, and patient's edu‐ cation concerning food texture modification and oral care before and after eating. During chemoradiotherapy, the group that received the walk‐and‐eat intervention had 100‐m less decline than controls in walk distance, 3 kg less decrease in handgrip strength, and 2.7 kg less reduction in body weight. Moreover, the experimental group had significantly reduced rates of intravenous nutritional support and wheel chair use [110]. Another randomized trial tested the effects of an interdisciplinary nutrition support team on clinical and hospitalized outcomes of esophageal cancer patients receiving concurrent chemoradiotherapy. Nutritional support included dietary counseling, oral nutritional supplements, enteral nutrition, and parenteral nutrition according to patient's needs. At the completion of treatment, nutritional status of patients in the interventional group was better compared to control group, as dem‐ onstrated by prealbumin, transferrin, and albumin levels. Bone marrow suppression and complications related to infections were significantly lower in the nutritional support group. Nutritional intervention was also associated with a lower average length of hospital stay and in‐patient cost [111]. Furthermore, nutritional intervention improved survival of esophageal cancer patients treated with definitive chemoradiotherapy. It is noticeable that this effect was observed only if nutritional support was provided at baseline (dietary advice, oral supple‐ mentation, or major intervention), and not if provided later in the treatment course [10].

According to ESPEN, in patients receiving radiotherapy, especially radiotherapy of the head and neck, thorax, and gastrointestinal tract, an adequate nutritional intake should be ensured primarily by individualized nutritional counseling and/or with use of oral nutritional

*Nutritional counseling Oral supplementation Immunonutrition Synbiotics*

*Parenteral nutrition support*

**Table 3.** Nutritional interventions during chemoradiotherapy.

supplements, in order to avoid nutritional deterioration, maintain intake, and avoid radio‐ therapy interruptions. In addition, for patients undergoing curative anticancer drug treat‐ ment who cannot meet their nutritional requirements despite counseling and oral nutritional supplements, ESPEN recommends supplemental enteral nutrition or, if this is not sufficient or possible, parenteral nutrition [79]. Therefore, assessment and maintenance of good nutri‐ tional status at baseline may be a simple and cost‐effective intervention that improves clinical outcomes in esophageal cancer patients during chemoradiotherapy treatment.

#### **4.3. Stent insertion**

immune system and exerts anti‐inflammatory properties, but the promising effects on clini‐ cal outcome during chemoradiotherapy in esophageal cancer are still under investigation. Additional clinical trials are needed to determine the preferred type, timing and duration of immunonutrition required to reduce inflammation and chemotherapy‐induced toxicities, and

Nutritional interventions, other than that examining the impact of specific immunonutrients on chemoradiotherapy‐related outcomes, include nutritional counseling and/or enteral sup‐ plements in order to maintain stable body weight and cope with feeding difficulties (**Table 3**). A recent randomized controlled trial compared the effects of a walk‐and‐eat intervention versus conventional medical care for patients with esophageal cancer undergoing neoadju‐ vant chemoradiotherapy. This intervention consisted of a structured walking protocol and weekly nutritional advice including weight and intake evaluation, counseling to overcome feeding difficulties, supplementation, if necessary, with enteral formulas, and patient's edu‐ cation concerning food texture modification and oral care before and after eating. During chemoradiotherapy, the group that received the walk‐and‐eat intervention had 100‐m less decline than controls in walk distance, 3 kg less decrease in handgrip strength, and 2.7 kg less reduction in body weight. Moreover, the experimental group had significantly reduced rates of intravenous nutritional support and wheel chair use [110]. Another randomized trial tested the effects of an interdisciplinary nutrition support team on clinical and hospitalized outcomes of esophageal cancer patients receiving concurrent chemoradiotherapy. Nutritional support included dietary counseling, oral nutritional supplements, enteral nutrition, and parenteral nutrition according to patient's needs. At the completion of treatment, nutritional status of patients in the interventional group was better compared to control group, as dem‐ onstrated by prealbumin, transferrin, and albumin levels. Bone marrow suppression and complications related to infections were significantly lower in the nutritional support group. Nutritional intervention was also associated with a lower average length of hospital stay and in‐patient cost [111]. Furthermore, nutritional intervention improved survival of esophageal cancer patients treated with definitive chemoradiotherapy. It is noticeable that this effect was observed only if nutritional support was provided at baseline (dietary advice, oral supple‐ mentation, or major intervention), and not if provided later in the treatment course [10].

According to ESPEN, in patients receiving radiotherapy, especially radiotherapy of the head and neck, thorax, and gastrointestinal tract, an adequate nutritional intake should be ensured primarily by individualized nutritional counseling and/or with use of oral nutritional

maintain muscle mass.

104 Esophageal Abnormalities

*Nutritional counseling Oral supplementation Immunonutrition Synbiotics*

*Parenteral nutrition support*

**Table 3.** Nutritional interventions during chemoradiotherapy.

There are various types of stents available, such as self‐expandable metallic stents, self‐ expandable plastic stents, and biodegradable stents. Esophageal stenting can be implemented to relieve dysphagia during preoperative chemotherapy and/or radiotherapy. A systematic review investigated the impact of stent insertion during neoadjuvant treatment on dysphagia improvement. Placement of an esophageal stent significantly improved overall dysphagia scores in all 12 studies reviewed. However, no consistent improvement in nutritional status was observed, defined by body weight and albumin levels. Moreover, stent insertion was associated with complications, such as migration and chest pain, frequently resulting in stent removal or replacement [112]. The European Society of Gastrointestinal Endoscopy (ESGE) does not recommend self‐expandable metal stents placement as a bridge to surgery or prior to preoperative chemoradiotherapy, since it is associated with a high incidence of adverse events. Other options, such as feeding tube placement are preferable and should be consid‐ ered in dysphagic or malnourished patients in the neoadjuvant setting [113].

### **5. Palliative care**

Management of patients undergoing noncurative treatments due to advanced disease is dif‐ ficult, since the goals are not to cure patients but to improve length and quality of remaining life. Nutritional support is a crucial part in the palliative care as long as its benefits outweigh its costs. Patients with metastatic disease present for the clinician not only clinical but ethical issues as well. Dysphagia is the main symptom in patients with unresectable disease which aggravates malnutrition and requires nutritional intervention [114]. Nutritional support of these patients includes intravenous fluids for hydration, feeding tubes, parenteral nutrition, and stent placement in order to supplement dietary and caloric intake. Various techniques have been proposed to manage dysphagia, such as brachytherapy, self‐expanding metal stents, thermal laser therapy, and photodynamic therapy. Each one of them has specific advan‐ tages and risks that should be taken into consideration. The authors of a recent meta‐analysis of 53 randomized controlled trials concluded that self‐expanding metal stent insertion is safe, effective, and improves dysphagia faster compared to other modalities. High‐dose intralumi‐ nal brachytherapy is a satisfactory alternative and might provide additional survival benefit with a better quality of life. Combinations of brachytherapy with self‐expanding metal stent insertion or radiotherapy seem to be the preferable option addressed to inoperative patients [115]. ESGE recommends placement of partially or fully covered self‐expandable metal stents for palliative treatment of malignant dysphagia over laser therapy, photodynamic therapy, and esophageal bypass [113].

Moreover, in esophageal cancer patients with short life expectancy unsuitable for esopha‐ geal stenting, percutaneous endoscopic gastrostomy (PEG) may be a suitable means in order to achieve nutritional support, while allowing patients to be at home [116]. Endoscopically assisted nasogastric tube feeding is also a feasible palliative option for nutritional support, with a low complication rate. Tube‐feeding patients had significantly higher enteral calorie intake, higher serum albumin, shorter hospital stay, and longer median survival compared to those who received *nil per os*, according to a retrospective study of patients with malig‐ nant esophageal obstruction [117]. Palliative care in the terminal phase should be followed in an individualized manner. ESPEN recommends that in dying patients, artificial hydra‐ tion and nutrition are unlikely to benefit patients. Nevertheless, in acute confusional states, patients might receive a short and limited hydration to rule out dehydration as precipitat‐ ing cause [79].
