Nutrition update in gastric cancer surgery

Abstract Patients with gastric cancer are often malnourished during tumor progression. Malnutrition is a risk factor for postoperative complications and a poor prognosis. Early evaluation and management of nutrition can improve these outcomes. Various combined indices in which albumin is the primary component are used to evaluate the nutritional status, including the Prognostic Nutritional Index, Glasgow Prognostic Score, and Controlling Nutritional Status score. Both the American Society for Parenteral and Enteral Nutrition and the European Society for Clinical Nutrition and Metabolism guidelines recommend immediate and early oral/enteral nutrition. However, few reports have described the additional effects of preoperative immunonutrition on clinical outcomes of gastric cancer surgery. Gastrectomy types and reconstruction methods that consider the postoperative nutritional status have been used when oncologically acceptable. Total gastrectomy has recently tended to be avoided because of its negative impact on nutritional status. New findings obtained from the emergence of continuous glucose measurement, such as glucose fluctuation and nocturnal hypoglycemia, may affect nutritional management after gastrectomy. Some prospective clinical studies on perioperative nutritional intervention have set postoperative body weight loss as a primary endpoint. It seems important to continue oral nutritional supplement, even in small doses, to reduce body weight loss after gastrectomy. Evidence generated by prospective, well‐developed randomized controlled studies must be disseminated so that nutritional therapy is widely recognized as an important multimodal therapy in patients undergoing gastric cancer surgery.

has been demonstrated by excessive surgical invasion in prospective randomized clinical trials (RCTs), 2-4 minimally invasive surgery including laparoscopic and function-preserving surgery is expanding.
Malnutrition is reportedly a risk factor for postoperative complications and a poor prognosis. 5 In addition to removing tumors, surgeons have begun to focus on perioperative nutritional management. For example, the concept of early recovery after surgery (ERAS), which was originally used for colorectal surgery, 6 has now been applied to GC surgery. The effectiveness of the ERAS protocol in GC surgery (i.e., reducing complications, hospital stay, and cost) has been suggested. However, Yamagata et al 7 warned that ERAS cannot achieve full penetration in Japan because most evidence is established in Western countries.
The aim of nutritional therapy is to improve the nutritional status, metabolism, incidence of postoperative complications, adherence to anticancer therapies, quality of life (QOL), and survival.
In this review, we outline the current status and topics regarding perioperative nutritional management for GC surgery based on recent evidence.

| N UTRITI ONAL S TATUS OF PATIENTS WITH G C
In patients with GC, malnutrition is caused by a decrease in food intake due to mechanical obstruction and cachexia, which occur during cancer progression. Cachexia is associated with tumor-host factors including tumor necrosis factor-α, interleukin-1, interleukin-6, and leptin dysregulation. These factors may significantly influence appetite, muscle mass, and adipose tissues, leading to weight loss. 8 Therefore, many patients with advanced GC often develop hypoproteinemia, dehydration, and electrolyte abnormalities. Nutritional evaluation is initially performed on all patients using the Subjective Global Assessment. 9

| Evaluation by biochemical factors
Albumin, rapid-turnover proteins (prealbumin, transferrin, and retinal-binding protein), C-reactive protein, total cholesterol, cholinesterase, glucose, hemoglobin, neutrophils, and total lymphocytes are among the well-known nutritional indicators monitored before GC surgery. Numerous studies have sought to develop more reliable, combined scoring systems that can identify patients with a poor nutritional status, such as the Prognostic Nutritional Index, Glasgow Prognostic Score, and Controlling Nutritional Status score. These systems have been used successfully to predict postoperative complications and survival. [10][11][12] Table 1 shows combined indices that can reportedly be used to estimate the nutritional status relevant to short-and long-term outcomes of GC surgery. While some of the algorithms are complicated, measurement of the serum albumin and lymphocyte levels is used more often as components of combined indices; they may still be the simplest, at-a-glance factors.

| Evaluation by physical factors
Body weight (BW) loss before surgery, which is a simple nutritional index obtained from the Subjective Global Assessment, has long been used in clinical practice. In 1991, Haugstvedt et al 13 reported that BW loss increased with age, with advanced stages of disease, in Lauren's diffuse vs intestinal tumor type, and with tumors located in the cardia. They further showed that increasing BW loss significantly reduced the resectability rate, but no association was found between preoperative BW loss and the postoperative complication rate.
Body mass index (BMI) is also a simple indicator of the physical condition, but it is paradoxical. Chen et al 14 evaluated the morbidity and mortality risks in 1249 patients with GC undergoing gastrectomy based on their preoperative BMI (low, <18.5; normal, 18.5-24.9; and high, >25.0 kg/m 2 ). They found that a low BMI was associated with more severe postoperative complications and a poorer prognosis.
Despite a higher risk of mild postoperative complication, patients with a high BMI exhibited paradoxically superior survival outcomes than patients with a normal BMI. Yang et al 15 measured the visceral fat area (VFA) and evaluated the impact of obesity on postoperative complications as compared with the BMI. They found that VFA was an independent risk factor for postoperative complications and showed that VFA was superior to BMI in accurately and effectively predicting the impact of obesity on short-term outcomes.
There is increasing evidence that as patients age, a relationship exists between sarcopenia and surgical outcomes. Sarcopenia is characterized by a loss of skeletal muscle mass and strength and is a major contributor to overall frailty. Sarcopenia is present in a large proportion of patients with advanced GC and significantly influences tolerance TA B L E 1 Combined indices estimating nutritional status for gastric cancer surgery to chemotherapy, surgical complications, tumor recurrence, and survival. 16 Moreover, one study showed that patients with a low skeletal muscle mass index had a higher age and significantly lower albumin level and BMI, indicating that skeletal muscle mass is correlated with the nutritional status of patients with GC. 17 Many studies have shown that the preoperative skeletal muscle mass index is a useful nutritional determinant that predicts postoperative complications and survival after GC surgery. 18 A preoperative exercise and nutritional support program have the potential to reduce sarcopenia and improve postoperative outcomes in advanced-age patients with sarcopenia and GC. 19

| PREOPER ATIVE NUTRITIONAL MANAG EMENT
As mentioned above, preoperative malnutrition may contribute to postoperative complications and a poor prognosis in patients with GC. Moreover, postoperative complications themselves can adversely affect the overall and recurrence-free survival of patients with GC. 20 Therefore, an appropriate assessment of the preoperative nutritional status through various biochemical and physiological tests and subsequent nutritional intervention before gastrectomy is essential for malnourished patients with GC.

| Recommendation of oral/enteral nutrition
For malnourished patients with GC, peripheral parenteral nutrition or total parenteral nutrition (TPN) is often performed. While peripheral parenteral nutrition often does not provide enough energy or nutrients, TPN can provide sufficient amounts of nutrients for a long time. However, parenteral nutrition causes various impairments of host defense mechanisms, including gut immunity, systemic mucosal immunity, hepatic immunity, and peritoneal host defense. 21 In addition, TPN requires a central vein catheter and is associated with more risks.

Both the American Society for Parenteral and Enteral Nutrition (ASPEN) and the European Society for Clinical Nutrition and
Metabolism (ESPEN) guidelines recommend oral/enteral feeding whenever possible. 22,23 Animal studies have demonstrated that fasting and malnutrition can result in intestinal mucosal atrophy and bacterial translocation. 24 Although enteral atrophy is observed during fasting in humans, the change is minimal, and whether it is the result of bacterial translocation remains unclear. 25 However, it appears that the immune barrier function is reduced. 26 Therefore, patients should be treated with oral nutrition (ON) when possible; otherwise, enteral nutrition (EN) is the indicated administration route. In patients with pyloric stenosis with gastric dilatation, the leading edge of the enteral diet tube is placed beyond the stenosis using a fluoroscopy or endoscopy. It is possible to perform EN while decompressing the stomach using the double elementary diet tube (W-ED ® tube; Covidien, Tokyo, Japan) ( Figure 1). This tube can also be applied in the case of anastomotic leakage. Parenteral nutrition alone or with EN should be considered unless adequate nutrition can be administered by EN alone.

| Immunonutrition
Many types of nutrients are used in enteral formulae (EF), each of which contains distinctive supplements. Therefore, they should be administered according to the nutritional status of each individual patient. In the 1990s, immunonutrition received significant attention after its usefulness was reported in various RCTs and metaanalyses based on pharmacological effects. 27 Both the ASPEN and ESPEN guidelines also recommended the administration of preoperative immunonutrients prior to cancer surgery. 28,29 Table 2 shows three studies from the 2000s that assessed the clinical outcomes F I G U R E 1 W-ED ® tube (double elementary diet tube). The W-ED ® tube (Covidien, Tokyo, Japan) is 150 cm long and has connecters for both drainage and nutrition. One lumen has its openings at the side of the tube, 60 cm above the leading edge, for decompression of the stomach. Another lumen has its openings at the end of the tube for feeding of preoperative immunonutrition in patients with GC. Okamoto et al 30  However, no surgeons will object to providing any kind of nutritional intervention for malnourished patients with GC even for a limited period until surgery. The ERAS guideline describes the need to identify malnourished patients and to provide EN to these patients. 33

| Nutrition support team
In the 1960s, a nutrition support team (NST) was created, accompanying the development of TPN in the United States to manage patients who were malnourished or at risk for becoming malnourished by a multidisciplinary approach. An NST consists of a physician, nurse, dietician, pharmacist, clinical laboratory technologist, rehabilitation therapists (speech-language pathologist, physical therapist, occupational therapist), dentist, dental hygienist, and radiological technologist, who are responsible for supporting all aspects of perioperative nutritional treatment. Some studies have confirmed that this multi-professional NST provides nutritional care more effectively than team members acting independently. 34 This innovation was adopted in Japan in the 2000s and has now become the gold standard for nutritional care in hospitals. Figure 2 shows a common NST activity flowchart with nutrition-related intervention for a patient throughout the perioperative course.

| Avoidance of TG
TG has many potential disadvantages, especially in terms of the hematological and nutritional status, that result in severe BW loss and decreased physical activity. Therefore, attempts to avoid TG, especially in advanced-age or high-risk patients, have been made to minimize postoperative malnutrition and BW loss when oncologically acceptable.
With the increase of upper GC cases in Japan, the ratio of proximal gastrectomy and subtotal gastrectomy with a small stomach remnant has increased. Proximal gastrectomy was once unfavorable because of problems such as reflux esophagitis and stenosis. In particular, reflux interferes with oral intake because of heartburn and vomiting. In recent years, however, proximal gastrectomy has been performed without hesitation even for advanced-age patients because the reconstruction procedures, with some modifications for preventing reflux, have become consistent. 37 Additionally, Furukawa et al 38 reported that laparoscopic subtotal gastrectomy with a very small stomach remnant had more favorable short-term outcomes and nutritional status than laparoscopic total and proximal gastrectomy. They considered that the remaining stomach, although very small, maintains ghrelin secretion and reduces reflux through cardia preservation, contributing to a favorable postoperative nutritional status.

| Early postoperative dietary management
Early initiation of ON or EN after gastrectomy has recently been recommended. This may be due to the "no fasting" element of ERAS. The ERAS consensus guidelines recommend offering patients drink and food at will from 1 day after TG. 33 In contrast, the Japanese Gastric Cancer Treatment Guideline ver.5 states that drink should be offered after postoperative day 1 and that a solid diet should begin from postoperative day 2 to 4 regardless of the F I G U R E 2 Nutrition support team (NST) activity flowchart. An NST consists of a physician, nurse, dietician, pharmacist, clinical laboratory technologist, rehabilitation therapists (speech-language pathologist, physical therapist, occupational therapist), dentist, dental hygienist, radiological technologist. These team members provide nutrition-related interventions to the patient through a multidisciplinary approach gastrectomy type. 39 The initiation of ON in the Japanese guideline seems slightly slower than that in Europe.

| Clinical studies of postoperative oral nutritional supplement (ONS)
Adjuvant S-1 chemotherapy is the standard treatment for patients with stage II or III GC in Japan. 39 Aoyama et al 43 reported that severe BW loss, which is closely associated with poor S-1 compliance, is an important risk factor for survival of patients with stage II or III GC who have undergone gastrectomy. Conversely, Yamashita et al 44 reported that BW loss did not affect S-1 compliance in their multicenter study of a larger number of patients with GC. Therefore, the association between BW loss and postoperative S-1 compliance is controversial. In some prospective clinical studies on perioperative nutritional intervention, BW loss was set as a primary endpoint (Table 3)

| Hypoglycemia as a post-gastrectomy syndrome
Late dumping syndrome is a well-known post-gastrectomy syndrome that negatively affects patient QOL by causing hypoglycemia secondary to excess insulin secretion following meal-induced hyperglycemia. With the recent emergence of continuous glucose monitoring, it has become apparent that patients with gastrectomy have a higher frequency of hypoglycemia and glucose fluctuation than expected. 57 This suggests that the formerly known "dumping syndrome" appears to explain only a fraction of the postoperative glucose fluctuations present during the course of a day. In Figure 3, the glucose profile in one of our patients who underwent TG indicated that postprandial hypoglycemia and nocturnal hypoglycemia were evident throughout the day. Glycemic variability and hypoglycemia are known to have adverse effects on cardiovascular events and cognitive dysfunction. 58,59

| CON CLUS I ON AND FUTURE PROS PEC TS
This review summarizes the current status and various nutritional issues in GC surgery. The primary endpoint of GC surgery is to improve survival, and the role of nutritional treatment is to provide support during the perioperative period while maintaining patient QOL. Direct evidence is difficult to obtain in the area of nutrition.
Evidence generated by prospective, well-developed RCTs must be disseminated so that nutritional therapy is widely recognized as a multimodal therapy for GC.

ACK N OWLED G EM ENT
We thank Edanz Group (https://en-autho r-servi ces.edanz group. com/) for editing a draft of this manuscript.

D I SCLOS U R E
Conflict of Interest: The authors declare no conflicts of interest for this article.

Takeshi Kubota
https://orcid.org/0000-0002-2246-3028 F I G U R E 3 Typical daily glucose profile of a patient with gastric cancer undergoing total gastrectomy. This profile shows the trend obtained by continuous glucose monitoring for a patient undergoing total gastrectomy in our hospital. The profile shows prominent glucose fluctuation with postprandial and nocturnal hypoglycemia. Red and yellow indicate the area below and above the target glucose range (80-140 mg/dL), respectively