Perioperative Nutritional Treatment for Patients With Gastric Cancer: Focusing on Recent Controversial Issues.

INTRODUCTION
Although the overall incidence of gastric cancer is declining, it remains one of the most common cancers in Korea and the fifth most common malignant tumor globally, with approximately 1.1 million new cases and approximately 800,000 deaths reported in 2020 [1]. During the past several decades, the overall outlook for gastric cancer has gradually improved with advancements in treatment and diagnostic methods leading to increased survival rates. The overall 5-year relative survival rate of patients with gastric cancer in Korea increased from 55.7% in early 2000’s to 77.0% in late 2010’s (P<0.0001) [2]. This increase in survival rates implies that there are more long-term survivors, while the problems of malnutrition and quality of life have become more serious. The rate of early gastric cancer has increased significantly due to carrying out health checkups and the development of diagnostic techniques [3] (Fig. 1) and this has led to active efforts to improve the quality of life, such as minimally invasive surgery and Enhanced Recovery After Surgery (ERAS) programs, whereas surgeons have renewed their focus on the problems arising from nutritional aspects.
As gastric cancer treatment has advanced, the field of clinical nutrition has also seen significant advancements in biochemical and metabolic knowledge, resulting in a significant synergy between the two fields of surgery and clinical nutrition. It is accepted that surgery causes major stress reactions involving insulin resistance and significant inflammatory responses. Also, conventional pain management employing high doses of opioids and excessive fluid therapy administered aggressively can cause postoperative ileus. However, during the last two decades, leading academic societies such as the European Society of Clinical Nutrition and Metabolism (ESPEN) and the American Society for Parenteral and Enteral Nutrition (ASPEN) have made great advances in the basics of clinical nutrition, while the ERAS program, a multimodal perioperative care pathway designed to achieve early recovery for patients undergoing major surgery has accumulated large amounts of data on the most effective perioperative care methods, and will be launching new trials. ERAS programs are complemented by prehabilitation programs that aim to make the patient get into better physical health before surgery. A structured preoperative evaluation and intervention approach is crucial in the management of patients undergoing gastrectomy, as the majority of aged patients have underlying diseases like diabetes, hypertension, lung or kidney diseases, and liver function abnormalities.
The changes in nutritional perspectives based on surgical technique have primarily resulted from the emergence of minimally invasive techniques, such as laparoscopic or robotic surgery, which minimize inflammation and insulin resistance. Techniques such as double-tract reconstruction surgery and jejunal pouch techniques are also being introduced [4]. Further, goal-directed fluid therapy, as an optimized intraoperative fluid therapy, has emerged in the field of anesthesia [5].
As for postoperative management, minimally invasive surgery and the implementation of ERAS and other measures have accelerated patient recovery. Further, nutritional risks as a complication have been significantly reduced compared with past practice, with improvements such as early oral intake, enteral or parenteral supplementation tailored to the caloric and protein needs of the patient, and a greater understanding of vitamins and dietary supplements. As a result of recent advancements in artificial intelligence and cutting-edge information technology, the day when personalized nutritional therapy for patients at each stage of recovery will become the standard method of patient care draws near. In this perspective, we examined the latest trends in perioperative nutritional therapy and identified the remaining issues to be resolved.

PREOPERATIVE SCREENING AND ASSESSMENT
Screening implies a process of identifying risk factors for a condition of deprived nutrition and assessment involves providing a nutritional diagnosis. However, in the process of discovering cancer and determining the exact stage of the disease, it is not easy to first identify nutritional problems or suggest solutions via a nutritional diagnosis. A poor nutritional status represents a well-recognized risk for complications in major surgery. Malabsorption or mechanical obstruction due to cancer itself and patient-related factors like comorbidities, socioeconomic status, and anorexia contribute to impair the preoperative nutritional status of patients destined for surgery [6]. Such preoperative malnutrition frequently combines with other morbid conditions like impaired functional capacity, frailty, and sarcopenia [7]. However, a dysfunctional nutritional condition is the single most efficient and useful component for assessing the risk of postoperative complications. Table 1 summarizes the critical variables for evaluating the nutritional and non-nutritional risks of having complications after major abdominal surgery [8].
Hence, it is important to identify modifiable risk factors as early as possible and correct the factors to enhance the recovery from surgery without complications. A poor nutritional status is a improvable factor so that the risk of postoperative complications and a prolonged hospital stay can be reduced [9].
Therefore, all patients scheduled for cancer surgery should undergo a standardized nutritional status screening test. Generally, the most widely used and validated screening tool is the Subjective Global Assessment (SGA). It involves a combination of medical history and physical examination to evaluate a patient's nutritional status. The assessment results in a rating of either A (well-nourished), B (moderately malnourished), or C (severely malnourished). In hospital settings, Nutritional Risk Screening 2002 (NRS-2002) is preferred for screening patients' nutritional status. Developed by Kondrup et al. [10] and recommended by ESPEN, it is a straightforward method for assessing whether a patient would benefit from a nutritional support plan. The screening process is typically done in two stages. The first is an initial screening with 4 key questions. If the answer to any of these initial screening questions is “yes,” a more detailed final screening is conducted. The final screening consists of two main aspects, nutritional status and severity of disease. Nutritional status includes body mass index (BMI), recent weight loss, reduced food intake, while severity of disease gauges the "stress metabolism" of the illness of a patient, which increases their nutritional requirements. If the patient is over 70 years of age, an additional point is often added reflecting the risk of age. A final score of 3 or more indicates that the patient is nutritionally at-risk. For patients who are at-risk, a formal nutritional care plan is recommended to be initiated. Patients with a score below 3 are considered at low risk and are typically re-screened on a weekly basis. The primary purpose of the NRS-2002 protocol is to act as a simple, quick, and reliable method to predict the likelihood of better or worse outcomes due to nutritional factors. Early identification of patients at-risk allows healthcare providers to intervene with appropriate nutritional support, which can help to improve clinical outcomes, reduce complications, and potentially shorten hospital stays.
The SGA has good reliability in the clinical and research setting when performed by experienced clinicians. However, the inter-rater reliability is not reliable yet and because SGA does not use specific, objective measurements for criteria like weight loss percentage or muscle mass reduction, the level of malnutrition discrimination is relatively low [11]. In the same context, Mini Nutritional Assessment is a well-known tool for screening of elderly patients, as the survey items are relatively simple. But its discriminating power is weak. Alternatively, NRS-2002 is recommended for identifying patients at nutritional risk in the hospital setting. It evaluates recent weight loss, reduced dietary intake, the severity of the disease, and incorporates age adjustment by an additional point for patients aged 70 years or older. Despite the advantages of reflecting disease severity and adjusting for age, it is not without limitations because it has no objective measure, such as muscle mass.
Recent research in nutritional screening and assessment is focused on validating existing tools for specific patient populations, developing new assessment methods using advanced technology, and applying international diagnostic criteria. There is a strong push toward improving the accuracy and convenience of assessments through technologies like Artificial Intelligence, alongside efforts to identify the most suitable tools for various clinical settings.
The Global Leadership Initiative on Malnutrition (GLIM) criteria provide a standardized, evidence-based framework for clinicians to diagnose malnutrition in adults in various healthcare settings [12]. The GLIM criteria, published in 2018, have become the globally accepted standard for diagnosing malnutrition [12]. Recent studies are focused on evaluating how well the GLIM criteria align with existing tools, although the Coronavirus disease-19 pandemic period has reduced research momentum and the evaluation process of GLIM criteria is also not much easier than existing screening tools [13] (Table 2). The GLIM diagnosis follows a 2-step procedure; first, risk screening and second, diagnostic assessment. Individuals at risk for malnutrition are identified using a validated screening tool. After screening, for those identified as at-risk, the diagnosis is confirmed by assessing 5 GLIM criteria (3 phenotypic and 2 etiologic criteria). A diagnosis of malnutrition requires that the patient meets at least one phenotypic and one etiologic criterion. The severity of malnutrition is determined on the basis of the phenotypic criteria alone (Fig. 2).
With regard to phenotypic criteria, the existing criteria of non-volitional weight loss are maintained within a range of >5% to >10% within the past 6 months. As for low values of BMI, the current age- and ethnicity-specific thresholds (e.g. for Asians, <17.8 kg/m2 if <70 years of age and <18.5 kg/m2 if >70 years of age) are maintained, as there is no compelling reason for a change. Akazawa et al. [14] reported that Asians should use 17.8 kg/m2 as the cutoff BMI value for being underweight rather than 18.5 kg/m2. For measuring muscle mass, the use of machine-based techniques like Dual X-ray absorptiometry, bioimpedance analysis, computed tomography, or ultrasonography imaging is recommended when available. However, in their absence, methods such as calf circumference measurement or a nutrition-focused physical examination are acceptable alternatives. Muscle strength carries an important meaning in sarcopenia diagnosis, is not a component of the GLIM diagnostic algorithm, and should not be used as a surrogate for assessing muscle mass.
Etiologic criteria include 2 parameters: reduced food intake or assimilation and inflammation or disease burden. Even though confirmation by laboratory markers is not always necessary, C-reactive protein can be used in cases of clinical uncertainty.
Over the past few years, the GLIM approach has been positively received by the global clinical nutrition community and has demonstrated strong predictive validity. However, several unsolved issues remain. Assessing muscle mass and its function and applying GLIM criteria to individuals with obesity are current challenges in this regard. Application of GLIM criteria in an intensive care setting and matching them with clinically relevant World Health Organization International Classification of Diseases codes for adult malnutrition have shown limited success.

PREOPERATIVE NUTRITION IN THE CONTEXT OF PREHABILITATION
The etymology of the word “prehabilitation” is a combination of the prefix “pre-” and the word “rehabilitation.” Prehabilitation aims to improve the resilience of the patient to withstand surgical stress by specific nutritional, exercise-based, and psychological interventions that enhance recovery after surgery. Although a prehabilitation program requires a multidisciplinary approach, this article will focus on the area of nutritional prehabilitation.
As mentioned above, it is now well recognized that preoperative malnutrition leads to adverse outcomes and increases overall medical costs [15]. Specifically, malnutrition was found to be associated with increased postoperative mortality, length of hospital stay, and hospitalization costs in patients with gastric cancer undergoing gastric resection surgery [16]. Korean university hospitals that are actively introducing the ERAS program are trying to implement a prehabilitation program, but it is very difficult to properly implement the recommended 2- to 4-week prehabilitation regimen due to the appropriateness assessment standard set by Health Insurance Review and Assessment Service of the Korean Government that requires patients diagnosed with gastric cancer to undergo surgery within 1 month. Moreover, patients diagnosed with gastric cancer fear the progression of the disease and desire surgery as soon as possible. Further, in cases of advanced gastric cancer where oral intake is difficult, preoperative nutritional treatment often involves parenteral nutrition. The potential for various metabolic and mechanical complications associated with parenteral nutrition itself cannot be ignored.
Supporting protein anabolism in preparation for surgery is another important goal of prehabilitation because the cancer itself can lead to loss of lean body mass through inflammatory responses and subsequent catabolic reactions [6]. This metabolic state is inevitably aggravated by the catabolic response induced by surgical stress, leading to insulin resistance and further loss of muscle mass [17]. Therefore, implementing preemptive nutritional anabolic strategies that can attenuate surgical catabolism, in malnourished as well as in non-malnourished patients, has been shown to facilitate surgical recovery [17]. To achieve the goal of protein anabolism, it is necessary to attain a positive protein balance, with protein synthesis (favored by dietary protein consumption, protein ingestion, and resistance exercise) exceeding protein breakdown (induced by fasting states, concomitant disease, treatments, or resistance exercise). Maximal muscle protein synthesis plateaus with the ingestion of 20–35 g of protein. However, more than 35 g of protein per meal may be required to also sustain non-muscle protein synthesis (i.e., whole-body protein). In addition, supplementation with a high dose of omega-3 fatty acids (2.0–2.2 g/day) and vitamin D may further potentiate the anabolic response of patients with reduced muscle mass [18].
Although many researchers have provided evidence to show that improving preoperative function through prehabilitation helps postoperative recovery, some recent studies have also shown fewer complications [78]. A recent multicenter randomized clinical trial (the PREHAB trial) conducted in patients with colorectal cancer awaiting surgery, which compared multimodal prehabilitation (including nutritional intervention) with standard preoperative care, reported less severe and fewer medical postoperative complications in patients treated with prehabilitation. A better postoperative functional recovery was also observed [19].

MEASUREMENT OF ENERGY REQUIREMENTS AND SUPPLEMENTAL PARENTERAL NUTRITION (SPN)
As the national healthcare screening program has expanded, the proportion of patients with early-stage gastric cancer among all gastric cancer cases in Korea has increased, and this is reflected in the diversity of BMI values and nutritional status of patients with gastric cancer including morbid obesity and sarcopenic obesity [3].
As mentioned earlier regarding the importance of prehabilitation for malnourished patients, there is a wide spectrum of patients from normal to obese to severely malnourished prior to surgery, from the very young to the very old, from those with no comorbidities to those with multiple comorbidities such as hypertension, diabetes, renal failure, cirrhosis, and chronic obstructive pulmonary disease. Therefore, accurate caloric and protein provision that is in line with the nutritional requirements of the patient is crucial. This is because it has been shown previously that too little caloric provision is a problem, while too much caloric supply is also associated with higher rates of complications and mortality (Fig. 3) [20]. Although the use of indirect calorimeters is becoming the standard in international guidelines [21], advances in surgical techniques have meant that patients are rarely transferred to the intensive care unit (ICU) unless they have severe complications or have very advanced gastric cancer. Critical care physicians are active in nutritional therapy, while patients in the general ward are likely to be neglected unless they have a surgeon interested in the patient.
In the Korean clinical context, indirect calorimeters are not very useful unless the patient is mechanically ventilated because of the high cost of consumables and the fact that health insurance does not yet cover the appropriate test fee of the procedure in Korea. Therefore, the most useful alternative calorimetric method for real clinical situations in Korea is to use predictive equations. Nevertheless, no suitable and useful calculation formula has been validated. The most commonly used formulas are shown in Table 3 [21].
As shown in Table 3, each formula shows accuracy as a % of the estimated value compared with the measured value obtained via the indirect calorimeter. Even though the accuracy is low, it does not act as a major variable because of the endogenous energy production that cannot be measured. In other words, even if the exact Resting Energy Expenditure value is measured, it can be stated that supplying less energy than that measured via indirect calorimetry is one way to prevent oversupply in the acute phase because endogenous calorie production varies from person to person and also depends on the severity of the disease. Immediately following surgery, patients are typically in an acute catabolic state. This release of acute-phase hormones like glucocorticoids and cytokines like tumor necrosis factor α leads to endogenous, non-inhibitable production of calories and proteolysis, independent of external energy and protein sources. Therefore, unless the surgery is minimally invasive and the patient is at high risk for inflammation, it is recommended to abstain from caloric and protein intake for approximately 24 hours.
If the underlying disease is not serious and oral intake is possible quickly after surgery, there will usually be no major nutritional problem. However, if fasting is required for a long period of time after surgery or there are problems such as swallowing difficulties even with oral intake, it may be difficult to meet the required goal of caloric and protein intake amounts through oral intake or enteral feeding alone (Fig. 4). SPN may be needed when oral feeding or enteral nutrition does not reach the target calories. Although there has been much debate about the onset and usefulness of SPN, recent studies have provided evidence supporting its role. Since a multicenter randomized trial published in the New England Journal of Medicine in 2011 comparing early and late parenteral nutrition has reported that early SPN was inferior in terms of postoperative recovery and incidence of complications, additional efforts to collect more evidence have continued [22]. The damage from early parenteral nutrition raised in that article was later attributed to endogenous energy production and to have resulted from excessive caloric supply.
The guidelines from the 2 major societies of clinical nutrition, namely ASPEN and ESPEN, mention the use of SPN in critically ill patients while recognizing that there is no strong evidence related to optimal timing. Recent meta-analysis of these trials suggests clinical benefits with SPN (namely, lower nosocomial infection and ICU mortality, with improved nutrition intake, and statistically encouraging trends toward functional recovery), which may ultimately improve functional recovery in patients in the ICU [23]. The attending surgeon must be aware of SPN indications and be cognizant of protocols for initiating and monitoring SPN therapy. A combination of evidence-based guidance and expert knowledge is needed to evaluate the needs of an individual patient. The gastrointestinal tract must be systematically assessed using a validated score, such as the Gastrointestinal Dysfunction Score [24].

SPECIFIC NUTRITIONAL THERAPY TO CONSIDER AFTER GASTRIC CANCER SURGERY
Gastrectomy is the treatment of choice in gastric cancer. However, the majority of patients with gastric cancer present with malnutrition phenomena post-surgery that lead to a reduced response to treatment and increased treatment-associated side effects, often inducing changes in treatment protocol and sometimes interruptions of treatment.
The majority of radical surgery involves the elimination of vagal nerve functions. This leads to the impairment of bowel movement and can cause abdominal distension and discomfort. Partial or total gastrectomy can cause a reduction or complete absence of the acidic environment in the remnant stomach or in the small bowel. The patient who has undergone partial or total gastrectomy must adhere to a targeted diet, to specific rules to be followed for proper nutrition, to continuous medical checks and, if necessary, to chemoradiotherapy. Chemotherapy following gastrectomy also induces anorexia, sore throat, dry mouth, taste change, nausea, diarrhea, constipation, and fatigue which eventually contribute to weight loss and malnutrition. A high risk of malnutrition among patients who underwent gastrectomy was shown to delay the rate of recovery and increase cancer-related deaths [25]. Although these do not represent evidence-based knowledge, the main dietary strategies known to clinicians and clinical nutritionists to date are summarized in Table 4.
Dietary iron metabolism involves absorbing iron from the diet, primarily in the duodenum and small intestine, and transporting it via the blood protein transferrin to cells for use in synthesizing essential proteins like hemoglobin. Iron is stored in the liver and macrophages as ferritin, and the body lacks an active iron excretion mechanism. Hence, iron balance is tightly regulated by controlling absorption via the hormone hepcidin. Absorption is influenced by dietary factors, with enhancers like vitamin C and inhibitors like phytates affecting bioavailability. In patients who underwent gastrectomy, the acidic environment of the stomach can be destroyed, and the oxidization of ferric form iron (Fe3+
) to ferrous form (Fe2+
) can be interrupted. This metabolic change leads to iron-deficiency anemia. Treatment for iron-deficiency anemia in patients who underwent gastrectomy involves oral iron supplements, which may require a higher dose than is standard for other conditions, and may sometimes require intravenous iron if oral treatment is ineffective or poorly tolerated. Long-term monitoring of iron levels is crucial, and a healthcare provider may also recommend vitamin C supplements to improve iron absorption.
Vitamin B12 deficiency can develop as early as approximately 1 year after total gastrectomy. Intrinsic factor, which is mainly produced by parietal cells of the oxyntic gastric glands, is necessary to absorb enteral vitamin B12. The clinical presentation of post-gastrectomy vitamin B12 deficiency has not been clearly defined, nor has the role of supplemental vitamin B12 therapy been standardized. Administration of vitamin B12 is effective both via the subcutaneous and the oral route [26]. Adachi et al. [27] also reported that oral vitamin B12 supplementation was effective in increasing the serum vitamin B12 concentration, with prompt resolution of the symptoms related to vitamin B12 deficiency. Kim et al. [28] also demonstrated that oral vitamin B12 replacement therapy provides safe and effective treatment for vitamin B12 deficiency after total gastrectomy in patients with gastric cancer. The rationale for this approach is the presence of a second, lower efficiency transport system for vitamin B12 that does not require intrinsic factor or a functioning terminal ileum but uses passive diffusion. Thus, prophylactic enteral vitamin B12 supplementation after total gastrectomy is a robust and convenient alternative to the subcutaneous route for preventing symptoms associated with vitamin B12 deficiency.
Finally, nutritional issues that may be considered in patients undergoing gastric cancer surgery include changes in the microbial environment and items related to immunonutritional therapy. Partial or total gastrectomy can cause the elimination of its natural acid barrier, which normally protects the intestines from excessive bacterial growth. This results in oralization of the gut bacteria, such as Streptococcus. The altered bacterial composition contributes to dysbiosis, where the gut microbiome becomes dominated by aero-tolerant and bile acid-transforming bacteria, while beneficial, anaerobic species are reduced [29]. However, there is no specific treatment method for dealing with these changes in the bacterial environment.
Regarding immunonutritional therapy, there are research reports on arginine, glutamine, omega-3 fatty acids, and nucleic acids, but none of them provide any meaningful evidence.

CONCLUSIONS
Perioperative nutritional treatment is now recognized as a therapeutic cornerstone, indispensable for mitigating the pervasive challenge of malnutrition in patients with gastric cancer and optimizing clinical outcomes. Significant advancements have been achieved through standardized screening protocols, notably the NRS-2002 and GLIM criteria, and the strategic implementation of prehabilitation regimens to enhance physiological reserve and reduce postoperative morbidity. Nevertheless, critical unresolved issues remain, including practical limitations in the precise determination of individual energy requirements (due to challenges with indirect calorimetry and predictive equations) and the need for rigorous, evidence-based refinement of protocols for SPN and post-gastrectomy micronutrient replacement (iron and vitamin). Prospectively, an intensified focus on precise personalization and robust multidisciplinary integration is warranted in future studies, prioritizing research into advanced, non-invasive assessment modalities, the clinical role of gut microbiota, and the efficacy of immunonutritional agents to comprehensively elevate the standard of care worldwide.