Neoadjuvant Gastric Cancer Treatment and Associated Nutritional Critical Domains for the Optimization of Care Pathways: A Systematic Review

(1) Background: Gastric cancer patients are known to be at a high risk of malnutrition, sarcopenia, and cachexia, and the latter impairs the patient’s nutritional status during their clinical course and also treatment response. A clearer identification of nutrition-related critical points during neoadjuvant treatment for gastric cancer is relevant to managing patient care and predicting clinical outcomes. The aim of this systematic review was to identify and describe nutrition-related critical domains associated with clinical outcomes. (2) Methods: We performed a systematic review (PROSPERO ID:CRD42021266760); (3) Results: This review included 14 studies compiled into three critical domains: patient-related, clinical-related (disease and treatment), and healthcare-related. Body composition changes during neoadjuvant chemotherapy (NAC) accounted for the early termination of chemotherapy and reduced overall survival. Sarcopenia was confirmed to have an independent prognostic value. The role of nutritional interventions during NAC has not been fully explored. (4) Conclusions: Understanding critical domain exposures affecting nutritional status will enable better clinical approaches to optimize care plans. It may also provide an opportunity for the mitigation of poor nutritional status and sarcopenia and their deleterious clinical consequences.


Introduction
Gastric cancer is the fifth most commonly diagnosed solid tumor and one of the leading causes of cancer-related deaths worldwide [1].
Gastric cancer patients are known to be at high risk of malnutrition, sarcopenia, and cachexia [2]. Often, malnutrition can be observed at diagnosis [2], and weight loss is also commonly reported at presentation [3]. Evidence has been accumulating to strengthen the adverse influence of an impaired nutritional status on a patient's clinical course, treatment response [4], and quality of life [5].
Neoadjuvant treatment (NT) encompasses the therapeutic approaches in the immediate period leading to surgery. NT in gastric cancer only includes chemotherapy [6] with the intention to reduce tumor size, increase the possibility of a R0 resection, attempt to treat potential micrometastatic disease, and improve overall survival.
ESMO's (European Society of Medical Oncology) 2022 guideline, which has been widely adopted in Europe [7], recommends a perioperative chemotherapy regimen with a combination of platinum/fluoropyrimidine for patients with resectable gastric cancer [8]. Following on from the MAGIC [9] and the FFCD/FNCLCC trials [10], the use of ECF (epirubicin, cisplatin, and 5-fluorouracil) or CF (cisplatin and 5-FU), respectively, is common. More recently, the FLOT4-AIO trial showed an increased benefit in the use of the FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) scheme in the perioperative setting [9]. This approach of a fluoropyrimidine-platinum doublet or triplet before surgery is recommended for 2 to 3 months [9]. During neoadjuvancy, most patients are managed at outpatient clinics; hence, it is crucial that this population be best supported to minimize adverse symptoms while remaining in the community. Further, and as a consequence, locally advanced gastric patients have longer care continuums with the prospect of accumulating several nutritional risk exposures along the way, encompassing both disease and iatrogenic impact.
Nutritional status has been shown to strongly impair chemotherapy (CT) success, postoperative prognosis, overall and disease-specific survival (DSS), the rate of complications, and the length of hospital stay.
Thus, a clearer identification and description of nutrition-related critical points throughout neoadjuvant treatment for gastric cancer might be relevant for improving patient care and outcomes.

Materials and Methods
This systematic review followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) reporting guidelines. The protocol has also been registered on the International Prospective Register of Systematic Reviews (PROSPERO), the University of York Centre for Reviews and Dissemination PROSPERO, August 2021 (CRD42021266760). Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420 21266760, accessed on 8 August 2021.

Sources and Searches
The following databases: Pubmed/Medline, US National Library of Medicine's PubMed, ISI's Web of Knowledge, Cochrane, and Scopus databases were systematically searched using the search string (((Gastric OR Stomach) AND (Cancer OR Neoplasm OR Carcinoma OR Malignancy)) AND (Neoadjuvant OR Pre-operatory) AND (Nutritional status OR Nutritional intervention OR Nutritional support OR Dietary counseling OR Oral nutritional supplements)). An example of the search strategy used can be found in File S1 (Supplementary Data).

Study Selection
Two reviewers (MC and ICM) screened the studies against the review's predefined inclusion criteria ( Table 1).
The types of studies that were included in this review were randomized clinical trials (RCTs), surveys, and observational studies such as cohort and case-control studies. All disagreements were debated until a consensus was reached with the assistance of a third subsequent reviewer (MC, ICM, and SCI). Fourteen studies were selected for inclusion.

Data Extraction
Data extraction was performed independently by two reviewers (MC and ICM), using a standardized data extraction template, and following the PI/ECO format. The extraction data divergence was resolved by the third independent reviewer (SCI). In cases of uncertainties about the data reported, the trials' authors are contacted in order to obtain more information; if contact is not possible, a team consensus decision is made about the inclusion or exclusion of studies.

Results
This systematic review included 14 studies (Figure 1), two of which (14.3%) were RCTs and 11 (78.6%) were cohorts, mainly retrospectively assessed; one out of the eleven included cohorts was assessed prospectively (9.1%). More than half (57.1%) of the included studies comprised body composition analysis data using CT scans or ultrasounds (42.9%), followed by nutritional biomarkers or indices (28.6%). Lastly, only three nutrition support studies (21.4%), comprising an immunonutrition and an ERAS protocol, were eligible.
The selected studies encompassed 1910 eligible patients, with 1360 included. The population characteristics may be found in the below diagram ( Figure 2).
The included study overview and findings can be found summarized in Table 2. Subsequently, the study findings were compiled into three previously defined critical domains: patient-related (Table 3), clinical-related (disease and treatment) ( Table 4), and healthcare-related (Table 5). For further definition of the critical domains it was considered that patient-related critical points would include baseline (admission for cancer care) descriptions of advanced age, comorbidities, presence sarcopenia, and/or frailty including performance status, nutritional status, body composition, and gastrointestinal or other nutrition impairing symptoms present before treatment; clinical-related (disease and treatment) would include all of the above but concerning disease characteristics, treatment induced changes and clinical outcomes; lastly, the healthcare-related domain would include descriptions of clinical care, institutional and organizational issues, such as nutritional risk screening, nutrition support, access constraints, among others deemed relevant.     [11]. * Pubmed/Medline, US National Library of Medicine's PubMed, ISI's Web of Knowledge, Cochrane, and Scopus databases; ** records that were excluded from analysis.    Loss of skeletal muscle was not associated with postoperative complications. NAC was an independent risk factor for loss of skeletal muscle.     BMI and BSA were lower in sarcopenic patients and associated with DLT.
Legend: NAC-neoadjuvant chemotherapy; LA-locally advanced; GEJ-gastroeosophageal junction; DLT-dose-limiting toxicity; NAT-neoadjuvant treatment; CT-chemotherapy; VAT-visceral adipose tissue; SAT-subcutaneous adipose tissue; DFS-disease-free survival; MN-malnutrition; BMI-body mass index; PA-prealbumin; PRNS-prognostic-related nutritional score; mSIS-modified systemic inflammation score; CT Scan-computed tomography scan; RECIST-response evaluation criteria in solid tumors; FLOT-fluorouracil plus leucovorin, oxaliplatin, and docetaxel; PGSGA-patient generated subjected global assessment; SMI-skeletal muscle index; CONUT-controlling nutritional status. # Nutrison fiber and oral nutritional supplementation (500 mL per bottle containing 500 kcal, 20 g protein, 19.45 g fat, and 61.5 g CH); 7 days before surgery apart from routine preoperative diet (35 kcal/kg/day). Both groups on Nutrison fiber within 48 h after surgery. ¥ Immune enteral diet enriched with arginine, omega-3 fatty acids, and nucleotides. $ ERAS group: sufficient preoperative patient education, normal diet until 6 h before surgery, liquid intake until 2 h before surgery, preoperative carbohydrate loading before surgery, analgesia with nonsteroidal anti-inflammatory drugs, minimization of opioid pain management, avoidance of perioperative fluid overload, no routine use of NGT, no abdominal drains, early removal of bladder catheters, liquid diet on recovery from anesthesia, semi-liquid diet on return of bowel function, tolerated liquid diet and forced ambulation on the day of the surgery; NGT placed preoperatively and remained until flatus occurred, intra-abdominal drains placed during surgery until the day before discharge, not allowed oral intake until bowel flatus gastrointestinal movement occurred, usually remained in bed for approximately 2 days after surgery. Conventional group: gastrointestinal preparation before surgery, fasting from midnight.

Advanced Age
Age was described as relating to neoadjuvant chemotherapy pathological response and lower blood counts. It is an independent risk factor that significantly impacts pathological response in patients older than 60 years old (OR = 1.840, 95% CI 1.016-3.332, p = 0.044) [17]. Additionally, older age was significantly associated with both a lower (p = 0.007) prechemotherapy prognostic nutritional index (PNI) [21] and a high (48.2% vs. 31.9%, p = 0.010) controlling nutritional status (CONUT) score [19]. Surprisingly, age did not arise as a risk factor for significant loss of skeletal muscle (p > 0.05) [13].

Sarcopenia (Baseline, Pre-Treatment)
Sarcopenia accounted for adverse effects during treatment, including early termination of CT and reduced survival, but also a reduced BMI and body surface area (BSA). Sarcopenia at diagnosis was prevalent in three quarters (73.1%) of patients in the Rinninela et al. study [18]. Zhang et al. [5] identified sarcopenia before NT as a significant risk factor for treatment adverse effects during univariate analyses, and, subsequently, by multivariate logistic regression analyses (OR, 2.901; 95% CI, 1.205-6.983; p = 0.018), it remained an independent predictor for overall treatment-related adverse effects [5].
Sarcopenic patients also seemed to have a lower BMI and BSA when compared with those who did not have sarcopenia [22].
Only one study assessed loss of skeletal muscle related to gender or comorbidities, such as type 1 diabetes, but did not find any significant association [13].

BMI (Baseline, Pre-Treatment)
Baseline BMI (pre-NAC) is associated with adverse effects during treatments and overall survival (OS). Two studies showed that both underweight and overweight at baseline BMI seem significantly associated with OS and a significant risk factor for adverse effects (pre-treatment BMI < 18.5 kg/m 2; univariate analysis: HR = 2.015; p = 0.002; multivariate analysis: HR =1.456; p = 0.163) [19] and a BMI of 25 kg/m 2 (p = 0.04) [5]. Zhou et al. [16] indicated that a lower BMI in this setting was also significantly associated with low skeletal muscle mass (p < 0.001) and higher nutritional risk scores, NRS 2002 (p < 0.001). A study by Rinninela et al. also showed a decrease in the mean of the BMI with FLOT (from 24.4 kg/m 2 ± 3.7 to 22.6 kg/m 2 ± 3.1; p < 0.0001) [18].

Body Composition (Baseline, Pre-Treatment)
In the studies included, several associations were described between different body compositions and OS, but not all were significant. Patients with low skeletal muscle or, both, low skeletal and adipose mass had progressively shorter OS than patients with normal body composition parameters (3 year OS rates were 44.4% and 76.3%, respectively, for low skeletal muscle and adipose mass patients or for low skeletal muscle mass only vs. 88.2% for normal body composition parameters, p < 0.001). Low skeletal muscle mass (HR: 1.7; 95% CI: 1.2-3.7; p < 0.001) and low skeletal muscle and adipose mass (HR: 3.5; 95% CI: 1.5-15.2; p = 0.002) were independent prognostic factors of 3 year OS, namely after radical gastrectomy [16]. Other studies verified that, before NAT, the group with low visceral adipose tissue (VAT), defined as <120 cm 2 , had significantly shorter OS (p = 0.033), as did the group with low (<99.5 cm 2 ) subcutaneous adipose tissue (SAT), after NAT (p = 0.032). In multivariate Cox regression analyses, low VAT before NAT (HR, 2542; 95% CI, p = 0.027) and low SAT after NAT (HR, 2.743; 95% CI, 1.248-6.027; p = 0.012) were significantly associated with low OS [5]. Moreover, patients with a marked loss of VAT (≥35.7%) during NAT had significantly shorter OS (p = 0.028) compared to those with no or minor (<35.7%) VAT losses. In this study, during NAT, marked loss of adiposity (as per VAT or SAT) was considered a risk factor for long-term survival. Marked (≥35.7%) VAT loss accompanied by marked SAT loss (high-risk group = NRS ≥ 3) independently predicted shorter OS (hazards ratio = 2.447; 95% confidence interval = 1.022-5.861; p = 0.045) [5]. However, Jin et al. [19] found no prognostic significance between the moderate or severe malnutrition group and the normal or light malnutrition group for OS at different times (pretreatment: p = 0.482; preoperative: p = 0.446; postoperative: p = 0.464, Kaplan-Meier with log-rank test).
There were no significant associations between different body compositions and progression free survival (PFS) or postoperative complications. Zhou et al. [16] found no significant differences in postoperative complications within 30 days among the different body composition groups, and Yamaoka et al. [13] found no association between postoperative complications and significant loss of skeletal muscle.
In most studies, there was no significant relation between body composition and tumor pathological response, except for Rinninela et al., where a decrease higher than 5% in SMI was associated with a higher Mandard tumor regression grade [5,18], whereas Jiang et al. reported that weight loss significantly influences the pathological response to treatment [17].

Nutritional Markers and Indices
Regarding nutritional markers, patients with low skeletal muscle and adipose mass had a higher incidence of hypoalbuminemia (p < 0.001), lower prealbumin (p < 0.001), and lower IGF-1 levels (p = 0.031). Despite this, there were no significant differences in the preoperative concentrations of retinol-binding protein and transferrin [16]. Zhang et al. [15] found correlations between a marked loss of VAT and lower albumin levels (p < 0.05).

Clinical-Related Critical Points (Disease and Treatment)
The independent prognostic factor for 3-year OS after radical gastrectomy was tumor stage III (HR: 4.1; 95% CI: 2.1-17.8; p < 0.001) [16]. According to Jiang et al. [17], the independent risk factors influencing the effect of neoadjuvant chemotherapy were histological types. In the same study, clinical T stage and histological type of biopsy significantly influenced pathological response to the treatment [17].
The pathological stage was not associated with a significant loss of skeletal muscle [13]. However, Jiang et al. [17] described that those patients that did not lose weight had a better, although not significant, trend for pathological response than patients suffering from weight loss (66.4% vs. 53.3%, p = 0.059). Likewise, Rinninela et al. described a change in body composition (a decrease in SMI of ≥5%) and a lack of tumor-regressive changes [18].

Healthcare-Related Critical Points
It is known that the identification of nutritional risk by assessment tools and higher scores achieved by PG-SGA are more associated with postsurgical complications, such as anastomotic leakage and intra-abdominal infection [24]. Zhao et al. [22] found that the trial group had a higher BMI than the control group (p < 0.005), and on the eighth day after surgery, the rate of malnutrition according to the PG-SGA and nutritional risk according to the NRS-2002 became lower in the trial group (p < 0.05). This group had a faster gastrointestinal recovery, a shorter-term use of drainage tubes, a shorter hospital length of stay, fewer complications (p < 0.05), and higher concentrations of serum prealbumin, total proteins, and albumin (p < 0.05) [22].
Regarding nutritional support, the group using immunonutrition intervention had fewer infectious complications when compared with the conventional intervention group, but the differences were not statistically significant (41.1% vs. 48.1%; p = 0.413). Although the immunonutrition group had a lower percentage of patients who were readmitted for surgical complications than the conventional group, this difference was also not significant. Claudino et al. found no significant difference in survival rates at 6 months (92.6% versus 85.0%; p = 0.154), 1 year (87.0% versus 78.5%; p = 0.153), and 5 years (69.6% versus 58.3%; p = 0.137). Nevertheless, the immunonutrition patient group showed a trend for longer survival when compared with the conventional nutritional group [23].
Patients without weight loss had a higher rate of oral nutritional supplements than patients with weight loss during neoadjuvant chemotherapy (82.3% vs. 70%, χ 2 = 4.261, p = 0.039) [17]. Legend: NAC-neoadjuvant chemotherapy; LA-locally advanced; GC-gastric cancer; GEJ-gastroesophageal junction; DLT-dose-limiting toxicity; NAT-neoadjuvant treatment; CT-chemotherapy; VAT-visceral adipose tissue; SAT-subcutaneous adipose tissue; DFS-disease free; MN-malnutrition; BMI-body mass index; PA-prealbumin; PRNS-prognostic-related nutritional score; mSIS-modified systemic inflammation score; CT Scan-computed tomography scan; PGSGA-patient-generated subjective global assessment; ONS-oral nutritional supplements; CONUT-controlling nutritional status; SMI-skeletal muscle index. # Nutrison fiber and oral nutritional supplementation (500 mL per bottle containing 500 kcal, 20 g protein, 19.45 g fat, and 61.5 g CH); 7 days before surgery apart from routine preoperative diet (35 kcal/kg/day). Both groups on Nutrison fiber within 48 h after surgery. $ ERAS group: sufficient preoperative patient education, normal diet until 6 h before surgery, liquid intake until 2 h before surgery, preoperative carbohydrate loading before surgery, analgesia with nonsteroidal anti-inflammatory drugs, minimization of opioid pain management, avoidance of perioperative fluid overload, no routine use of NGT, no abdominal drains, early removal of bladder catheters, liquid diet on recovery from anesthesia, semi-liquid diet on return of bowel function, tolerated liquid diet and forced ambulation on the day of the surgery; NGT placed preoperatively and remained until flatus occurred, intra-abdominal drains placed during surgery until the day before discharge, not allowed oral intake until bowel flatus gastrointestinal movement occurred, usually remained in bed for approximately 2 days after surgery. # Conventional group: gastrointestinal preparation before surgery, fasting from midnight, NGT placed preoperatively and remained until flatus occurred, intra-abdominal drains placed during surgery until the day before discharge, not allowed oral intake until bowel flatus gastrointestinal movement occurred, usually remained in bed for approximately 2 days after surgery.

Discussion
Gastric cancer (GC) is one of the most significant malignancies worldwide, with an annual burden prediction of~1.8 million new cases and~1.3 million deaths by 2040 [25]. Preoperative nutritional status is known to affect prognosis, OS, and DFS rates in surgical patients [26]. Indeed, the presence of MN in patients with radical surgical resections contributes to an increased incidence of postoperative complications and extended hospitalization [27].
It has been shown that NAC improves the overall therapeutic effects in locally advanced GC patients and does not increase the incidence of surgical complications. Additionally, undergoing GC surgery without previous NAC might significantly decrease the chance of effective reduction and radical resection [28]. NAC has been established because it confers clinical benefits over surgery [9], and it seems to be capable of enhancing immunological status, ameliorating GC patients' postoperative prognosis. Nevertheless, these widely adopted treatment proposals (e.g., FLOT) are also known to be frequently associated with a variety of gastrointestinal adverse effects, including anorexia, nausea, vomiting, stomatitis, and diarrhea, which can lead to a further deterioration of a patient's nutritional status, especially because these frequently present an already high risk of MN [29]. Furthermore, nutritional-related problems are one of the leading causes of hospital readmissions. Commonly, patients are not able to meet nutritional needs because of inadequate intake due to intolerance to oral and/or enteral feedings, typically manifested by nausea, vomiting, and/or early satiety [18]. For all these reasons, this review attempted to identify nutrition-related critical points during GC neoadjuvant management and their associations with clinical outcomes, as described in the selected literature.
Fourteen studies were analyzed, with 1360 patients included. Most studies were related to body composition and nutritional indexes. The results can be categorized as patient-and clinical-(disease-and treatment-) related ones. This review found considerably fewer concerning healthcare-related critical points, besides the application of nutritional risk identification tools.
Sarcopenia was predominantly considered a significant risk factor for adverse effects or the worst outcomes during treatment [5]. In addition, lower BMI and BSA relate to DLT and seem to lead to early treatment termination [14]. Interestingly, and still concerning the relationship of BSA with DLT, sarcopenic obesity was indeed associated with early treatment termination and reduced survival [12].
In these studies, GC patients' clinical outcomes, including OS, were shown to be closely related to many nutritional parameters, such as body weight. In fact, a lower BMI was associated with a poor OS [19], while a higher BMI seems to also be a significant risk factor for adverse effects during treatments [5]. Importantly, patients who lose weight during NAC seem to be at higher risk of worse CT effects. CT adverse effects, such as nausea, vomiting, and dysgeusia, may compromise food intake, which in turn could exacerbate weight loss. This weight loss is often sharp and marked and may contribute to the loss of skeletal muscle and to MN, which might account for the description of a low BMI being related to a poorer OS. Even though BMI signifies a relationship between weight and height and cannot describe body compartments. Furthermore, NAC trajectories are long, and the timing of some of the body composition analyses might not capture the dynamic nature of the body composition variations throughout treatment.
Adding on, GC patients, who simultaneously present with a high BMI and sarcopenia, had a higher BSA but low muscle mass [14]. This is an important consideration, as it is now established that patients with low muscle mass during CT treatments will have higher toxicity and more treatment interruptions. When compared with patients with normal muscle mass, sarcopenic obesity seems capable of shaping low OS [12]. Visceral adipose tissue, strongly linked with inflammation, is shown to have a higher risk of relapse in several cancer types. Here, DFS is also associated with low VAT, both before and after NT [12]. Indeed, adiposity levels are known to be associated with both increased cancer incidence and progression in multiple tumor types, and obesity is estimated to contribute to up to 20% of cancer-related deaths [30]. Adipose tissue mechanistically disrupts physio-logical homeostasis, but the underlying relationships between obesity and cancer are still poorly understood.
Concerning a patient's pathological response following treatment, this was also associated with weight loss, even though body composition did not seem to be. In addition, patients with low skeletal muscle and adipose mass had a higher incidence of hypoalbuminemia and low IGF-1 levels.
Regarding postoperative complications (within 30 days), Zhou et al. failed to show a significant association with body composition. Nonetheless, a higher BMI with a high VAT after NAC was significantly correlated with postoperative and treatment complications [15,16].
In relation to nutritional interventions, immunonutrition did not seem to have a significant association with complications or survival rates. On the other hand, patients with nutritional support strategies, such as oral nutritional supplements, were shown to have better weight stability throughout the proposed treatments [22,23].
Age has been found to be associated with physiological changes influencing drug pharmacokinetics, thus affecting cancer therapies [31]. In this review, one study related age to pathological response [17], showing a better pathological response in older patients than in younger ones. This could imply a more aggressive gastric cancer in younger patients and, hence, a poorer clinical response. Interestingly, older patients present lower CONUT and PNI scores, indicative of lower serum albumin and lymphocyte counts. Ageing also carries the risk of an impaired immune and hematologic system, potentially making elderly patients more vulnerable to infections and, in turn, more susceptible to earlier treatment termination [31].
Yamaoka et al. found that age was not a risk factor associated with a significant loss of skeletal muscle after total gastrectomy, even though it is expected that a higher percentage of muscle wasting occurs in the elderly over 65 years of age [13].
This systematic review tried to clarify the exposures and critical determinants that may be impacting GC patients' nutritional status during neoadjunvancy, and our findings seem to reinforce the importance of body composition throughout the course of NT. GC is known to be accompanied by MN, altered metabolism, and cancer-associated cachexia, with a significant impact on the patient's nutritional status, muscle compartments, function, and OS [32]. GC patients will then be exposed to the burden of persistent inflammation and metabolic deregulation, along with decreased food intake due to anorexia, nausea, and digestive impairments such as epigastric pain and early satiety. Many of these symptoms endured since clinical presentation and/or diagnosis, if unabated, will potentially be made worse by the prolonged multimodal treatment, which, in turn, might aggravate any involuntary weight loss or sarcopenia [26,33]. Although current guidelines already recommend screening and the systematic identification of nutritional risk as the first step for the nutritional care process of cancer patients, and as sarcopenia's independent prognostic value becomes more established, body composition assessment could emerge as a broader tool to support clinical decision making in patients with GC, namely dose and toxicity management [34].
Regardless, the exact role of nutritional support during NAC has yet to be fully explored. Even though the evidence shows that nutritional support in the immediate perioperative period with immune-nutrient-enriched formulas seems to reduce surgical complications, little is known about the type of nutritional interventions during NAC [26,33].
In addition, it is urgent to better comprehend the role of nutritional support in stabilizing and reversing sarcopenia and its role during cancer-associated body composition changes, specifically throughout NAC.
Most of the studies found and included in this review had a retrospective design and recruited a small sample size (single center). Many have also identified the following limitations: heterogeneous clinical data, inconsistencies in the prescribed treatment plan, time to follow up, and diverse cut-off values (File S2-Supplementary Data). This review has also identified a lack of studies documenting wider aspects that might influence nutritional status, such as healthcare and organizational critical points. Patients with NT proposals will be exposed for longer to treatments and hospital visits, and this might be even more concerning for those having to accommodate farther travel to reach reference centers. More is needed to better understand the nutritional status implications of these prolonged care continuum exposures and subsequent clinical outcomes.
Finally, NT is a period that normally encompasses several weeks and could undoubtedly represent an opportunity to identify, manage, and tackle nutritional-related issues that seem to be associated with several clinical outcomes and to provide the best supportive measures for GC patients.

Conclusions
Neoadjuvant chemotherapy in gastric cancer patients has the potential to contribute to an increase in catabolic stress, nutritional impact symptoms, malnutrition, and sarcopenia. Pursuing a better understanding of the exposure to critical domains affecting nutritional status risk and their determinants will enable proactive clinical approaches and optimized care plans by deploying appropriate and timely nutrition support so that there is an opportunity to mitigate poor nutritional status and sarcopenia alongside their deleterious clinical consequences.