Nutritional status and adjuvant chemotherapy in gastric cancer: An underestimated determinant of treatment success

Abstract

Adjuvant chemotherapy is the cornerstone of curative treatment for resected gastric cancer (GC). However, its real-world effectiveness is frequently compromised by incomplete treatment delivery and reduced dose intensity. Although tumor-related factors have traditionally guided therapeutic decision-making, host-related determinants of treatment feasibility remain underappreciated in the literature. Nutritional status is a prevalent and clinically measurable determinant that directly influences treatment tolerance and outcomes. Nutritional risk, as assessed by validated screening tools such as the Nutritional Risk Screening 2002, has consistently been associated with chemotherapy completion, the incidence of severe treatment-related toxicity, and survival outcomes. Malnutrition predisposes patients to treatment-related toxicity, dose reductions, and early treatment discontinuation, thereby attenuating the survival benefits observed in randomized clinical trials. The dynamic nature of nutritional deterioration during adjuvant therapy further underscores the limitations of single time-point assessments. Nutritional decline often progresses during systemic treatment, even in patients without a baseline nutritional risk, with important implications for adherence to chemotherapy and maintenance of relative dose intensity. Recognizing nutrition as a modifiable determinant of therapeutic success has relevant implications for contemporary GC management. In this editorial, we comment on the article by Zhou et al published in the recent issue of the World Journal of Gastrointestinal Surgery, which critically examines emerging evidence linking nutritional status to adjuvant chemotherapy feasibility in GC, with particular emphasis on dose intensity as a mechanistic mediator and on the clinical implications for routine practice.

Key Words: Gastric cancer; Adjuvant chemotherapy; Nutritional status; Nutritional risk; Dose intensity; Chemotherapy tolerance; Clinical outcomes

Core Tip: Nutritional status substantially influences the feasibility and effectiveness of adjuvant chemotherapy in patients with resected gastric cancer. Nutritional impairment is common and closely associated with chemotherapy tolerance, maintenance of relative dose intensity, and treatment completion, all of which are critical determinants of oncologic outcomes. Simple and validated screening tools, such as Nutritional Risk Screening 2002, enable early identification of patients at increased risk of treatment-related toxicity and non-completion. Incorporating routine nutritional assessment and timely nutritional support into adjuvant treatment pathways may represent a practical strategy for optimizing chemotherapy delivery in everyday clinical practice.

This editorial refers to "Impact of nutritional status on treatment completion and prognosis during adjuvant chemotherapy following gastric cancer surgery" by Zhou et al, 2026; https://doi.org/10.4240/wjgs.v18.i2.114607.

---

INTRODUCTION

Adjuvant chemotherapy is the cornerstone of curative-intent treatment for patients with resected stage II-III gastric cancer (GC). Landmark randomized trials, including ACTS-GC and CLASSIC, have unequivocally demonstrated that postoperative systemic therapy significantly improves disease-free and overall survival compared to surgery alone[1,2]. Nevertheless, the translation of these benefits into routine clinical practice remains suboptimal, as a substantial proportion of patients fail to complete the planned treatment or maintain adequate relative dose intensity (RDI).

This discrepancy between trial efficacy and real-world effectiveness has increasingly shifted attention toward host-related determinants of treatment feasibility. Among these, nutritional status has emerged as a clinically relevant yet frequently under-recognized determinant of chemotherapy tolerance and delivery. Malnutrition is highly prevalent in GC, driven by tumor-associated hypercatabolism, postoperative anatomical and functional changes, and treatment-related adverse effects. From a biological perspective, nutritional depletion may alter drug pharmacokinetics through reduced lean body mass and hypoalbuminemia, leading to increased free drug fractions and impaired drug clearance. Consistently, malnutrition has been associated with higher toxicity rates, more frequent treatment interruptions, and inferior oncologic outcomes[3-5].

Despite this growing body of evidence, nutritional factors remain inconsistently integrated into adjuvant treatment planning, which continues to be largely driven by tumor-related characteristics and chemotherapy regimens. As a result, the contribution of nutritional vulnerability to treatment delivery and real-world outcomes is often insufficiently examined.

Accordingly, this editorial adopts a progressive framework to examine the role of nutrition in the adjuvant treatment of GC. It first outlines the biological and clinical basis of malnutrition in GC, then reviews the clinical value of nutritional risk stratification tools, and finally discusses how nutritional impairment may influence chemotherapy dose intensity and the actual effectiveness of adjuvant treatment in everyday practice.

MALNUTRITION IN GC: PREVALENCE AND BIOLOGICAL BASIS

Malnutrition is highly prevalent among patients with GC and results from a complex interplay between tumor-associated hypercatabolism, postoperative anatomical and functional alterations, and treatment-related adverse effects. Reported prevalence rates range from 40% to 80%, with nutritional status frequently worsening after gastrectomy[3-6].

Nutritional impairment has been consistently associated with increased postoperative morbidity, impaired immune competence, delayed recovery, reduced tolerance to systemic therapies, and inferior oncologic outcomes[7-9]. In the adjuvant setting, malnutrition is similarly linked to reduced tolerance to chemotherapy and increased treatment-related complications.

Despite strong evidence, nutritional assessment remains inconsistently integrated into routine oncologic workflows, particularly during the adjuvant phase of the disease. Clinical decision-making continues to focus predominantly on tumor stage, chemotherapy regimen, and timing of initiation, whereas host-related factors, such as nutritional status, are often underrecognized. This gap highlights the need to systematically incorporate validated nutritional assessment tools into the perioperative and adjuvant treatment pathways for GC. Beyond global malnutrition, alterations in body composition - particularly sarcopenia - have emerged as critical determinants of chemotherapy tolerance. Reduced skeletal muscle mass has been consistently associated with increased chemotherapy-related toxicity, impaired drug metabolism, and reduced survival across multiple solid tumors[10-13]. In GC, sarcopenia may further exacerbate postoperative vulnerability and limit the feasibility of adjuvant treatment[12]. These findings suggest that conventional nutritional screening tools may underestimate the complexity of metabolic impairment unless integrated with body composition assessment.

NUTRITIONAL RISK SCREENING: THE CLINICAL VALUE OF NUTRITIONAL RISK SCREENING 2002

Recent interest in nutritional risk during adjuvant chemotherapy for GC has been renewed by the study of Zhou et al[14], published in World Journal of Gastrointestinal Surgery, who evaluated the association between nutritional status and treatment completion and outcomes in patients receiving postoperative chemotherapy. Their work has contributed to bringing nutritional vulnerability into sharper clinical focus during adjuvant treatment, prompting renewed attention to the role of structured nutritional assessment in this setting[14].

Among available nutritional screening instruments, the Nutritional Risk Screening 2002 (NRS-2002) has emerged as a pragmatic and widely validated tool in oncologic practice. NRS-2002 integrates the degree of nutritional impairment, disease severity, and patient age, thereby providing a multidimensional assessment of physiological reserve and potential vulnerability to treatment-related stress[15]. This composite approach allows identification of patients at increased risk of treatment-related complications beyond what can be captured by anthropometric or laboratory parameters alone.

Multiple studies have demonstrated that elevated NRS-2002 scores are associated with higher rates of postoperative morbidity, reduced adherence to chemotherapy, and poorer survival in gastrointestinal malignancies[16,17]. In GC, high NRS-2002 scores have been consistently linked to inferior tolerance to adjuvant chemotherapy and worse long-term oncologic outcomes[18,19].

In the study by Zhou et al[14], an NRS-2002 score ≥ 3 was associated with lower chemotherapy completion rates, a higher incidence of grade ≥ 3 toxicities, and inferior disease-free and overall survival among patients receiving adjuvant chemotherapy for GC. Importantly, these findings position NRS-2002 as a clinically informative screening instrument rather than a diagnostic instrument, suitable for routine implementation at the point of care.

Other nutritional indices, including the Prognostic Nutritional Index (PNI), the Controlling Nutritional Status (CONUT) score, the Global Leadership Initiative on Malnutrition (GLIM) criteria, and the Patient-Generated Subjective Global Assessment, have also been investigated in GC[8,18-20]. Each tool offers distinct advantages and limitations. The GLIM criteria provide a standardized framework for diagnosing malnutrition but require assessments such as muscle mass that may not be readily available in routine practice[9]. The PNI and CONUT scores rely on serum biomarkers and may be influenced by systemic inflammation or hepatic dysfunction[20]. Patient-Generated Subjective Global Assessment is a comprehensive, patient-centered instrument that captures both subjective and objective elements of nutritional status, although its application can be time-consuming[19]. Comparative data among these tools remain limited, and their relative performance in predicting adjuvant chemotherapy feasibility has yet to be prospectively validated. A head-to-head evaluation of NRS-2002, GLIM, CONUT, and PNI in patients with resected GC could help inform the development of an evidence-based nutritional assessment strategy tailored to oncology practice.

FROM NUTRITIONAL IMPAIRMENT TO REDUCED DOSE INTENSITY: A CAUSAL PATHWAY

The clinical relevance of nutritional status extends beyond its prognostic associations and is closely linked to treatment delivery during adjuvant chemotherapy (Figure 1). The concept of RDI represents a cornerstone of systemic treatment efficacy in oncology. Historical and contemporary evidence indicates that reductions in RDI are associated with inferior survival outcomes across a broad range of malignancies[21,22]. In GC, maintaining adequate dose intensity appears particularly relevant in the adjuvant setting, where treatment intent is curative, and treatment delivery is frequently compromised in real-world practice[23]. Malnutrition has been associated with an increased susceptibility to chemotherapy-related toxicity through multiple biological mechanisms, including impaired immune competence, altered pharmacokinetics and drug metabolism, reduced tissue repair capacity, and heightened systemic inflammation[9]. Collectively, these vulnerabilities are associated with a higher likelihood of dose reductions, treatment delays, and premature discontinuation of chemotherapy in routine clinical practice.

Figure 1 Nutritional impairment as a driver of reduced chemotherapy dose intensity in gastric cancer. The figure conceptualizes the biological and clinical cascade linking malnutrition to impaired delivery of adjuvant chemotherapy. Host-related factors, including sarcopenia and systemic inflammation, promote increased toxicity and decreased treatment tolerance, ultimately leading to suboptimal dose intensity and inferior survival outcomes. This framework supports a shift toward patient-centered, nutrition-integrated oncologic care. RDI: Relative dose intensity.

RDI has consistently been shown to correlate with oncologic outcomes across solid tumors, including gastrointestinal malignancies, underscoring its role as an important mediator of treatment efficacy[24]. In the adjuvant setting, emerging evidence suggests that reduced dose intensity is associated with inferior disease-free survival in patients receiving chemotherapy for GC. Taken together, these observations support a biologically and clinically coherent framework in which nutritional impairment contributes to reduced treatment tolerance and compromised chemotherapy delivery. This, in turn, may attenuate the survival benefit observed in randomized clinical trials. While this framework is primarily supported by observational data, it provides a relevant conceptual basis for understanding the gap between trial efficacy and real-world effectiveness. However, the strength of this proposed pathway depends on the level of evidence supporting it, which warrants careful appraisal of the methodological limitations of the core observational data.

METHODOLOGICAL CONSIDERATIONS AND LIMITATIONS OF THE AVAILABLE EVIDENCE

Accordingly, interpretation of this framework requires careful appraisal of the methodological limitations of the core observational studies on which it is based. Given the central role attributed to the study by Zhou et al[14] in framing the present editorial, a detailed discussion of its methodological limitations and their implications for clinical interpretation is warranted. While the findings presented by Zhou et al[14] provide relevant observational evidence regarding the prognostic value of nutritional screening, several methodological caveats warrant careful consideration. First, the retrospective design and relatively small, single-center cohort limit the generalizability of the results. More importantly, this design precludes the establishment of a definitive causal relationship between nutritional risk, as assessed by NRS-2002, and adverse oncologic outcomes[15]. While NRS-2002 is often preferred for its multidimensional nature, direct head-to-head comparisons with PNI or CONUT in this specific setting are lacking, and its relative superiority remains to be prospectively confirmed.

Consequently, these results should be viewed as a robust, hypothesis-generating framework rather than a definitive mandate for clinical practice. To transition from clinical association to proven causation, there is a clear need for multicenter, prospective randomized controlled trials aligned with current international oncology nutrition guidelines[25]. These trials must prioritize 'therapeutic feasibility’ as a primary endpoint, specifically investigating whether early, structured nutritional interventions can directly improve chemotherapy completion rates and maintain RDI. Only through such rigorous prospective validation can systematic nutritional management be elevated from an elective adjunct to a definitive, widely accepted component of standard adjuvant care in the adjuvant treatment of GC.

DYNAMIC NUTRITIONAL DETERIORATION DURING ADJUVANT THERAPY

Beyond this methodological appraisal, an additional clinically relevant observation is that nutritional status is dynamic and frequently deteriorates during chemotherapy. Even patients without baseline nutritional risk may experience measurable nutritional decline over the course of treatment, whereas those already at risk tend to show significantly greater and more rapid deterioration. These observations underscore the inherent limitations of single time-point nutritional assessments and highlight the need for longitudinal nutritional monitoring during adjuvant therapy.

This pattern of nutritional impairment appears to be self-reinforcing. Patients with compromised baseline nutritional status are more likely to develop severe treatment-related toxicity, which worsens anorexia, gastrointestinal symptoms, and metabolic derangements, thereby exacerbating nutritional deterioration. In turn, this interplay has been associated with an increased likelihood of dose reductions, treatment delays, and premature discontinuation of chemotherapy, potentially undermining treatment completion and oncologic outcomes[9,26]. In this context, and as discussed above, these observations should be interpreted cautiously given the retrospective, single-center nature of the available evidence and the absence of standardized nutritional interventions.

INTEGRATING NUTRITION INTO THERAPEUTIC DECISION-MAKING: A CALL TO ACTION WITHIN CLINICAL PRACTICE

Consequently, the available evidence supports a conceptual shift toward recognizing nutrition as an integral component of adjuvant treatment strategies, rather than as a purely supportive adjunct. Routine nutritional risk screening using validated tools such as the NRS-2002 may represent a pragmatic approach to identifying patients at increased risk of treatment intolerance when adjuvant chemotherapy is being considered. Importantly, nutritional assessment appears most informative when applied longitudinally rather than as a single baseline evaluation, allowing early recognition of clinically meaningful deterioration during treatment. Importantly, nutritional status should not be regarded as a static prognostic marker but as a modifiable therapeutic target. Evidence from randomized trials and meta-analyses indicates that early and individualized nutritional interventions can reduce treatment-related complications, improve tolerance to systemic therapies, and enhance clinical outcomes in patients at nutritional risk[5,27,28]. Despite this, nutritional care remains inconsistently implemented in routine oncology practice, highlighting a persistent gap between evidence and clinical application (Table 1).

Table 1 Nutritional risk factors, clinical impact, and implications for adjuvant chemotherapy in gastric cancer.

Nutritional domain	Clinical indicators	Biological/functional impact	Consequences on chemotherapy	Clinical implications
Weight loss	> 10% body weight loss	Energy depletion, catabolism	Increased toxicity	Consider treatment delay and nutritional support
Sarcopenia	Reduced skeletal muscle mass (CT-based)	Impaired drug metabolism, frailty	Dose-limiting toxicity	Adjust dosing strategy, monitor closely
Reduced oral intake	Caloric/protein deficit	Negative energy balance	Poor tolerance to therapy	Early nutritional supplementation
Systemic inflammation	Elevated CRP, hypoalbuminemia	Catabolic state, immune dysfunction	Increased complications	Anti-inflammatory and nutritional strategies
Hypoalbuminemia	Albumin < 3.5 g/dL	Reduced physiological reserve	Treatment interruption	Risk stratification before therapy
Global malnutrition (GLIM criteria)	Combined phenotypic + etiologic criteria	Multisystem impairment	Reduced RDI	Multidisciplinary management

GLIM: Global Leadership Initiative on Malnutrition; CT: Computed tomography; CRP: C-reactive protein; RDI: Relative dose intensity.

A PRACTICAL ROADMAP FOR CLINICAL IMPLEMENTATION

From a practical standpoint, integration of nutritional care into adjuvant treatment pathways can follow a structured and reproducible approach. Nutritional risk screening using validated tools such as the NRS-2002 should be performed at baseline, before initiation of adjuvant chemotherapy, and repeated at predefined intervals during treatment (e.g., every 1-2 chemotherapy cycles) or in the presence of clinically relevant toxicity or unintentional weight loss[5,15,25]. Patients at nutritional risk should be promptly referred to a multidisciplinary nutritional care team, with escalation from individualized dietary counseling to oral nutritional supplementation, enteral nutrition, or parenteral support as clinically indicated[5,25,29]. Importantly, the primary objective of nutritional intervention in this setting should be preservation of treatment feasibility - namely chemotherapy completion and maintenance of RDI - rather than nutritional optimization per se[24]. Embedding this pathway within routine oncology workflows, supported by standardized referral protocols and electronic health record-based alerts, may facilitate consistent implementation and longitudinal monitoring in real-world practice[16].

IMPLICATIONS FOR CLINICAL RESEARCH AND GUIDELINE DEVELOPMENT

For patients identified as being at nutritional risk, early and structured nutritional interventions, including individualized dietary counseling, oral nutritional supplementation, enteral nutrition or parenteral support, when clinically indicated, can be initiated with the explicit aim of preserving treatment tolerance, maintaining RDI, and improving adherence to chemotherapy. Prospective evidence indicates that targeted nutritional support in high-risk oncology patients can reduce complications, improve treatment tolerance, and favorably influence clinical outcomes[29,30].

Beyond immediate clinical practice, these considerations have significant implications for both clinical research and guideline development. Future clinical trials on GC should incorporate nutritional risk stratification and standardized nutritional interventions as integral components of the study design, with chemotherapy completion, toxicity, quality of life, and survival included as prespecified endpoints. Future prospective trials should ideally adopt treatment completion rates and RDI as primary endpoints to rigorously evaluate the impact of structured nutritional interventions on therapeutic feasibility. Similarly, international and national clinical guidelines should explicitly integrate nutritional screening and intervention into adjuvant treatment pathways, recognizing nutrition as a modifiable determinant of therapeutic success with direct relevance to real-world outcomes of patients. However, translating this conceptual shift toward integrated nutritional care into routine oncology practice remains challenging. Key barriers include limited availability of trained clinical nutrition professionals, the absence of standardized referral pathways, inadequate integration of nutritional assessment tools into electronic health records, and the lack of institutional performance metrics dedicated to nutritional care. These obstacles contribute to the persistent underutilization of nutritional screening in gastrointestinal oncology, despite its well-documented clinical relevance. Real-world evidence from the EuroOOPS study, a large international multicenter initiative, demonstrated that systematic implementation of the NRS-2002 tool was feasible and associated with improved clinical outcomes across diverse healthcare settings[16]. In parallel, the European Society of Clinical Nutrition and Metabolism guidelines on nutrition in cancer patients strongly advocate for structured and repeated nutritional screening as a core component of standard oncologic care, highlighting its role in improving treatment tolerance and reducing complications[5]. Leveraging these established models, a multifaceted implementation strategy - combining electronic health record-embedded screening alerts, nurse-led or pharmacist-led assessment pathways, and telehealth-based nutritional consultations - may help overcome logistical barriers and facilitate the systematic integration of nutritional care into routine oncology practice. Embedding nutrition-related indicators within institutional quality frameworks could further promote sustainable adoption.

CONCLUSION

Accumulating evidence indicates that nutritional status is a decisive and modifiable determinant of the feasibility and effectiveness of adjuvant chemotherapy in GC. Beyond its established prognostic significance, nutritional impairment directly influences treatment tolerance, RDI, and completion rates, thereby shaping the real-world oncologic outcomes. The consistent association between nutritional risk and chemotherapy delivery highlights nutrition as an upstream factor in the therapeutic pathway, rather than a secondary supportive consideration.

Validated screening tools, such as the NRS-2002, provide a practical and reliable means of identifying patients at increased risk of treatment-related toxicity and non-completion. Notably, nutritional status is not static and often deteriorates during adjuvant therapy, underscoring the need for longitudinal assessment rather than a single time-point evaluation. Failure to recognize and address this dynamic vulnerability may undermine the effectiveness of adjuvant treatment as delivered in routine care.

Integrating systematic nutritional assessment and timely, individualized nutritional interventions into adjuvant treatment pathways may represent a cost-effective strategy; however, formal health economics analyses are needed to confirm the financial impact of such interventions. Recognizing nutrition as a core component of therapeutic decision-making is essential to bridging the gap between trial efficacy and real-world effectiveness. From an editorial perspective, the integration of nutritional assessment into adjuvant treatment decision-making reflects a necessary shift from tumor-centered to patient-centered oncology. Future research should prioritize interventional strategies aimed at preserving treatment feasibility, with nutritional optimization as a core component of precision supportive care. Accordingly, it should be prioritized in both routine clinical management and future research on GC.