Prognostic value of neutrophil-to-lymphocyte ratio in gastric cancer: Enhancing clinical relevance

Abstract

Gastric cancer (GC) is a leading cause of cancer-related deaths, highlighting the need for reliable prognostic biomarkers to guide treatment. Wei et al’s systematic review and meta-analysis evaluates the neutrophil-to-lymphocyte ratio (NLR) as a potential biomarker for GC patients undergoing neoadjuvant chemotherapy. NLR is a simple and cost-effective measure of systemic inflammation that shows promise in predicting treatment response and survival outcomes, including overall survival and progression-free survival. However, variations in NLR thresholds and timing of measurements affect its accuracy and clinical utility. Moreover, the studies reviewed primarily involved Asian populations, which may limit the generalizability of the findings. To improve NLR’s clinical relevance, future research should focus on standardizing NLR thresholds, refining measurement timing, and incorporating additional inflammatory markers like platelet-to-lymphocyte ratio and Glasgow prognostic score. Addressing confounders and including diverse patient populations will help improve NLR’s reliability as a prognostic marker for GC.

Key Words: Gastric cancer; Inflammatory markers; Neoadjuvant chemotherapy; Neutrophil-to-lymphocyte ratio; Prognostic biomarker; Survival outcomes

Core Tip: The neutrophil-to-lymphocyte ratio (NLR) shows promise as a prognostic biomarker for gastric cancer, but its clinical use faces challenges, such as inconsistent cut-off values and unclear timing for measurement. Standardizing these factors, exploring additional inflammatory markers, and refining research methodologies will enhance NLR’s reliability and clinical utility in managing gastric cancer.

TO THE EDITOR

We commend the systematic review and meta-analysis by Wei et al[1], published in the World Journal of Gastrointestinal Oncology, which investigates neutrophil-to-lymphocyte ratio (NLR) as a prognostic biomarker for gastric cancer (GC) patients undergoing neoadjuvant chemotherapy (NAC). The study highlights NLR’s potential to predict treatment response, overall survival, and progression-free survival. Its ease of use and low cost make it a valuable tool in clinical practice, particularly in resource-limited settings. However, further research is needed to refine its clinical application and improve its utility in GC management.

STANDARDIZING NLR THRESHOLDS AND TIMING

A key challenge in using NLR as a prognostic marker is the lack of standardization in its cut-off values. The review found a significant association between elevated NLR and poor survival outcomes, but the thresholds used across studies varied widely. Reported NLR cut-offs ranged from 1.5 to 5.0, with no clear justification for selecting specific thresholds. This variability makes it difficult to draw consistent conclusions. Future studies should aim to determine an optimal standardized NLR cut-off based on patient demographics and disease stage. Establishing such thresholds would help ensure more reliable comparisons between studies and improve the clinical utility of NLR.

The timing of NLR measurement is another important factor that warrants attention. The authors mention assessing NLR at baseline and during treatment, but the exact timing of these measurements is unclear. Systemic inflammation can fluctuate during chemotherapy, and NLR levels measured immediately after chemotherapy cycles may differ from those taken during remission or before the start of NAC[2-4]. Standardizing the timing of NLR assessment, such as at the beginning of treatment and regular intervals during therapy, could provide more accurate prognostic data. This approach would enhance its value in clinical decision-making.

IMPROVING GENERALIZABILITY AND ADDRESSING SELECTION BIAS

While the study is a comprehensive retrospective analysis, concerns about the generalizability of the findings remain. Most of the participants were from Asia, which could limit the applicability of the results to other populations. Differences in genetic, environmental, and lifestyle factors may influence the relevance of these findings globally. Future studies should include more diverse cohorts, especially from regions with high GC rates, to ensure that the findings are applicable worldwide. Prospective multicenter studies could help overcome these limitations and provide more reliable evidence on the role of NLR in GC prognosis.

Retrospective studies are also prone to selection bias, which may distort the results. It is unclear whether the authors accounted for potential confounders, such as comorbid conditions, variations in chemotherapy regimens, and differences in treatment responses. Factors like obesity, diabetes, or other inflammatory diseases can significantly affect NLR levels and should be considered in future analyses[5-7]. Employing multivariable regression models that control for these confounders would strengthen the study’s validity and improve the accuracy of its conclusions.

BROADENING PROGNOSTIC APPROACHES WITH MULTIPLE INFLAMMATORY MARKERS

While NLR is a useful marker of inflammation, it is important to consider additional inflammatory markers for a more comprehensive understanding of GC prognosis. Other indices, such as the platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic inflammation response index (SIRI), and the Glasgow prognostic score (GPS), have shown potential in providing valuable prognostic information in GC[8-11]. Future studies should explore how NLR correlates with these markers and whether combining them could improve the prognostic value of NLR. Logistic regression models could be used to assess the associations between NLR and other inflammatory markers, such as PLR, MLR, SIRI, or GPS. Researchers could then compare these models using analysis of variance to determine if the inclusion of additional markers significantly improves NLR’s prognostic accuracy.

Incorporating NLR into established clinical models could also strengthen its role as a prognostic tool. For example, combining NLR with the tumor node metastasis staging system and other molecular or histopathological markers might provide a more comprehensive risk prediction. Including factors like tumor size, lymph node involvement, and vascular invasion in multivariable analysis could offer a fuller picture of a patient’s prognosis. This integrated approach would help clinicians make more informed, individualized decisions regarding the management of GC.

SUGGESTIONS FOR EXTENDING THE CURRENT REVIEW AND ANALYSIS

To further enhance the findings of this review and meta-analysis, we suggest including studies involving other inflammatory biomarkers, such as PLR, MLR, SIRI, and GPS. A network meta-analysis could then be performed to compare the prognostic accuracy of NLR with these markers. This approach could help identify the most predictive inflammatory marker for GC prognosis or determine if a combination of markers offers superior prognostic value[12].

Additionally, exploring the potential non-linear effects of NLR on GC prognosis could provide further insights. Given the complexity of the inflammatory process, there may be a non-linear relationship between NLR and survival outcomes[13]. Models like spline regression could help identify threshold effects, where the association between NLR and survival is stronger or weaker at specific NLR levels. Finally, subgroup analyses based on tumor stage, treatment regimens, and NLR cut-off values would help refine our understanding of NLR’s prognostic value across different patient populations and clinical scenarios.

CONCLUSION

Wei et al’s review offers valuable insights into the prognostic role of NLR in GC patients undergoing NAC. The study highlights the importance of systemic inflammation in predicting treatment outcomes and survival. However, several areas warrant further investigation. Standardizing NLR cut-offs, considering additional inflammatory markers, and refining the timing of measurement are essential to improving the clinical applicability of this marker. Further research in these areas will enhance our ability to use NLR as a reliable and precise tool in the management of GC.