Pretreatment Neutrophil to Lymphocyte Ratio Independently Predicts Disease-specific Survival in Patients With Resectable Gastroesophageal Junction and Gastric Cancer

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To the Editor:
We read with great interest the recent article by Wang et al.1 They carefully examined their data in an attempt to evaluate the correlation between disease-specific survival and the pretreatment neutrophil to lymphocyte ratio (NLR) in a large cohort with gastroesophageal junction and gastric cancers. They showed its independent predictive power for long-term outcomes. Several studies have obtained consistent results for the prognostic value of this ratio in patients with resectable esophagogastric tumors.2 Furthermore, their findings appear to be highly reliable because they treat NLR as a continuous variable, rather than simply dividing the patients into 2 groups using an arbitrary cut off value as in other studies. Therefore, we basically agree with their findings and conclusions.
Although we appreciate their study for its large scale and detailed evaluation, we have concerns regarding the interpretation of their results. Recent success with neoadjuvant chemotherapy3 or chemoradiotherapy4 for esophagogastric tumors strongly suggests that neoadjuvant therapy offers a considerable survival benefit. In fact, 508 patients (34% of their cohort), not a small proportion, received neoadjuvant treatment. Therefore, its presence or absence may well have affected the survival analysis. Indeed, a recent report with an even larger sample size not receiving neoadjuvant chemotherapy failed to show a positive impact of NLR on 5-year overall survival rates in patients with stage II/III gastric cancer.5
It is generally accepted that cancer-associated inflammation is modulated by cancer cells, host stromal cells, and their interactions. Systemic inflammatory responses in patients with cancer are presumably attributable to persistent local tissue damage due to cancer growth and invasion, resulting in consecutive systemic acute-phase responses. Interestingly, significant reductions in both the neutrophil and the lymphocyte count occurred after neoadjuvant treatment of 508 patients in their analysis. Accordingly, NLR did not change after versus before neoadjuvant treatment. When neoadjuvant treatment shrinks the tumor and thereby diminishes the acute phase tumor response, NLR would theoretically change, that is, be reduced, according to the general concept of cancer-associated inflammation. Therefore, NLR may well not be a simple secondary event triggered by the tumor burden but rather be a specific score reflecting aspects of patient status. Even though patients receiving neoadjuvant therapy had markedly higher median pretreatment NLR, their results may highlight the possibility that NLR does not reflect the tumor response to neoadjuvant treatment or the exact extent of the tumor burden, and that the score before initial treatment is the actual determinant of overall patient outcomes. Although the results obtained by Wang et al are very interesting, considering the status of neoadjuvant therapy in their multivariate survival analysis might provide further valuable insights.
Another important issue is that neutrophils are involved in acute-phase reactions that occur in a range of inflammatory diseases. When patients have an infectious disease, or other inflammatory disorders such as collagen disease or synchronous malignant tumors before initial treatment, systemic inflammation is induced and the NLR score is strongly impacted. Therefore, patients must be carefully selected when analyses are conducted to precisely evaluate systemic inflammatory status, associated with the tumor, before treatment. On this basis, it seems unlikely that the NLR data obtained 3 months before initial treatment, which the authors employed for their analysis, actually reflect pretreatment status.
Standard treatment strategies for progressive diseases have changed dramatically because of the development of more effective chemotherapeutic regimens, including chemoradiotherapy, which have improved patient outcomes. In the study by Wang et al, the patients were recruited over a 15-year period during which treatment regimens would inevitably have changed. Therefore, we again emphasize the importance of assessing the status of neoadjuvant therapy in their multivariate survival analysis.

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