This study examined the associations of postoperative NLR, and its preoperative to postoperative changes, with the prognosis of gastric cancer patients, as well as the clinical utility of these measurements. The results showed that postoperative NLR and changes in NLR are independent prognostic factors for OS in patients with gastric cancer.
Increasing evidence supports an association between cancer and inflammation [19]. In particular, inflammatory processes contribute to cancer initiation, promotion, progression, and invasion [20]. In addition, inflammation is one of the seven main characteristics of cancer [21]. However, the precise mechanism underlying the association between increased NLR and poor long-term outcome in cancer patients is unclear. As NLR depends on two factors (neutrophil and lymphocyte counts), a high NLR may contribute to postoperative prognosis through the following possible mechanism. First, tumor-associated neutrophils may play a role in cancer progression by releasing factors that modulate the extracellular matrix and inflammation in the tumor microenvironment [22]. In particular, they play important roles during the initial angiogenic process in experimental tumor models [23]. Second, lymphocytes are the immune cells most responsible for the body’s protective effector immune response and antitumor response. That is, a decrease in circulating lymphocytes indicates a reduction of immune surveillance, thus enabling tumor growth [24]. The results of our clinical study support previous basic research in the same area.
The main strength of this study was its use of reliable NLR cut-off values, based on a large pool of data for gastric cancer patients. In addition, because a complete blood count is routinely obtained in all cancer patients during follow-up, evaluation of the prognosis of these patients required no additional effort. Thus, our method based on measurements of a systemic inflammatory parameter is a simple, cost-effective, and reproducible technique for assessing the survival of gastric cancer patients. Although the present study had a similar setting to a previous study of preoperative NLR [12], our analysis focused on postoperative NLR and dynamic changes in NLR. It is useful to evaluate the postoperative NLR because it may reflect residual host immune activity [25]. The postoperative systemic inflammatory state plays an important role in preventing tumor recurrence. That is, a postoperative increase in NLR indicates a pro-tumor inflammatory response of the host, whereas a postoperative decrease shows an anti-tumor immune response of the host [6]. For clinicians, therapeutic decision-making during the routine follow-up of high-risk patients after surgery is challenging, where early intervention is crucial to prevent recurrence. In clinical fields, tumor markers such as CEA, CA 19-9, and CA 72-4 are widely evaluated as laboratory follow-up tools. However, there are certain limitations to using these markers to detect recurrence and predict survival after surgery, because these markers have low sensitivity. Marrelli et al. reported sensitivities of 44% for CEA, 56% for CA 19-9, and 51% for CA72-4 in patients with recurrence [26]. However, the use of postoperative NLR and changes in NLR combined with existing tumor makers may provide a novel postoperative risk stratification tumor marker model.
The prognostic role of preoperative inflammatory markers has been well studied in gastric cancer patients [12-18]. However, the prognostic role of postoperative NLR in such patients has attracted less research attention [5, 9-11]. Some researchers have evaluated the prognosis based on the simple postoperative value [5, 11], while others have evaluated it according to preoperative to postoperative changes in NLR [9, 10]. The prognostic importance of this change reflects a dynamic change in the balance between host inflammatory and immune responses rather than the simple preoperative or postoperative NLRs. In Korea, a few studies have examined the associations between postoperative inflammatory markers, especially the NLR, and the prognosis of patients with gastric cancer. Kim et al. suggested that postoperative NLR predicts long-term recurrence after gastric cancer surgery. However, they used the postoperative day 3 NLR value and did not examine the dynamic change from preoperative to postoperative NLR, unlike our study [5]. Min et al. studied changes in NLR, similar to our study, but they divided the patients into two groups, i.e., negative and positive groups, according to the difference between preoperative and postoperative values. In addition, the postoperative NLR evaluation was performed at 3 to 6 month after surgery [10]. To the best of our knowledge, this is the first study to demonstrate the prognostic value of both the postoperative NLR and NLR change in Korean gastric cancer patients. Another strength of our study was that these two prognostic indicators were identified using the same data.
Despite its strengths, our study also had some limitations. First, we performed retrospective analysis of data collected from a single institution. Second, some bias can occur, because our study enrolled the patients even if there was recurrence within 6 months after operation. Thus, authors tried to perform additional analyses excluding recurrence within 6 months after operation. The results were shown in Supplement table. The trend was similar with our original study described in result section except for non-significant P value of the preoperative NLR in multivariate analysis for OS. Third, we did not evaluate changes in other inflammatory markers such as CRP, procalcitonin, PLR, and neutrophil-to-platelet ratio (NPR). Further studies are needed to validate the significance of our postoperative risk stratification model including NLR and other inflammatory markers, including CRP, procalcitonin, PLR, and NPR. Fourth, our study only demonstrated the postoperative 6-month NLR after surgery due to its retrospective nature. There is no consensus regarding the appropriate timing for measurement of postoperative inflammatory markers as prognostic predictors, with time points to check postoperative NLR ranging from 3 days to 6 months in previous gastric cancer studies [5, 9, 10]. Surgery is a major event that induces an acute inflammatory response [27]. The acute inflammatory reaction caused by surgery resolves within a short time, and its effects on the tumor disappear completely by several months postoperatively. Although there have been no reports regarding the exact time when inflammation due to the surgical wound healing process ceases, several groups have suggested that 1 month postoperatively is an appropriate check-up point [29, 29]. Further studies are required to determine the optimal check-up time point for reflecting postoperative NLR as a prognostic predictor in gastric cancer patients.