Novel prognostic indicator combining inflammatory indicators and tumor markers for gastric cancer

Gastric cancer (GC) is the fifth-most common malignancy in humans and ranks third in a tumor-related mortality according to the latest epidemiologic data [1]. Radical resection combined with chemotherapy has consistently been the core method for curing GC. Unfortunately, due to the highly aggressive nature of GC, almost 50% of patients suffer from tumor recurrence or metastasis after curative resection, and the 5-year survival rate remains less than 30% [2, 3]. Currently, the most common criteria used to predict GC patients’ long-term outcomes include the TNM staging system, tumor markers, and inflammation indicators, but clinical outcomes can vary in patients who have the same stages and similar treatment regimens [4‐6], indicating that these systems provide incomplete prognostic information.

In 1863, Virchow first discovered the relationship between inflammation and cancer [7]; subsequently, an increasing number of related studies were carried out. A growing number of studies have proven the relationship between malignant tumors and inflammation [8‐12]. Many scholars believe that immune status is closely related to survival in patients with various malignancies, including GC [6, 13‐15]. The neutrophil-to-lymphocyte ratio (NLR) is a significant prognostic indicator of gastric cancer. Current researchers not only believe that gastric cancer patients with higher NLRs have a poorer prognosis [9, 16] but also indicate to a certain extent that the incidence of complications after surgery, such as anastomotic leakage, has increased [16, 17]. The NLR has been adopted for prognostic evaluation in many cancers, as well as the platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR).

The relationship between GC and tumor markers has basically been clarified, and a series of studies have explored the value of tumor markers in the diagnosis and prognosis of gastric cancer [18‐20]. At the same time, tumor markers, such as carcinoembryonic antigen (CEA) and CA19-9, have been used to determine prognosis and monitor the therapeutic effects of treatments. The level of CEA may be increased in gastric carcinoma, lung carcinoma, and especially colorectal carcinoma, while CA19-9 is used mainly as a specific marker for pancreatic cancer.

However, these indicators remain controversial. For both inflammation indicators and tumor markers, the specificity and sensitivity in predicting the long-term outcome of GC patients alone are poor, and thus, there is an urgent need for a new, easy method to predict GC more accurately and perform targeted follow-up treatment and observation for patients who may have a poorer prognosis. Therefore, we attempted to combine inflammation indicators and tumor markers with a high predictive value to predict the prognosis of GC patients more accurately. In addition, we used prospective clinical data to investigate whether the new indicator could effectively predict postoperative outcomes of GC and compared its predictive value with other traditional indices.

Advances in modern medicine have allowed scholars to gradually turned their attention to the early treatment and follow-up of various malignant tumors, which puts forward extremely high requirements on how to distinguish patients with a poor prognosis. To date, researchers have established several scoring systems that reflect inflammation or tumor status [23‐25]. Our study enrolled 425 GC patients and found that the NLR and CA19-9 were independent prognostic factors for postoperative OS. Based on this, we developed a novel index combining these inflammatory and tumor markers and confirmed that the new index could provide better prognostic value than either the NLR or CA19-9 alone.

Inflammation is an important characteristic of the tumor microenvironment and is associated with the promotion, progression, and metastasis of tumors [8]. Tumor cells produce cancer-related inflammatory mediators, resulting in relative neutrophilia, thrombocytosis, and lymphocytopenia. These phenomena cause an elevated NLR and PLR [26] and further affect the occurrence, progression, and metastasis of tumors [27]. Neutrophils are currently believed to promote cancer cell proliferation and metastasis by producing proangiogenic chemokines and vascular endothelial growth factor [28‐30], and lymphocytes are antitumor factors involved in cytotoxic activity [31]. Numerous studies have proven the relationship between a high NLR and poor outcomes in various malignancies, such as gastric cancer [9, 16], colon cancer [13], and pancreatic cancer [32]. The present study revealed the NLR as an independent factor with a cutoff value of 2.46, and its AUC was higher than that of other hematological parameters.

Carbohydrate antigen (CA) 19-9 is one of the most common tumor markers of gastric cancer, and positivity is frequently related to tumor stage, poor prognosis, recurrence, and metastasis [18‐20]. Jing et al. [19] found that surgery can significantly reduce the level of CA19-9; if the level returns to normal after surgery, the prognosis is not significantly different from that of patients with normal CA19-9 before surgery. As confirmed in our study, the prognosis of GC patients with low levels of CA19-9 before surgery was significantly better than that of patients with high levels. Of course, we consider the NLR and CA19-9 to represent not only simple changes in several indicators but also the balance of tumor and antitumor status in the body. When this balance is broken, tumor promotion is prioritized, leading to a poor prognosis.

Unfortunately, previous conclusions on these indicators have not always been consistent. Some scholars have insisted that there was no significant correlation between the preoperative NLR and survival time in GC patients [33‐35]. In addition, controversy about CA19-9 also exists. Researchers have reported a low positive rate of CA19-9 in GC patients [36, 37]. In addition, some scholars believe that CA19-9 cannot accurately predict the prognosis of patients with GC [18], especially early GC [37]. This means that using an indicator alone to predict prognosis may lose some potential information, resulting in limited predictive value. In this study, we discussed the predictive significance of various inflammatory indicators and tumor markers in the prognosis of GC in detail and innovatively introduced a new index, the NLR-CA19-9 score (NCS). We found that the NCS not only could serve as an independent prognostic factor but also had a higher AUC than other inflammatory and tumor markers for OS, 12-, 36-, and 60-month survival, which means that the NCS has a stable prognostic ability that was better than that of other indicators. It was worth noting that there were no significant differences in AUC between the NCS and NLR, PLR, or CEA at 12 months after surgery. We believed that the survival of patients at 12 months after surgery was relatively higher (87.3%), resulting in no statistically significant difference. With the progress of follow-up, the survival of patients had declined, and the differences had gradually become apparent. Therefore, the differences were all statistically significant for OS and 36- and 60-month survival (p<0.05). Moreover, a model including the NCS (C-index, 0.788) was superior to that constructed without it (C-index, 0.743) in predicting OS after radical gastrectomy. Importantly, the novel index in our model could be conveniently attained from routine laboratory inspection, which was advantageous because it avoids the potential unavailability of other predictors.

The results of this study that the NCS, as a novel scoring system, has favorable sensitivity and specificity in predicting the long-term postoperative outcomes of GC patients and could provide more precise and informative prognostic value than other indicators. This new indicator may have vital use in predicting recurrence, therapeutic intervention, and surveillance strategies, especially when incorporating the TNM stage. For example, patients with a higher NCS could be strongly recommended to receive postoperative multimodal treatment, such as chemotherapy, immunotherapy, or targeted therapy and should receive a more rigorous follow-up schedule, with comprehensive medical examinations at least every 3 months for 5 years, such as gastrointestinal endoscopy, CT with contrast, and serum tumor markers, which may provide a survival benefit for GC patients.

Several limitations remain in our present study. First, the main drawback of our study is its retrospective nature, and bias in the process of patient selection cannot be avoided. Second, because the specific time of tumor recurrence in some patients cannot be completely determined, we did not study the relationship between various indicators and postoperative progression-free survival (PFS). Third, the pathological stages of the patients in our study are relatively broad, so the conclusion may not apply to patients with a particular TNM stage. But we are still expanding the sample size to verify whether our conclusion are applicable to similar stages.

In conclusion, to the best of our knowledge, the NCS is an independent prognostic factor for OS in GC patients and provides great value in predicting postoperative overall survival. It is an effective complement to existing GC assessment systems. Future studies should consider combining the NCS into the current TNM system to more specifically predict the prognosis of GC patients, who will be likely to benefit from a rigorous follow-up strategy.