This study was the first that assessed the prognostic effect of SII in GC patients with late recurrence to the best of our knowledge. We showed that SII was the only prognostic factor for RFS in the GC patients with late recurrence. Recurrence rates were higher for SII-high patients than SII-low patients in the late recurrence group. However, there was no prognostic effect of SII for RFS in the GC patients with early recurrence.
In a study evaluating prognostic effect of SII on operable GC patients, Wang et al. showed that SII was an independent prognostic factor for disease-free survival (DFS) and OS.15 This study did not stratify the patients as early and late recurrence. In addition, 13% of all patients had R2 resection, and about 1 out of 4 patients had not received adjuvant chemotherapy.15 However, no patient was performed R2 resection, and the rate of patients without adjuvant treatment was 7.3% in our study. Another study that included operable GC patients also showed that SII was an independent prognostic factor for DFS and OS. This study also showed that SII-low patients had a better prognosis than SII-high patients in 1, 3, and 5 years after surgery.16 However, similar to the study of Wang et al., patients who underwent R2 resection and metastatic patients were included in this study.16
In our study, we determined that SII could be a prognostic factor for late recurrences in operable gastric cancer, but not for early recurrences. It should be kept in mind that extent of resection and adjunctive treatment could affect the recurrence in patients with operable GC.17, 18 Unlike the studies mentioned above, we did not include patients with R2 resection. Besides, the rate of adjuvant chemotherapy was higher in our study.
Tumor-associated inflammation is divided into three categories as preceding inflammation, tumor-elicited inflammation, and therapy-induced inflammation.5 The calculation of SII before surgery may exclude the effect of therapy-induced inflammation. The prognostic impact of SII on the late tumor recurrence can be explained by the chronic effect of the inflammatory process. It is well-known that systemic inflammation contributes to tumor growth, metastasis, therapy resistance.5 Besides, increased tumor invasion, and inhibition of adaptive immunity are considered a result of tumor-associated inflammation.19 Neutrophil increases inflammation in the tumor microenvironment (TME) by secretion chemokines, cytokines, and reactive oxygen species (ROS), thus, causes tumor growth and therapy resistance.20 On the other hand, platelets also have a significant effect on tumor-associated inflammation. It plays an essential role in tumor angiogenesis.21 Furthermore, cytokines secreted by platelet contribute to tumor-associated inflammation in the TME; thus, causing drug resistance.22
Our study suggested that more prolonged chronic inflammation may be associated with recurrence. To date, there was no clear evidence for the relation between the duration of inflammation and cancer recurrence in the operable solid tumors. However, it is well-known that the duration of chronic inflammation is one of the critical factors for cancer pathogenesis.23 The prognostic effect of SII on the late recurrences may be explained with prolonged exposure to chronic inflammation.
Recently, a study conducted by Hirahara et al. did not show the prognostic value of SII on OS in the overall population.24 Similar to our study, there were no patients with R2 resection in this study. However, Hirahara et al. showed that SII was a prognostic factor in elderly patients.24 In fact, it may be contributed to our hypothesis regarding the association between the late recurrence and more prolonged chronic inflammation exposure.
Our study has several limitations. First, it was a retrospective study; thus, we had missing data for some patients. It also resulted in a small patient cohort. Second, we conducted this study in multicenter. This resulted in using different laboratory devices for peripheral complete blood counting. Furthermore, surgical techniques and adjunctive treatment options might show differences between the centers. Third, we did not know the causes of death for all patients, and cancer-specific survival may differ from overall survival. All these shortcomings may have affected the outcomes.
In conclusion, SII might be an independent prognostic factor for late recurrence in patients with operable GC. If validated in well-designed prospective studies, SII could help predict long-term oncologic outcomes and help in making better treatment decisions in these patients.