Systemic inflammation index as a predictor of lung cancer recurrence and recurrence of other types of cancers

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Sumy State University

Systemic inflammation index as a predictor of lung cancer recurrence and recurrence of other types of cancers

Kmyta O.P., Kononenko M.H.

Lung cancer is one of the most common tumors. Today a lot of attention is paid to prediction of prognosis in oncological patients. Systemic inflammation indicators are now actively investigated. Systemic inflammation indicators are represented by neutrophil-to-lymphocyte ratio (NLR), platelet-to- lymphocyte ratio (PLR), systemic inflammation index (SII) and systemic inflammation response index (SIRI). All these indicators are determined from blood counts. This made them cost-effective and affordable.

In elder patients with different tumors Li et al found that a high SII > 390*109 cells/L was correlated with low differentiation of tumor tissue (P = 0.002) and poor one-year survival (P = 0.006). Patients with low SII had improved survival and higher tumor differentiation (Stage I-II), but SII was not associated with Ki-67 expression [1]. According to the data of a retrospective study conducted in Great Britain by Nost et al, it was found that SII can not only be predictor of poor prognosis in cancer, but also as an indicator showing presence of risk factor for the occurrence of an oncological process. In the study 17 types of cancer were investigated, but constant correlation was observed only for 7 locations. Thus, the highest correlation was demonstrated for colorectal and lung cancer. It was found that in patients with colorectal cancer five years before primary diagnosis SII was increase 1.09 times, while one month before primary diagnosis - 1.5 times [3].

Team of researchers was investigating the prognostic value of SII in esophageal cancer. The study proved that the index correlated with an unfavorable prognosis for patients with esophageal cancer. It was shown that the higher index the shorter overall survival in patients after surgery. In addition, it was determined that negative influence of the increased SII index was manifested by the depth of invasion, clinical stage, and metastasis to the lymph nodes [4]. Jiang et al. also proved that in esophageal cancer SII index can be used as a predictor of poor prognosis. They showed that the higher index, the lower overall and recurrence-free survival [5].

Yan et al analyzed SII as Prognostic Marker for Patients with synchronic colorectal peritoneal carcinomatosis. Scientists detected that elevated NLR, PLR and SII significantly correlate with worse survival outcome, but only low SII value was described as an independent favorable prognostic factor for overall survival (P=0.044). Moreover, SII could predict survival outcome for the patient's receiving completeness of cytoreduction score (CCR) 0/1 or CCR2/3 [6].

Fu et al showed that preoperative SII may be a powerful prognostic biomarker in patients with hepatocellular carcinoma. Thus, five-year overall survival (OS) was lower in patients with high SII than in patients with low SII (56.1% vs. 82.4%, p = 0.002). SII > 226 x 109/L was detected as independent prognostic factors for OS, as well as maximum tumor size> 5 cm, microvascular invasion, and poor differentiation. However, SII did not predict 5year recurrence-free survival (high vs. low SII: 64.1% vs. 78.4%, p = 0.073) [7].

Another location that studied was the cervical cancer. It was shown that in cervical cancer a high index value also correlates with poor prognosis. But correlation was proved only for tumors with large size. It was also proven that the SII index was the only independent predictor of poor prognosis in radically operated patients [8].

Shui et al confirmed negative impact on prognosis in patients with pancreatic cancer. Thus, increased SII index was associated with poor overall survival (HR=1.50, 95% CI=1.15-1.96, p=0.002), RFS/PFS/DFS (HR=1.52, 95% CI=1.01-2.28, p=0.045), CSS (HR=2.60, 95% CI=1.65-4.09, p < 0.001). However, no correlation was found between SII and other parameters of pancreatic cancer, such as sex, tumor location, lymph node metastasis, stage, vascular invasion, and differentiation degree. This study showed that an elevated SII index was significant prognostic marker for both short- and long-term survival outcomes for patients with pancreatic cancer [9].

Influence of SII on prognosis in patients with diffuse large B-cell lymphoma was studied by Liu et al. As a result of the study, it was determined that the 5-year overall survival in patients with a higher index score is lower than in patients with a lower score (67% vs. 62%, P=0.034). But SII index detected as a predictor of OS only in univariate analysis, but it is not an independent factor [10].

Ruan et al were investigating SII as a prognostic factor in elderly patients with cancer cachexia. It was found that in elderly patients with cancer cachexia SII was not the best predictor of prognosis. Advanced lung cancer inflammation index (ALI) was detected as prognosis predictor: low ALI associated with higher death risk [11].

Scientists from China were investigating influence of SII on the prognosis in patients with small cell lung cancer (SCLC) treated with etoposide plus platinum-based drugs. Patients were divided into two groups: with low and high index level. It was determined that high level of the index before treatment correlated with advance disease. So, it was found that the overall survival in patients with a low index was over 17 months, while with a high - 12 months [12]. Hong and al also found that systemic immune- inflammation index (SII) > 1,600 x 109/L, predicted poor prognosis in SCLC patients, but not an independent predictor [2].

The study compared SII rates in patients with lung cancer (small cell and non-small cell) with a control group (who had no evidence of the disease). As a result of the study, it was determined that the indices of indicators were significantly higher in patients with non-small cell lung cancer than in patients with small cell lung cancer and the control group. It was also determined that NLR, PLR and SII were higher in SCLC than in control group. Elevated levels of SII (p = 0.018) were associated with primary relapse-free and overall survival for NSCLC, whereas any marker was not associated with relapse-free survival in small cell lung cancer [13].

Qi et al investigated the effect of inflammatory indices on overall survival in patients with extensive-stage small-cell lung cancer treated with first-line chemotherapy and atezolizumab. It was found that inflammatory indices can influence on overall survival, but SII index was not an independent predictor. However, the cut-off values of the SII were determined - 533.28 [14].

Islas-Vazquez et al investigated the effect of inflammatory markers on overall survival in patients with lung adenocarcinoma. As a result, it was determined that in patients with higher OS, lower rates of NLR and SII from the third cycle of chemotherapy were observed [15].

Fu et al. found that high rates of SII index was associated with worse recurrence-free survival (RFS) (P<0.001) and overall survival (OS) (P<0.001). And SII was an independent risk factor for worse RFS (P=0.038) and OS (P=0.043), but only in patients with adenocarcinoma (P<0.001), stage I disease (P<0.001), solid nodules (P=0.002) [16]. Shoji et al also found that in early stages NSCLC preoperative high SII levels were significantly correlated with postoperative recurrence (p = 0.0458), but SII was not detected as independent predictor as monocyte-lymphocyte ratio (MLR) [17].

Watanabe et al conducted a study in radically operated patients with non-small cell lung cancer. All patients underwent lung resection. Before the operation, peripheral blood tests were performed, and inflammation indices were calculated. After statistical processing, it was established that increase of SII index is associated with an earlier recurrence of the disease. Thus, in patients with a lower index, relapse occurred 12 - 16 months later than in patients with a high index [18]. Guo et al also investigated SII as a predictor prognosis in patients with surgically resected NSCLC. They found that SII was an independent prognostic factor for OS (HR 1.256, P = 0.034). Furthermore, the SII retained prognostic significance in adenocarcinoma subgroup. The prognostic value of the SII was higher than NLR and PLR [19].

Keit et al were investigating prognostic implication and influence on survival of SII in patients undergoing definitive chemoradiation therapy for stage III NSCLC. A low SII (<1.266) at the moment of primary diagnosis was independently associated with an improved OS (HR: 0.399, 95%, CI: 0.247-0.644, P<0.001), DSS (HR: 0.383, 95%, CI: 0.228-0.645, P<0.001), and PFS (HR: 0.616, 95%, CI: 0.407-0.932, P=0.022) [20]. Biswas et al also investigated prognostic value of SII in patient with stage III locally advanced non-squamous NSCLC if SII measured at the midtreatment window for RT (weeks 3-4). The investigation was based on randomized phase III trial PROCLAIM. There were 2 schemes of treatment: pemetrexed + cisplatin (PEM) vs. etoposide +cisplatin (ETO), in combination with radiotherapy. It was found that SII was significant mid-treatment predictor of both overall (adjusted HR = 1.6, p < 0.0001) and progression-free (aHR = 1.3,p = 0.0072) survival. Other parameters also should be considered in prognosis: age, body mass index, sex, race, and chemotherapy regimen [21].

Yucel et al were investing influence of SII on survival in patients with EGFR-positive advanced non-small cell lung cancer. It was found that progression-free survival was better in low SII (22.4 vs. 13.01 months, HR: 0.50; 95% CI 0.32-0.80; P: 0.003). The overall survival was also significantly longer in SII-low group (32.4 vs. 20.4 months; HR, 0.47; 95% CI 0.27-0.81; P: 0.005) [22].

Xu et al studied influence of SII on survival in patients with pathologically confirmed NSCLC and bone metastasis. SII were collected on baseline. It was found that optimal cut-off value for SII was 618.3 x 109/L. SII >618.3 x 109/L was more often observed in patients with a greater number of distant metastases. SII (HR = 1.456, 95% CI = 1.100-1.927, P = 0.009), as well as systemic chemotherapy (HR = 0.596, 95% CI = 0.437-0.813, P = 0.001) were described as independent prognostic factors. Also, it was found that SII was prognostic for patients aged <65 years (P = 0.002), woman (P = 0.021), nonsmokers (P = 0.010), histology of adenocarcinoma (P = 0.022), ECOG-PS <2 (P = 0.013), two or more distant or bone metastases (P = 0.004 vs P = 0.009 respectively) [23].

Li et al were determined predictive significance of systemic immune-inflammation index on overall survival and radiosensitivity in advanced non-small-cell lung cancer. The optimal cutoff value for SII was determined -555.59. Median OS (p < 0.001) in the low SII group was higher than the OS in the high SII group (32.8 months vs 8.5 months respectively). SII-low group had a better radiosensitivity. So SII was defined as independent prognostic factor for OS and predictive factor for radiosensitivity.

It was shown that high level of SII associated with poor OS and poor radiosensitivity [24].

Yan et al described influence of SSI on OS and benefit after adjuvant chemotherapy in patients with resectable NSCLC. It was found that preoperative SII level was associated with sex, smoking history, histologicy, type of the lesion, resection type, pathological stage, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), fibrinogen and bone metastasis (P<0.05). The univariate and multivariate analyzes revealed that SII was an independent prognostic factor for disease- free survival (P=0.033) and overall survival (P=0.020). Also was demonstrated that patients with a high SII may benefit from adjuvant therapy, while increased preoperative SII may independently predict the poor DFS and OS in patients with resectable NSCLC [25]. Wang et al also discovered that elevated pretreatment SII indicated significantly poorer OS (P<0.001), DFS/PFS (P=0.014) and CSS (P=0.007). Compared with the neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR), the SII showed a much higher prognostic value in NSCLC [26].

Li et al were detecting the prognostic values of systemic immune-inflammation index (SII) in patients with NSCLC and brain metastases who underwent radiotherapy. It was found that SII could be an independent predictor for patients with brain metastasis (hazard ratio: 1.486; p = 0.019). As well as brain radiotherapy modality, history of smoking, number of metastases in brain, intracranial symptoms and Radiation Therapy Oncology Group were independently related to survival (p < 0.05) [27]. Other group of scientists also found that in patients with NSCLC and brain metastases SII could be independent prognostic factor for OS (p=0.004). It was mentioned that in group of patients with high SII shorter overall survival was observed [28].

Conclusion

inflammation index cancer biomarker

1. Systemic inflammatory index is novel, cost - effective and affordable predictor of prognosis in cancer of different localizations: lung, colon, esophageal, cervical, pancreatic cancer.

2. Systemic inflammatory index is independent predictor of OS in patients with NSCLC of early stages, surgically resected, as well as in advance stages with numerous metastases in brain and bones

3. Systemic inflammatory index is not independent predictor of OS in patients with SCLC

4. In NSCLC poor prognosis is correlated with high SII

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