More than half of HCC patients in Indonesia are diagnosed at an advanced or late stage, as shown by studies by Loho et al. and Jasirwan et al. [1, 3]. Patient characteristics are highly dependent on local epidemiology, where the Asia Pacific region is generally dominated by the age of diagnosis under 60 years and the etiology of hepatitis B, while in the European and American populations it is dominated by more advanced age and the etiology of hepatitis C [11–13]. The majority of patients at this stage can only undergo supportive therapy, as a result of poor liver function reserve, number of multiple/diffuse nodules, large nodule size, portal vein thrombus, and metastases [11, 13].
The survival found in this study was shorter than the results in other studies. This is understandable because our patients were only given supportive therapy, so survival would be much different from studies involving subjects receiving palliative therapy, such as sorafenib [3, 14]. In other studies that have a similar setting to ours, the baseline characteristics of the subjects such as the etiology of HCC, liver function reserve, and tumor parameter profile will be differentiators of survival [11, 15].
NLR is the ratio of neutrophils and lymphocytes that play an important role in the inflammatory process and tumor carcinogenesis. High levels of neutrophils are known to promote tumor adhesion and metastasis through the secretion of various growth factors, especially vascular endothelial growth factor (VEGF) and various proteases, while lymphocytes are known to play an important role in defense against tumors where low lymphocytes reflect a low host immune response to malignancy [16].
Previous studies regarding NLR in advanced HCC, in both the treated and untreated groups, have been shown to predict post-treatment survival well for overall survival and progression-free survival. The cut-off point commonly used was 3.0-4.0. A recent meta-analysis by Liu et al. summarizes studies assessing NLR performance in patients treated with sorafenib [9]. Patients with lower NLR levels were shown to have a better response to sorafenib. This NLR-related result is also in agreement with the findings of the study by Aino et al. in advanced HCC patients with untreated extrahepatic metastases [17, 18].
SII is a combination parameter of neutrophils, lymphocytes, and platelets which is still relatively new to use. The rationalization for platelets to be included in the score index is the ability of platelets to protect circulating tumor cells, induction of epithelial-mesenchymal transition, and promotion of extravasation of tumor cells to metastasize. Initially, SII was popularized by Hu et al. for the evaluation of survival of HCC patients undergoing surgical therapy, where an SII cut-off point > 330 was found indicating poor survival prediction and a higher relapse rate [16].
Other studies related to the application of SII in advanced HCC are still limited. In the sorafenib-treated group, Gardini et al. and Conroy et al. showed that the predictive ability of overall survival, progression-free survival, and better sorafenib response if the value of SII was lower than the optimal cut-off [19, 20]. Zhao et al. looked at HCC patients who were only given supportive care, and the study found SII to be an independent prognostic factor for survival [21]. Until now, there has not been an optimal SII cut-off that can consistently predict survival. The study by Gardini et al. used an SII cut-off point of 360. The cut-off value in advanced HCC patients is predicted to be higher, as found by the study of Conroy et al., especially in our study population group where patients were not on therapy.
The prognostic significance based on AUROC is generally considered good if it has an AUROC of more than 0.7. With the findings of our study, it can be concluded that NLR does not have a good predictive ability of survival, and vice versa for SII. Studies comparing the performance of NLR and SII in advanced HCC are very limited. There have been no studies in untreated HCC patients, but there are several studies in sorafenib-treated patients. The study by Gardini et al. and Conroy et al., both showed the superiority of SII compared to NLR in predicting survival [19, 20].
The main difference between SII and RNL is the platelet parameters. The results in this study re-emphasized the importance of platelets to be included in the predictor index of advanced HCC survival. Platelet integration is considered to represent more fully the inflammatory environment and carcinogenesis that occurs in untreated advanced HCC. High platelet levels, according to Pavlovic et al., are associated with larger tumor size and poor survival in a wide variety of cancers [22]. HCC is a unique type of tumor because it can provide 2 types of images. The first feature is a pattern of thrombocytosis, in which large HCC together with residual liver cells can produce thrombopoietin, which mobilizes platelets from the bone marrow. The next feature is a pattern of thrombocytopenia, as a result of hypersplenism, impaired hepatic thrombopoietin production, and autoantibodies, generally associated with smaller HCC, lower albumin, and baseline fibrosis/cirrhosis [22].
Our study has several limitations. First, this study used a retrospective study design that relies on medical record data, so it may not fully correspond to the real condition of the patient if it was not properly or completely documented in the medical record. Second, researchers have tried to obtain survival data from medical records and contact the patient's family contact number recorded in the system, but there was still some survival data that must be assumed from the patient's last visit history. Third, the NLR and SII data analyzed in this study are only one-time data, and it is interesting to know the dynamics of the parameters that occur and their implications for potential predictors of survival.
In conclusion, the discriminatory ability based on AUROC of SII was better than that of NLR in predicting one-year survival in patients with advanced HCC who did not undergo therapy. Related to this, we recommend that in the future, further research be conducted regarding the prediction model for advanced HCC survival by including SII as a component, and research on the role of SII as a predictor of therapeutic response in HCC patients given systemic therapy can also be developed.