**3.5. Neutrophil-to-lymphocyte ratio in HCC patients undergoing tumour ablation**

survival rate in high *versus* low NLR group was 81.3, 56.7 and 51.0 *versus* 90.9, 74.2 and 66.8% (p = 0.041). Similarly, the 1-, 3- and 5-year recurrence-free survival rate in high *versus* low NLR group was 65.3, 48.5 and 39.4 *versus* 80.0, 68.0 and 65.2%. The difference was also significant as reflected by p = 0.013 [41]. Further, NLR was an independent prognostic factor for overall and recurrence-free survival after liver transplantation for HCC as was shown by multivariate analysis of 160 Western patients [42]. NLR was proved to be an independent risk factor for overall survival (p < 0.001) and recurrence-free survival (p = 0.003) in 248 male patients treated by liver transplantation [43]. Harimoto et al. reported on 213 patients receiving living donor liver transplantation for HCC. High preoperative NLR ≥ 2.66 was an independent predictor

NLR can be used in prognostic models to identify patients who exceed Milan criteria but still have good overall and tumour-free survival. In study reported by Wang et al., male patients were enrolled and thus the proposed models were verified in males only [43]. Combination of NLR and Hangzhou criteria has been suggested to identify patients who can be successfully treated by liver transplantation [45]. NLR has been included in the MORAL scores to predict recurrence after liver transplantation, and these scores were superior to Milan criteria [46]. Complex evaluation of NLR along with fibrinogen increases the prognostic accuracy in order to predict disease-free survival and overall survival in HCC patients treated by liver transplantation [41]. Pretransplantation NLR along with levels of C-reactive protein has been combined with Milan criteria to develop new selection criteria for living donor liver trans-

However, contrasting findings have been published as well. Thus, NLR did not predict posttransplantation recurrence or worse overall survival in 150 patients within Milan criteria [48]. Limited prognostic impact of NLR was found in 124 patients who underwent living donor liver transplantation [49]. In Western patients, NLR was not predictive of treatment success regarding liver transplantation or other tested approaches (hepatectomy, transarterial chemoembolisation). Although the group was quite small (75), Child-Pugh and Model for End Stage

In patients with unresectable HCC, treated by multikinase inhibitor sorafenib, high NLR (>3.1) was a significant independent prognostic factor, associated with worse overall survival. Better treatment response was observed in patients with low NLR [51]. The findings were confirmed by another study, reporting on 442 sorafenib-treated patients (Japan, Italy and United Kingdom) with advanced HCC. High NLR again was an independent prognostic fac-

Regarding combined approach, high pre-treatment NLR (>3.0) was an independent predictor of worse overall survival in 40 patients with unresectable HCC treated by transcatheter arterial embolisation and sorafenib. The median survival in high *versus* low NLR group was 14 months (95% CI = 10.1–17.9) *versus* 26 months (95% CI = 17.4–34.6). The difference was significant (p = 0.001) and biologically remarkable [53]. Other researchers have also confirmed that NLR was independent predictor of overall survival in patients with advanced HCC

tor, predicting shorter survival with HR 1.218; 95% CI: 1.108–1.322; p < 0.0001 [52].

of recurrence [44].

plantation beyond Milan criteria [47].

54 Hepatocellular Carcinoma - Advances in Diagnosis and Treatment

treated by sorafenib [54].

Liver Disease (MELD) scores were informative [50].

**3.4. Neutrophil-to-lymphocyte ratio in sorafenib-treated HCC patients**

NLR has been investigated in regard to different embolisation and ablation techniques. High NLR (>3) predicted significantly worse treatment results (p = 0.014) and early disease progression (p < 0.0001) in 86 treatment-naive patients subjected to arterial chemoembolisation or radioembolisation [55]. Elevated pre-treatment NLR (>1.85) was associated with overall survival and disease-free survival in 178 HCC patients subjected to transcatheter arterial chemoembolisation (TACE). The median survival in high *versus* low NLR group was 8 *versus* 17.5 months. The 1-, 3- and 5-year overall survival rates in these groups were 42.1, 19.6 and 9.5 *versus* 57.3, 44.1 and 27.2%, respectively (p < 0.001). Differences in disease-free survival were significant as well (p < 0.001). Multivariate analysis confirmed NLR as a significant (p = 0.04), independent prognostic factor for survival after TACE [56].

In patients with advanced HCC treated by hepatic arterial infusion chemotherapy, high NLR was a significant predictor of lower response rate, worse progression-free and overall survival [57]. Baseline NLR was a significant predictor of treatment response and progression-free survival after hepatic arterial infusion chemotherapy for advanced HCC [58]. In patients receiving hepatic arterial infusion chemotherapy by cisplatin and fluorouracil, response rate and overall survival were associated with NLR [59].

Dynamic changes of NLR had independent prognostic significance (p = 0.035) in HCC with portal vein tumour thrombosis treated by microwave ablation after transarterial chemoembolisation [60]. In 506 patients treated by thermal ablation of recurrent HCC, high pretreatment NLR (≥2.14) was a prognostic factor for recurrence-free survival, confirmed by Cox multiple regression analysis. The 1- and 3-year recurrence rates in high *versus* low NLR groups were 57.9 and 82.5 *versus* 20.7 and 31.6%. The difference was statistically significant, confirmed by p < 0.001 [61].

Pre-treatment NLR was associated with worse overall survival in early HCC after radiofrequency ablation. Post-treatment NLR was associated both with worse overall survival and recurrence in early HCC after radiofrequency ablation [62]. Similarly, NLR dynamics, but not pre-treatment NLR, was an independent prognostic factor for overall survival and recurrencefree survival in patients with small HCC treated by radiofrequency ablation [63]. In patients treated by radiofrequency ablation for HCC, post-treatment NLR was associated with recurrence and survival. Pre-treatment NLR was associated with recurrence only in patients who had HBV infection and HCC but not in those who developed HCC in association with HCV infection [64]. In unresectable HCC treated by radioembolisation, elevated NLR was an independent predictor of worse survival [65].

#### **3.6. Neutrophil-to-lymphocyte ratio and tumour characteristics**

NLR has been mostly assessed in correlation with survival or treatment response. However, some observations are reported on the association between systemic inflammatory response and tumour morphology in gross and microscopic level. Thus, high NLR is observed in patients having larger tumours, multiple HCC foci, higher grade of HCC and vascular invasion [29]. In few studies, the infiltration of neutrophils and macrophages in liver tumours has been assessed. Peritumoural tissues are characterised by higher ratio between neutrophils and T lymphocytes, and higher ratio also correlates with lower overall survival. The combination of these findings suggests that neutrophils might facilitate tumour progression. They suppress adaptive immunity by death ligand expression [66]. Correlation between NLR and PD-L1 expression in the centre of tumour but not peritumoural tissues has been described [67]. High NLR was associated with CD163-positive tumour-associated macrophages [24]. High NLR was associated with higher peritumoural but not intratumoural CD163 and IL-17 expressing cells [68].

Several meta-analyses have recently been carried out to evaluate PLR in hepatocellular carcinoma. Significant association between higher PLR and increased risk of death was reported by Hu and Yu, reporting odds ratio for death 1.59; 95% CI: 1.15–2.20 on the basis of metaanalysis of six studies with 1446 HCC patients [76]. The association between high PLR and worse overall survival was confirmed by Ma et al., Song et al., and Zhao et al. [77–79]. In a meta-analysis of nine studies including 2017 patients, high PLR was associated with poor overall survival (HR 1.63; 95% CI: 1.42–1.88; p < 0.001) as reported by Ma et al. [77]. Evaluating 2507 patients in 11 studies, high PLR was significantly associated with worse overall survival, as reflected by hazard ratio HR = 1.78; 95% CI: 1.36–2.34; p < 0.001 [78]. In a meta-analysis of 10 studies including 2315 patients, high PLR was associated with the HR for worse overall

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http://dx.doi.org/10.5772/intechopen.76599

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Controversial findings are reported regarding PLR and recurrence-free survival. The association has been confirmed by some research groups [77, 78] but denied by others. In a meta-analysis of nine studies including 2017 patients, high PLR was significantly (p < 0.001) associated with poor recurrence-free survival: HR = 1.32; 95% CI: 1.15–1.52. In a meta-analysis of 11 studies comprising 2507 patients, elevated PLR was significantly associated with worse recurrence-free survival, as reflected by hazard ratio HR = 1.82; 95% CI: 1.56–2.13; p < 0.001. In contrast, by metaanalysis of 2315 patients in 10 studies, high PLR was not significantly associated with worse

High PLR also showed correlation with high tumour size exceeding 3 cm, TNM stage, lymph node metastases and distant metastases [78]. The findings regarding vascular invasion are controversial again, as the association is confirmed in some studies [78] but not others [77]. No association between PLR and tumour multifocality and higher grade has been confirmed [77].

The prognosis and treatment options of HCC patients depend not only on tumour progression but also on the extent of liver dysfunction. As a consequence, several staging systems have been proposed to predict prognosis for HCC, including Glasgow prognostic score (GPS), based on the levels of C-reactive protein and albumin (**Table 1**). GPS in HCC patients with hepatocellular carcinoma is an independent prognostic predictor after hepatic resection, with higher score indicating worse prognosis [80]. Thus, among 144 patients who underwent surgical resection for HCC, GPS 2 was associated with worse disease-free (HR = 2.527; 95% CI: 1.163–5.490; p = 0.019) and overall (HR = 8.012; 95% CI: 2.818–22.784; p < 0.001) survival, but GPS 1 with shorter overall (HR = 2.277; 95% CI: 1.029–5.039; p = 0.042) survival than seen in patients preoperatively presenting with GPS 0 [80]. The independent prognostic role of GPS for overall survival was confirmed by other research teams [81] and meta-analysis [82]. Modified GPS score and dynamics of GPS score have also shown prognostic value. Thus, elevated modified GPS was associated with overall survival (HR = 2.21; 95% CI: 1.73–2.82; p < 0.05) in a meta-analysis of 2047 HCC patients [83]. Dynamics of GPS (assessed in association with hepatitis B infection status) was an independent predictor of overall survival in 247 patients treated by liver resection [84]. In addition, GPS was related to blood transfusion requirement and postoperative pulmonary complications after liver resection for HCC [85]. In patients undergoing liver transplantation for HCC, elevated GPS, reaching 1 or 2, was

recurrence-free survival as the HR was 1.21; 95% CI: 0.87–1.67; p = 0.26 [79].

**3.8. Glasgow prognostic score in hepatocellular carcinoma**

survival of 1.60; 95% CI: 1.23–2.08; p = 0.0005 [79].

### **3.7. Platelet-to-lymphocyte ratio in HCC patients**

Platelet-to-lymphocyte ratio (PLR) is another frequently assessed estimate of SIR, although fewer publications have been devoted to PLR than to NLR. Nevertheless, prognostic role of PLR has been evaluated in different aspects of HCC patient treatment, including surgery [31, 69, 70], transplantation, sorafenib treatment, TACE and ablation techniques.

In the largest Western series enrolling 370 HCC patients, treated by surgical resection, higher preoperative PLR was identified as an independent risk factor of worse overall survival and recurrence-free survival [31]. Other research groups have confirmed the association between PLR and prognosis. Higher preoperative PLR is an independent predictor of worse overall survival in HCC patients undergoing curative liver resection [69, 70] as was shown in two large Eastern cohorts comprising 778 [70] and 1804 [69] patients, respectively. The significant association with overall survival (p < 0.001) was retained in specific subgroups, e.g., patients having cirrhosis or being positive for HbsAg [70]. In some studies, the associations between PLR and prognosis were statistically significant but not independent. Thus, PLR was significantly associated with disease-free and overall survival in 332 HCC patients after hepatectomy [71]. The association between higher PLR and shorter recurrence-free survival in HCC patients undergoing curative liver resection was statistically significant but not independent [70]. Finally, no association has been found in some studies. Hence, in 113 HCC patients undergoing curative resection, PLR was not confirmed as a significant prognostic factor for recurrence-free survival. NLR was found to be superior in this study [28].

PLR has been analysed in the context of liver transplantation. Already in early studies, statistically significant association was found between pretransplantation PLR and cancer recurrence after liver transplantation. In 146 patients, the recurrence-free survival was 80.7 *versus* 91.6%; the difference was statistically significant as confirmed by p = 0.02 [72].

In 122 Chinese patients undergoing transarterial chemoembolisation (TACE) for HBV-related HCC, high pre-treatment PLR (≥96.13) was an independent, statistically significant (p = 0.001) factor that predicted worse survival [73].

In 414 patients affected by recurrent HCC and treated by thermal ablation, high pre-treatment PLR (≥87.87) was associated with higher risk of recurrence and worse recurrence-free survival. The 1- and 3-year recurrence rates in high *versus* low PLR groups were 56.0 and 79.5 *versus* 39.9 and 54.8%; p < 0.05 [74].

Regarding sorafenib-treated cases, PLR has not shown prognostic value in patients receiving sorafenib for advanced HCC. Although the negative result could be attributed to the small group size (16 patients), significant association with NLR was still confirmed [75].

Several meta-analyses have recently been carried out to evaluate PLR in hepatocellular carcinoma. Significant association between higher PLR and increased risk of death was reported by Hu and Yu, reporting odds ratio for death 1.59; 95% CI: 1.15–2.20 on the basis of metaanalysis of six studies with 1446 HCC patients [76]. The association between high PLR and worse overall survival was confirmed by Ma et al., Song et al., and Zhao et al. [77–79]. In a meta-analysis of nine studies including 2017 patients, high PLR was associated with poor overall survival (HR 1.63; 95% CI: 1.42–1.88; p < 0.001) as reported by Ma et al. [77]. Evaluating 2507 patients in 11 studies, high PLR was significantly associated with worse overall survival, as reflected by hazard ratio HR = 1.78; 95% CI: 1.36–2.34; p < 0.001 [78]. In a meta-analysis of 10 studies including 2315 patients, high PLR was associated with the HR for worse overall survival of 1.60; 95% CI: 1.23–2.08; p = 0.0005 [79].

Controversial findings are reported regarding PLR and recurrence-free survival. The association has been confirmed by some research groups [77, 78] but denied by others. In a meta-analysis of nine studies including 2017 patients, high PLR was significantly (p < 0.001) associated with poor recurrence-free survival: HR = 1.32; 95% CI: 1.15–1.52. In a meta-analysis of 11 studies comprising 2507 patients, elevated PLR was significantly associated with worse recurrence-free survival, as reflected by hazard ratio HR = 1.82; 95% CI: 1.56–2.13; p < 0.001. In contrast, by metaanalysis of 2315 patients in 10 studies, high PLR was not significantly associated with worse recurrence-free survival as the HR was 1.21; 95% CI: 0.87–1.67; p = 0.26 [79].

High PLR also showed correlation with high tumour size exceeding 3 cm, TNM stage, lymph node metastases and distant metastases [78]. The findings regarding vascular invasion are controversial again, as the association is confirmed in some studies [78] but not others [77]. No association between PLR and tumour multifocality and higher grade has been confirmed [77].
