Value of Preoperative Systemic Immune-Inflammation Index and Albumin-Bilirubin Grade in Patients with Hepatocellular Carcinoma Undergoing Transarterial Embolization

Background : The systemic immune-inflammation index reflects the systematic inflammatory status, and the albumin-bilirubin grade reflects the liver function. In patients with hepatocellular carcinoma receiving transarterial chemoembolization, their combined clinical utility has not been fully explored. Herein, we purposed to determine the prognostic worthiness of systemic immune-inflammation index–albumin-bilirubin scores in patients receiving transarterial chemoembolization for unresectable hepatocellular carcinoma. Methods: Patients who were treated with transarterial chemoembolization after being diagnosed with hepatocellular carcinoma between 2008 and 2016 were recruited for this research work. Systemic immune-inflammation index and albumin-bilirubin scores were determined prior to treatment. The clinico-pathological factors related to overall survival were determined via univariate along with multivariate analyses. Results: A total of 295 patients were retrospectively studied. Patients with systemic immune-inflammation index–albumin-bilirubin score of 2 had the worst outcomes, exhibiting a median overall survival of 11 months (95% CI, 8.44-13.56 months) in contrast with subjects in the systemic immune-inflammation index–albumin-bilirubin 1 group (median OS, 26 months; 95% CI, 21.25-30.75 months) and the systemic immune-inflammation index–albumin-bilirubin 0 class (median OS, 31 months; 95% CI, 12.76-49.24 months). The 1-, 3-, and 5-year rates of survival were 45.3%, 1.3%, and 0% for patients in the systemic immune-inflammation index–albumin-bilirubin 2 category; 76.4%, 35.0%, and 14.6% for those in the systemic immune-inflammation index–albumin-bilirubin 1 category; and 85.6%, 46.7%, and 35.0% for those in the systemic immune-inflammation index–albumin-bilirubin 0 category, respectively (P < .001). Conclusions: The systemic immune-inflammation index–albumin-bilirubin score could be a simple indicator to estimate the prognosis in individuals with hepatocellular carcinoma being treated with transarterial chemoembolization. Patients in the systemic immune-inflammation index–albumin-bilirubin 2 category were more likely to be related to a shorter overall survival.


INTRODUCTION
Hepatocellular carcinoma (HCC) is the sixth most frequent cancer globally and the fourth primary cause of cancer-linked deaths. 1 In most cases, HCC can be prevented by resection because of the tumor location and size or liver dysfunction. Transarterial chemoembolization (TACE) has been suggested as the first line of therapy for Barcelona Clinic Liver Cancer (BCLC) B stage HCC, some BCLC A stage HCC cases, and may also benefit BCLC-C stage HCC individuals with moderate liver function. 2 However, patients treated with TACE have diverse clinical outcomes owing to remarkably heterogeneous characteristics of tumor burden coupled with liver functional reserve. Thus, a potential prognostic indicator is needed to identify patients with potentially poor prognosis after TACE. Several investigations described 2 markers of HCC prognosis, the systemic immune-inflammation index (SII) along with the albumin-bilirubin (ALBI) grade.
Systemic immune-inflammation index may indicate how well the host immunological and inflammatory responses are balanced. 1 The SII is computed as follows: SII = peripheral platelet counts × peripheral neutrophil counts/ peripheral lymphocyte counts. 1 An elevated SII is closely related to the prognosis of many solid tumors, such as HCC. 1,2 Some investigations have documented a relationship of elevated SII with dismal prognosis in individuals with HCC being treated with TACE. 3,4 The Child-Turcotte-Pugh (CTP) score, which was developed in 1964 and later updated to evaluate prognosis following surgery for variceal bleeding in individuals with cirrhosis, is the most extensively used model to estimate liver functional state. 5,6 Many HCC staging systems, including the BCLC staging approach, use CTP categorization for assessment of the severity of the liver disease. 7 However, the CTP score harbors some limitations consisting of subjective factors (encephalopathy along with ascites) and interrelated factors (serum albumin and ascites) and has not been statistically proven. 8 Recently, ALBI grade was proposed as an optional measurement model of liver function based only on albumin along with bilirubin. 9 ALBI = (albumin × −0.085) + (log 10 bilirubin × 0.66), in which the units of bilirubin are micromole per liter and that of albumin is gram per liter. 9 There are 3 grades in ALBI: ALBI > −1.39 is grade 3, ALBI >−2.60 to ≤−1.39 is grade 2, and ALBI ≤−2.60 is grade 1. 9 Albumin-bilirubin grade has been verified in several investigations with diverse stages of the disease and numerous medications, including TACE, and has proved to be a valuable tool for objectively assessing liver function along with treatment outcome in individuals with HCC. [10][11][12][13] To date, no research work has attempted to assess the predictive worthiness of combining inflammatory along with liver function markers in individuals with HCC receiving TACE. Thus, the purpose of this research work was to determine if combining SII with ALBI grade improves prognostic accuracy.

MATERIALS AND METHODS
This research work was granted approval by the Ethics Committee of the Third Central Clinical College of Tianjin Medical University. In this premise, all procedures involving human participants were as per the Declaration of Helsinki, 1964. All subjects granted written informed consent prior to TACE.

Study Design and Patient Selection
A review of the electronic medical records of subjects with newly diagnosed HCC who had been treated with TACE between March 2008 and December 2016 at our hospital was done. Diagnosis of HCC was done via contrastenhanced dynamic computed tomography or magnetic resonance imaging exhibiting early hyper-enhancement in arterial phase, as well as delayed washout in the venous phase. 14-16 All individuals with HCC enrolled in this research work were classified as BCLC stage A, B, and C. Comprehensive demographic information consisting of HCC etiology, the burden of tumor, status of liver function, and laboratory data along with performance status was gathered. Subject enrollment criteria consisted of (1) monotherapy with TACE as the initial treatment; (2) Eastern Cooperative Oncology Group performance status 0-1; and (3) CTP A or B liver function. Subject exclusion criteria consisted of the following: (1) had diffused HCC; (2) had incomplete baseline data; (3) survival was <3 months; (4) underwent hepatectomy or liver transplantation; (5) underwent other local treatments; (6) underwent systemic therapy; (7) severe underlying cardiac and renal diseases; (8) known active or chronic infection at blood sampling time; and (9) had other types of cancer. Hepatocellular carcinoma linked to hepatitis B virus (HBV) was characterized by individuals who tested positive for the HBV surface antigen (HBsAg). Individuals who tested positive for anti-hepatitis C virus (HCV) antibodies were regarded to have HCC caused by HCV. Alcoholism was described as daily alcohol consumption of at least 40 g for men and 20 g for women, over a period of more than 5 years. All the patients with HBsAg or HCV-RNA positive received antiviral treatment. All the patients were informed about systematic treatments if they were eligible for treatment. Patients who accepted systemic therapy were excluded from this study. Patient baseline data were recorded 1-7 days before TACE. At our center, portal vein thrombosis and major vascular invasion in subjects with good hepatic function are not regarded as absolute contraindications to TACE. Patient clinical data were reviewed and analyzed according to confidentiality requirements.

Defining the Combined Inflammation and Liver Function Grade
The optimal cut-off value of SII was determined via receiver operating characteristic (ROC) curve assessments, on the basis of ROC curve most prominent point for "sensitivity" along with "1−specificity," respectively. Next, using the Youden index (maximum [sensitivity + specificity − 1]), the appropriate cut-off value was computed. 17 Thereafter, a new grading system for inflammation and liver function, the SII-ALBI score, was developed by combining the SII with the ALBI grades. The SII-ALBI score was calculated as follows: patients in whom SII was elevated on the basis of the ROC curve assessment and ALBI was grade 2 or 3 were designated a score of 2; subjects exhibiting an elevation in one or neither of these parameters were designated a score of 1 or 0, respectively (Table 1).

TACE Procedure and Follow-up
Two senior interventional radiologists with comparable expertise in the management of HCC executed uniform TACE. Under local anesthesia, the Seldinger approach was adopted in accessing the right femoral artery. With a selective or supra-selective injection, a mixture of fluorodeoxyuridin, cisplatin and/or pirarubicin in ≤20 mL lipiodol was injected, followed by embolization with polyvinyl alcohol particles or gelatin sponge. The chemotherapeutic agent dose was computed on the basis of the body surface area. If new nodules, enlarged lesions, or elevated low lipiodol uptake were observed, TACE was repeated after an interval of 1.5-3.0 months. Treatment was terminated if a subject could not tolerate the therapy owing to a decline in clinical status or if a complete response was achieved. A follow-up of all patients post-TACE was performed until death or the cut-off date (July 31, 2021).

Associations between SII-ALBI Grade and Clinicopathological Features of Individuals with HCC
Among the 295 subjects, 15 (5.1%) harbored an SII-ALBI score of 0, while 143 (48.5%) and 137 (46.4%) harbored an SII-ALBI score of 1 and 2, respectively. The SII-ALBI 2 class had a remarkably higher alpha-fetoprotein (AFP) level, a bigger largest size of the tumor, and a higher BCLC C stage versus the other groups (P < .05). summarizes the clinico-pathological characteristics along with demographic features of subjects on the basis of the SII-ALBI score.

DISCUSSION
Transarterial chemoembolization constitutes the standard treatment for BCLC-B stage HCC patients and some patients in BCLC-A stage with contraindications to resection and thermal ablation. 18 However, given its impacts on enhancing survival and decreasing financial burden, numerous BCLC-C stage HCC subjects with compensatory hepatic function also undergo TACE. The prognosis of patients after TACE varies widely given the high heterogeneity among patients. Hence, we believe that simple and useful markers to precisely estimate the prognosis of patients being treated with TACE are needed. Herein, we found that combining inflammation and liver function-based SII-ALBI is an independent prognostic indicator for estimating the survival of patients undergoing TACE monotherapy as the initial treatment. Moreover, SII-ALBI 2 category was established to be related to a relatively dismal prognosis following TACE.
This study has demonstrated that a high SII (>152.80) independently predicted shorter survival in patients undergoing TACE. Congruent with our data, SII values were also documented to be a predictive risk factor for patients with HCC following treatments other than TACE, for instance, hepatectomy, sorafenib therapy, or liver transplantation. 1,19,20 systemic immune-inflammation index constitutes a systemic inflammatory index that employs neutrophil, lymphocyte, along with platelet counts to precisely indicate the degree of systemic inflammation. Besides, inflammation is a remarkable factor in the tumor microenvironment. Neutrophilia could repress immune cells, for instance, lymphocytes, activated T cells, as well as natural killer cells, so impairing the immune system. 21,22 Lymphocytes are pivotal elements of the adaptive immune system because they are responsible for immunosurveillance along with immunoediting functions. Lymphocyte invasion was demonstrated to be a sign of an efficient anti-tumor cellular immune response. 23 The entrance of cancer cells into the circulation initiates platelet recognition, which is increased by cell surface receptors, immune cells, cellular products, and extracellular factors. In other cases, these cross-talks dampen the immune system recognition and removal of cancer   cells or increase endothelial arrest, as well as trapping in the microvasculature and survival. 24 The ALBI grade is a new assessment approach for hepatic function, which is considered to be better relative to the CTP score for assessing hepatic function along with treatment outcomes in individuals with HCC via numerous studies. [10][11][12][13] The CTP score was inferior with regards to stability, because it included subjective factors (encephalopathy and ascites) and had inter-related factors (serum albumin and ascites), and it was not statistically proven. 8 In contrast, ALBI grade is a more objective and simple method to assess liver function, which may be better to evaluate individuals with HCC. 25 Hepatocellular carcinoma subjects with relatively poorly preserved hepatic function are associated with more treatment-related toxicity, shorter survival, slower recovery, and increased complications. 26 We hypothesized that combining SII with ALBI would enhance the accuracy of predictive evaluation for patients with HCC who underwent TACE, because the combination could assess both the inflammation status and the hepatic function of these patients.
Herein, 295 subjects with newly diagnosed HCC were included. The TACE monotherapy was performed as the initial treatment for all the patients. All the patients with HBsAg or HCV-RNA positivity received antiviral treatment, because studies suggest that antivirals are beneficial to the management of hepatitis-B-related HCC and sustained virological response after oral direct-acting antivirals therapy may result in improved liver dysfunction and facilitate additional HCC-directed therapy. 27,28 The multivariate along with univariate analyses results exhibited that baseline SII and ALBI were independent influencing factors for the OS of patients with HCC who underwent TACE.
For the baseline data, SII-ALBI score had a better discriminative potential when compared with either SII or ALBI alone. Systemic immune-inflammation index -albu min-b iliru bin 2 category was associated with relatively higher AFP levels, bigger largest tumor size, more BCLC C stage, and worse OS. The results of this study can help to establish patients who had a potentially poor prognosis after TACE in order to modify the treatment plan and give timely systematic treatment.
To the best of our knowledge, this is the first research work to evaluate the prognostic value of SII-ALBI combination in patients with HCC who underwent TACE. However, this research premise had some limitations. This was a retrospective study from a single center, which may lead to potential bias because of the limited sample size. So, a multi-center and prospective cohort study with a large sample size is necessary to verify the prognostic value of SII-ALBI score in HCC after TACE and the potential underlying mechanism.

CONCLUSION
This study exhibited that for individuals with HCC who underwent TACE, the SII-ALBI score at baseline could be a simple indicator to estimate the prognosis. Subjects with HCC in the SII-ALBI 2 category were more likely to have a shorter OS. Hence, SII-ALBI score should be considered when formulating or adjusting the treatment plan in individuals with HCC being treated with TACE.