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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 3  |  Page : 740-748

Intermediate stage hepatocellular carcinoma: Comparison of the value of inflammation-based scores in predicting progression-free survival of patients receiving transarterial chemoembolization


1 Department of Medicine Medical Oncologist Chemotherapy and Minimally Invasive Treatment of Malignant Tumors, Jinshazhou Hospital of Guangzhou University of Chinese Medicine International Tumor Medicine Center, Guangzhou, People's Republic of China
2 Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center; Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China
3 Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China
4 Department of Nursing, Medical College of Shaoguan University, Guangzhou, People's Republic of China
5 Department of Medicine MedicalOncologist Chemotherapy and Minimally Invasive Treatment of Malignant Tumors, Jinshazhou Hospital of Guangzhou University of Chinese Medicine International Tumor Medicine Center, Guangzhou, People's Republic of China

Date of Submission06-Jan-2021
Date of Decision20-Jan-2021
Date of Acceptance23-Mar-2021
Date of Web Publication9-Jul-2021

Correspondence Address:
Weijun Fan
Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510 060; State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510 060
People's Republic of China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_29_21

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 > Abstract 


Context and Aims: The identification of inflammation-related prognostic heterogeneity in intermediate-stage hepatocellular carcinoma (HCC) can reveal more effective first-line treatments. Our study aimed to compare the intermediate-stage HCC patients' different inflammation-based scores in predicting their progression-free survival (PFS) after transarterial chemoembolization (TACE).
Materials and Methods: We analyzed retrospectively a total of 128 intermediate-stage HCC patients who received first-line TACE treatment. We used the Cox-proportional hazards modeling to identify the independent prognostic factors. We compared the inflammation-based scores abilities to predict the PFS through the time-dependent receiver operating characteristic curves and area under the curves.
Results: The multivariate analysis showed that tumor size and platelet-to-lymphocyte ratio (PLR) were the independent prognostic factors for PFS (P < 0.05). The PLR predicted the intermediate-stage HCC patients' PFS receiving the TACE treatment better than other inflammation-based scores (e.g., the neutrophil-to-lymphocyte ratio, the Glasgow Prognostic Score (GPS), the modified GPS, the Prognostic Index, the Prognostic Nutritional Index, the lymphocyte-to-monocyte ratio, and the systemic immune-inflammation index) (P < 0.05). An easy-to-use novel inflammation score based on tumor size – PLR-size score significantly improved the PFS prediction performance (P < 0.05).
Conclusions: As a first-line treatment, TACE was not well suitable for all intermediate-stage HCC patients, while the PLR was a better inflammation-based score than others. Tumor size should be regarded as an essential variable in affecting intermediate-stage HCC patients' first-line treatment strategies.

Keywords: Hepatocellular carcinoma, inflammation-based score, progression-free survival, transarterial chemoembolization


How to cite this article:
Liu Y, Shi M, Chen S, Wan W, Shen L, Shen B, Qi H, Cao F, Wu Y, Huang T, Chen G, Mo J, Ye D, Zhang Y, Feng Z, Fan W. Intermediate stage hepatocellular carcinoma: Comparison of the value of inflammation-based scores in predicting progression-free survival of patients receiving transarterial chemoembolization. J Can Res Ther 2021;17:740-8

How to cite this URL:
Liu Y, Shi M, Chen S, Wan W, Shen L, Shen B, Qi H, Cao F, Wu Y, Huang T, Chen G, Mo J, Ye D, Zhang Y, Feng Z, Fan W. Intermediate stage hepatocellular carcinoma: Comparison of the value of inflammation-based scores in predicting progression-free survival of patients receiving transarterial chemoembolization. J Can Res Ther [serial online] 2021 [cited 2021 Jul 29];17:740-8. Available from: https://www.cancerjournal.net/text.asp?2021/17/3/740/321030




 > Introduction Top


The transarterial chemoembolization (TACE hereon) is a standard therapy recommended for intermediate-stage (Barcelona clinic liver cancer [BCLC] Stage B) hepatocellular carcinoma (HCC) patients.[1],[2] However, whether TACE is suitable for all intermediate-stage HCC patients, it still deserves further studies. The guideline suggests that the available BCLC staging system is generally limited to predict the HCC patients receiving TACE's objective response rate.[2] Therefore, it is crucial to identify prognostic heterogeneity associated with TACE-alone in intermediate-stage HCC patients.

Inflammation-based scores are based on blood indicators related to prognosis before treatment. Several studies have recently shown the inflammation-based scores' essential importance in predicting the HCC patients receiving TACE's survival. Some of these metrics are the neutrophil to lymphocyte ratio (NLR),[3] the platelet to lymphocyte ratio (PLR),[4] the Glasgow Prognostic Score (GPS), the Prognostic Index (PI),[5] and the lymphocyte to monocyte ratio (LMR).[6] Besides, the modified GPS (mGPS), the Prognostic Nutritional Index (PNI), and the systemic immune-inflammation index (SII) are regarded survival predictors in HCC patients receiving other treatment.[7],[8],[9],[10] However, the inflammation score value to predict progression-free survival (PFS) after TACE and which inflammation-based score is more suitable for PFS prediction in intermediate-stage HCC patients receiving TACE is unclear. Therefore, this retrospective study aimed to compare the different inflammation scores' value to predict intermediate-stage HCC patients' PFS after the TACE treatment.


 > Materials and Methods Top


Patients and follow-up

We retrospectively analyzed 128 intermediate-stage HCC patients who received TACE-alone as an initial treatment at Sun Yat-sen University Cancer Center (SYSUCC) between January 2014 and June 2019. These HCC patients meet the following criteria: (1) Patients with HCC pathological or imaging examination confirmation; (2) patients undergoing TACE-alone as first-line treatment at the diagnosis of intermediate-stage HCC; (3) patients with useful liver function (albumin-bilirubin [ALBI] Grade 1–2); (4) patients without macroscopic extra-hepatic metastasis and intrahepatic vascular invasion evidence; (5) patients without other treatments for HCC before progression; (6) patients without severe coagulation function disorders; (7) patients with complete preoperative critical baseline data. Patients who underwent either a contrast material-enhanced computed tomography or a magnetic resonance imaging re-examination approximately 1–3 months after TACE treatment. Tumor response assessment was based on the modified response evaluation criteria in solid tumors 1.1 (mRECIST 1.1) by at least two diagnostic radiologists. We defined the PFS as the interval time from the initial TACE to the disease's progression or death. SYSUCC ethics committee approved our study and conducted it following the Declaration of Helsinki. The informed consent was waived because of its retrospective nature.

The transarterial chemoembolization protocols

The hepatic arteriography identifies and super selects the arteries supplying tumor nutrition using the Seldinger technology. Then, the microcatheter is selectively and super selectively inserted into these arteries. Later, the embolic material (e.g., lipiodol, blank microspheres) and the chemotherapeutics (e.g., lobaplatin or pirarubicin) can be targeted through the microcatheter. The applied dose depends on the tumor's complete embolization. The completed TACE's endpoint is based on the blood flow stagnation within the arteries supplying tumor nutrition and tumor staining absence during angiography.

Statistical analysis

We represented continuous variables conforming to a normal distribution by mean ± standard deviation (hereon). Otherwise, we described them by median and quartile. We either used the Mann–Whitney U test or t-test to compare the continuous variables. We used the Chi-square or the Fisher's exact test to compare the binary variables. We summarized the calculation and definition for inflammation-based scores (e.g., mGPS, GPS, PLR, NLR, PNI, PI, LRM, SII, and PLR-size score [PSS]) in [Table 1]. We calculated the ideal cutoff values of the tumor size, NLR, PLR, LRM, SII before TACE based on the status and the time of PFS by the “survivalROC” R package.[11] We used the Cox-proportional hazards regression analysis to identify the PFS' independent prognostic factors. We compared the different variables' abilities to predict the PFS through the time-dependent receiver operating characteristic (ROC) curves and the estimated area under the curves (AUC).[12] We calculated the PFS between the different groups using the Kaplan–Meier and compared it with the log-rank test. We conducted our two-sided statistical analyses using the SPSS software version 25.0 (IBM Corporation, New York, United States) and R version 3.6.1(https://www.r-project.org/), and P < 0.05 suggested statistical significance.
Table 1: Systemic inflammation-based biomarkers

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 > Results Top


Study population

We included a total of 128 intermediate-stage HCC patients undergoing TACE treatment in our study. Among the experimental individuals, 16 were female (12.5%) and 112 were male (87.5%), with an average age of 56.96. Regarding their liver function, 69 (53.9%) of the patients had ALBI grade 1, and 59 (46.1%) of them had ALBI grade 2. However, no patient had ALBI grade 3. The total number of HBV-infected patients was 110, which accounted for a larger proportion of these patients (85.9%). The median diameter of the tumor was 6.20 cm. We summarized other clinical characteristics in [Table 2].
Table 2: Baseline characteristics of the 128 patients

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Calculation of ideal cutoff value of variables

The variable's ideal cutoff value is calculated by the survival ROC that can fit the Cox-proportional hazards model to survival status and survival time. The ideal cutoff value of tumor size, NLR level, PLR level, LRM level, and SII level were 6.6, 1.57, 92, 4.4, and 480.3, respectively.

Prognostic factors for progression-free survival

Our univariate results showed that age, tumor size, lymphocyte counts, NLR, PLR, GPS, LMR, and SII scores were statistically associated with PFS [P < 0.05; [Table 3] and [Figure 1]. However, the results we obtained with our multivariate analysis, where we used the patient's age, tumor size, lymphocyte counts, platelet counts, NLR, PLR, GPS, mGPS, LMR and SII scores, suggested that tumor's size and PLR were PFS's independent prognostic factors for HCC [Table 3].
Table 3: Univariate and multivariate prognostic factors for progression-free survival based on time-dependent Cox regression

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Figure 1: Kaplan–Meier curves of PFS in different inflammatory biomarkers among 128 patients with intermediate-stage HCC received TACE. a. PFS by GPS; b.PFS by mGPS; c. PFS by PI; d. PFS by PNI; e. PFS by NLR; f. PFS by PLR; g. PFS by LMR; h. PFS by SII. PFS = Progression-free survival, GPS = Glasgow Prognostic Score, mGPS = Modified Glasgow Prognostic Score, PI = Prognostic Index, PNI = Prognostic Nutritional Index, NLR = Neutrophil to lymphocyte ratio, LMR = Lymphocyte to monocyte ratio, PLR = Platelet to lymphocyte ratio, SII = Systemic immune-inflammation index, TACE = Transarterial chemoembolization

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Comparison of performance between other inflammation scores and platelet-to-lymphocyte ratio

We constructed time-dependent ROC curves at 3, 6, 12, and 18 months after the PFS treatment and calculated their corresponding AUC value to compare the PLRs performance and the other inflammation-based scores (i.e., PI, PNI, NLR, GPS, mGPS, LMR, and SII), which indicated that PLR was superior to other inflammation-based scores in predicting the PFS of intermediate-stage HCC undergoing TACE [Figure 2] and [Table 4].
Figure 2: The time-dependent ROC curves at 3 (a), 6 (b), 12 (c), and 18 (d) months of PFS based on different inflammatory biomarkers. ROC = Receiver operating characteristic, PFS = Progression-free survival, GPS = Glasgow Prognostic Score, mGPS = Modified Glasgow Prognostic Score, PI = Prognostic Index, PNI = Prognostic Nutritional Index, NLR = Neutrophil to lymphocyte ratio, LMR = Lymphocyte to monocyte ratio, PLR = Platelet to lymphocyte ratio, SII = Systemic immune-inflammation index, TACE = Transarterial chemoembolization

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Table 4: Comparison of the performance and discriminative ability between the preoperative prognostic factors and platelet to lymphocyte ratio and platelet to lymphocyte ratio- size score

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Correlations analysis between platelet-to-lymphocyte ratio and patient characteristics

We depicted the correlations between PLR and patients'characteristics in [Table 5]. A higher PLR was significantly associated with more elevated platelet and neutrophil counts, reduced lymphocyte counts, higher C-reactive protein (CRP), and alpha-fetoprotein (AFP) level, better liver function (shorter prothrombin time and total bilirubin), lower immune status (higher NLR), and larger tumor size [all P < 0.05; [Table 5]].
Table 5: Relationship between baseline characteristics and platelet to lymphocyte ratio score

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The novel inflammation-based score based on tumor size – platelet-to-lymphocyte ratio-size score

We proposed a novel inflammation-based score based on tumor size–PSS [hereon; [Table 1]]. The survival curve showed that the PSS divided patients into subgroups with significantly different PFS [Figure 3]a. The PSS had a considerably higher AUC value than the PLR or the tumor size [Figure 3]b, [Figure 3]c, [Figure 3]d and [Table 4].
Figure 3: Kaplan–Meier plots for PSS of PFS in patients with intermediate-stage HCC received TACE (a) and time-dependent ROC curves at 6 (b), 12 (c), and 18 (d) months of PFS based on PSS, PLR, and tumor size. ROC = Receiver operating characteristic, PFS = Progression-free survival, PLR = Platelet to lymphocyte ratio, PSS = PLR-size score, TACE = Transarterial chemoembolization

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 > Discussion Top


Our study found that PLR was an independent and more advantageous PFS predictor for intermediate-stage HCC patients who underwent TACE treatment than other inflammation-based scores (i.e., PI, PNI, NLR, GPS, mGPS, LMR, and SII). We also proposed a novel inflammation-based score (i.e., PSS) based on tumor size, which significantly improved the prognostic prediction's performance.

Several studies have shown that systemic inflammation is related to poor prognosis in many cancer types.[13],[14] As we all know, HCC is related to chronic inflammation and fibrosis caused by different causes, including chronic hepatitis B and C infections and fatty liver disease. Specifically, chronic liver inflammation promoted immune tolerance by promoting Tregs activity, the secretion of interleukin-10 and transforming growth factor-β (TGF-β) by Kupffer cells and liver sinusoidal endothelial cells, immune checkpoints' upregulation, such as programmed death receptor 1 (PD-1), programmed cell death ligand 1, and Cytotoxic T-lymphocyte-associated protein 4 receptor (CTLA-4).[15],[16],[17],[18],[19],[20],[21] Chronic liver diseases can also stimulate cell proliferation and tissue regeneration by epidermal growth factor and insulin-like growth factor, promote angiogenesis by vascular endothelial growth factor and platelet-derived growth factor, and accelerate the formation of extracellular matrix by TGF-β.[22] Those studies suggested, theoretically, that inflammation plays a critical role in liver cancer prognosis. Therefore, the investigation of inflammation-related indicators in HCC patients before treatment is essential. At present, studies suggested PLR, PI, PNI, NLR, GPS, mGPS, LMR, and SII as effective inflammation-related prognostic indicators in HCC patients.[3],[4],[5],[6],[7],[8],[9],[10] Therefore, we compared those inflammation-based scores' predictive value and only found that the PLR was the independent inflammation-based predictor for intermediate-stage HCC patients that received TACE treatment with the best prognostic prediction performance.

The PLR was an integrated inflammation-based predictor based on peripheral platelet and lymphocyte counts. Our study showed among patients with intermediate-stage HCC after TACE with a higher PLR. More HCC patients had significantly higher platelet counts and reduced lymphocyte counts. Platelets play pro-inflammatory roles in cancer-associated inflammation. They stimulate pro-inflammatory factors secretion, such as CXCL5 and CXCL7, induce leukocyte recruitment, and promote the neutrophil extracellular traps' formation, causing tumor metastasis and tumor thrombosis formation.[23] Besides, platelet-derived TGF-β, and direct connection between tumor cells and platelets synergistically promote cancer cells' transformation into an aggressive mesenchymal phenotype, thereby enhancing metastasis.[24] Specifically, a study showed that platelets can contribute to the growth and metastasis of HCC.[25] However, lymphocytes play critical roles in the cancer-related immunobiology (i.e., immunosurveillance and immunoediting) and lymphopenia is caused by immune checkpoint inhibitors' expression (i.e., PD-1, TIM-3, and CTLA-4).[26],[27] Some clinical studies have also shown that lymphopenia was significantly associated with a worse prognosis of HCC.[28],[29],[30] Therefore, the PLR was a useful predictive biomarker of patients' efficacy with intermediate-stage HCC after TACE theoretically and practically. Besides, our study also showed that intermediate-stage HCC patients after TACE had higher PLR values, more neutrophil counts, higher CRP, higher AFP levels, more inferior immune status (higher NLR), and larger tumor sizes. This suggests that a higher PLR often has more inadequate responses, an elevated inflammation background, and more malignant tumor characteristics. Though we found a higher PLR accompanying better liver function (shorter prothrombin time and total bilirubin), the multivariate analysis found that liver function is not an independent prognostic factor of PFS. Besides, our study showed that the PLR and tumor size were the independent prognostic indicators of PFS in patients with intermediate-stage HCC after TACE. Based on this result, we proposed a novel inflammation-based score based on tumor size – PSS that improved significantly prognostic prediction performance. Therefore, our novel inflammation-based score can provide individualized treatment evidence for patients with intermediate-stage HCC in clinical practice by thoroughly assessing baseline variables before treatment. For example, the treatment of intermediate-stage HCC patients with higher PLR and/or tumor size over 6.6 cm, could use optional first-line TACE-based treatment combined with therapies, such as sorafenib,[31] microwave ablation,[32] apatinib,[33] or hepatic arterial infusion chemotherapy,[34] instead of the TACE-alone.

Although our meaningful findings, several limitations should still be clarified. First, this study is a single-institution and retrospective. Second, the proportion of patients with a score 2 of mGPS, GPS, and PI is small, which may weaken their prognostic prediction performance to a certain extent. Third, although the PLR is currently the most potent inflammation-based score in predicting the PFS of intermediate-stage HCC after TACE, more predictive inflammation-based scores will be revealed.

Financial support and sponsorship

This work was supported by grants from the National Natural Science Foundation of China (No. 81771954) and Guangdong Science and Technology Department (Grant No.:2019B110233001 and 2017A010105028).

Conflicts of interest

There are no conflicts of interest.



 
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