Combination of the gamma-glutamyltransferase-to-prealbumin ratio and other indicators may be a novel marker for predicting the prognosis of patients with hepatocellular carcinoma undergoing locoregional ablative therapies

1. The proposed Fib-GPR and N-GPR scores for HCC patients might effectively predict recurrence and mortality.

2. Our scores, which were based on γ-GT, may possess some advantages for making a true clinical decision for patients with HCC undergoing TACE plus local ablation therapy.

3. This is a retrospective single-center study and thus is affected by confounding factors; therefore, our results need to be validated by further multicenter studies.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths and the sixth most common cancer worldwide, with approximately 841,000 new cases and 782,000 deaths annually [1]. In China, HCC accounts for more than 83.9~92.3% of primary liver cancer cases and is currently a serious health problem [2, 3]. In recent years, significant advances in locoregional therapies have led to excellent results with therapy that are highly comparable to those with surgical resection, especially in patients with small single tumors because the therapy are associated with minimal invasion, rapid recovery, and few complications. Locoregional ablation plus transcatheter arterial chemoembolization (TACE), which can reduce the tumor bulk and heat sink effect, are potential treatment strategies for patients who are not eligible for surgical resection due to dysfunction or coagulopathy [4]. However, high recurrence and low overall survival (OS) rates reduce the quality of life of HCC patients and thus should be urgently managed. Therefore, valid markers for predicting patients’ prognosis are of great significance in choosing the optimal therapeutic modality.

As an almost ubiquitous enzyme, γ-glutamyltransferase (γ-GT) initiates the degradation of extracellular glutathione and is also conjugates and correlates with biotransformation, nucleic acid metabolism, and oncogenesis [5]. Previous studies have shown that high levels of γ-GT are significantly associated with unfavorable prognoses in HCC patients [6, 7]. Prealbumin (PA), which is synthesized by the liver, is a recently identified biomarker indicative of liver synthetic functions and has not been included in the traditional Child-Pugh classification system. Several scholars have demonstrated that low preoperative serum levels of PA could be used to predict the long-term prognosis of HCC patients undergoing liver resection [8, 9].

A limited number of studies have investigated whether γ-GT combined with PA could predict the prognosis of HCC patients treated with TACE plus locoregional ablation. Therefore, the present research aimed to study the data of HCC patients who received combined therapies as the primary treatment and validate the predictive value of combining GPR with other parameters for HCC patients.

In China, the incidence and mortality of HCC globally accounts for approximately half of all patients with liver cancer. Hence, HCC has aggravated the medical burden in China and is a serious health problem [12]. TACE combined with ablation therapy is a potential therapeutic strategy for HCC; however, the problem of recurrence seriously influences the efficacy of combined treatments. Thus, an exploration for effective predictive indicators of RFS and OS is of great significance, and these predictors might assist clinicians in adopting timely strategies to prevent recurrence and improve outcomes of HCC patients.

The results of the present study showed that high Fib and AFP levels were independent risk factors for RFS in patients with HCC who underwent combined treatments. Elevated plasma Fib levels have been associated with tumor progression in several malignancies, including esophageal carcinoma, small cell lung carcinoma, and non-small cell lung carcinoma [13‐17]. The following triggers might explain our findings. First, Fib may contribute to the adhesion of tumor cells to platelets, to platelet aggregation and thrombin formation around the tumor cells, thus protecting them against attacks from natural killer cells. Second, oncogenesis is typically accompanied by inflammatory responses and leukocyte infiltration into the tumor stroma, which may convert Fib to the fibrin matrix, thereby promoting tumor angiogenesis. Third, Fib may serve as an extracellular matrix that regulates the growth of cancer cells by binding to various types of growth factors, which may promote cellular adhesion, proliferation, and metastasis and inhibit the apoptosis of tumor cells [18, 19]. AFP, a biomarker for HCC, plays a substantial role in the regulation of hepatocarcinogenesis. However, the relationship of AFP with prognosis in patients with HCC remains elusive. The current research showed that a high AFP level is an independent risk factor for RFS in patients with HCC who received combined therapies, which was in agreement with Yang et al.’s conclusion [20]. The elevated AFP level may be an indication of vascular invasion and HCC progression, both of which contribute to an elevated risk for early recurrence [21].

The present study confirmed that low neutrophil levels are an independent risk factor for only OS in patients who received combined therapies, which is controversial with several results. For my part, liver disease may inhibit the hematopoietic function of marrow, another aspect is that hypersplenism may lead to neutropenia. However, bias resulting from fewer death cases cannot be ignored [22].

The multivariate regression analysis revealed that the number of tumors and GPR were independent predictors for both RFS and OS of HCC patients. Multiple tumors are typically characterized by the multicentric development of neoplasms. In addition, there may be microscopic lesions around the tumors that cannot be clearly detected by imaging examinations and are more likely to relapse and metastasize. A previous study reported that the expression of γ-GT provides tumor cells with an additional source of cysteine and cystine from the cleavage of extracellular glutathione and oxidized glutathione [23]. In addition, compared to that in patients with small tumors and single tumors, γ-GT levels are notably higher in individuals with large and multiple tumors, which are more likely to relapse [24]. Additionally, a number of previously conducted studies indicated that macrophages and neutrophils can facilitate the release of γ-GT, which disrupts the HCC microenvironment, causing the progression of cancer, and this finding was in agreement with our findings [25, 26]. PA is synthesized by the liver, and the half-life of PA is as short as 1.9 days, compared with albumin’s half-life of 19–21 days. This exogenous albumin deriving from supplemental infusion of human serum albumin and blood transfusion persists in the body for a long time, which may make liver function estimation inaccurate. Therefore, many scholars chose prealbumin as a more sensitive marker to predict prognosis than albumin during cachexia progression [27, 28]. Additionally, low preoperative prealbumin levels are a negative independent prognostic factor for cancer-specific recurrence and survival [19, 29].

A number of studies have indicated the predictive values of the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), NLR-PLR, albumin-bilirubin index (ALBI), and improved platelet-albumin-bilirubin index (PALBI). I think it may be explained as follows. First, neutrophilia inhibits the cytolytic activity of immune cells [30]. And the platelets secrete vascular endothelial growth factor and platelet-derived growth factor, which contribute to angiogenesis, cell proliferation and tumor metastasis [31]. Second, the infusion of exogenous albumin may inhabit HCC cells growth via the modulation of AFP and growth-controlling kinases [32]. And elevated serum TBIL is a sensitive marker of liver injury. A systematic review summarized serum ALB and TBIL as the two most prominent prognostic markers [33]. A recent study reported that the AUC value of NLR-PLR for predicting the 2-year OS rate was 0.653, while another study demonstrated that the AUC values of ALBI and PALBI were 0.642 and 0.675, respectively [34, 35]. The results of the present study suggested that the AUC value of the GPR-related combined indicator for predicting OS was 0.704. These indicators are different from genes or proteins, which are directly associated with the occurrence and progression of HCC, so AUC value of these markers may be not high. Through preoperative evaluation, patients are divided into different groups according to risk of recurrence and death. For patients with high risk of recurrence, follow-up strategies should be adjusted to more closely monitor the tumor progression, which help doctors take timely interferential measures to reduce the recurrence rate and improve the long-term prognosis of patients. Therefore, the GPR-related indicators for HCC patients who received combined therapies might be viewed as significant markers to effectively predict the risk of early recurrence and mortality.

Medical imaging examinations, such as CT and MRI, are not appropriate routine methods for monitoring prognosis because of the unclear visualization of microscopic metastases, high cost of inspection, and radiation hazards. Consequently, valid serum markers from routine blood and liver function examinations are of great significance for determining the optimal therapeutic modalities. However, this is a retrospective single-center study that was affected by confounding factors; thus, our results need to be validated by further multicenter studies.

In summary, the proposed Fib-GPR and N-GPR scores based on independent risk factors might effectively predict the risk of early recurrence and mortality for HCC patients who received combined therapies and may possess a number of advantages for making a true clinical decision for patients with HCC who underwent TACE plus locoregional ablative therapy.