Exploring the clinical value of preoperative serum gamma-glutamyl transferase levels in the management of patients with hepatocellular carcinoma receiving postoperative adjuvant transarterial chemoembolization

Hepatocellular carcinoma (HCC) is still one of the most common malignancies globally [1, 2], and approximately 854,000 patients have been newly diagnosed as HCC per year [3]. But the prognosis remains unfavorable with the median overall survival of 30 to 40 months [3], regardless of substantial advances in the early detection, treatment and surveillance. Radical resection has been still the most cost-effective curative treatment for patients with HCC [4, 5], but the long-term prognosis remains far from satisfactory with the 5-year recurrence rate up to 70% [1]. Hence, strategies designed to prevent the recurrence are badly warranted in clinic.

Transarterial chemoembolization (TACE) is typically considered to be the first-line treatment for unresectable HCC according to the current guidelines [3, 4], but it has been also tried prevalently to prevent the recurrence of patients receiving resection, especially in China [6‐8]. A number of studies found that postoperative adjuvant TACE (PA-TACE) could decrease the incidence of early recurrence and improve the long-term prognosis [9, 10], but worries on its efficacy have never lessen: 1) PA-TACE was found not benefit for all patients receiving resection [11], 2) adverse events (AE) related to TACE was unavoidable [12], and 3) PA-TACE might potentially cause distant metastasis [13, 14]. Hence, identifying the potential beneficiaries from PA-TACE is the key.

Gamma-glutamyl transferase (γ-GT) is a cell-membrane-bound enzyme modulating the metabolic process of glutathione (GSH) [15]. which is well concerned in the prognosis of tumors mainly because it is non-invasive and easily acquired. In the recent two systematic review and meta-analysis [16, 17], preoperative γ-GT levels is confirmed to be considerably correlated with the unfavorable clinicopathological characteristics and poor prognosis of HCC patients. To the best of our knowledge, serum GGT has been reported open in the management of palliative TACE for advanced HCC [18] and PA-TACE for resectable intrahepatic cholangiocarcinoma [19], but there are seldom reports about serum γ-GT guiding the management of PA-TACE for resectable HCC. Therefore, we extracted the data from the primary liver cancer big data (PLCBD), which was designed to collect data on primary liver cancer from multi-centers in China, to identify it.

γ-GT is an emerging biomarker for HCC early detection and prognosis prediction [25, 26], but its clinical value is far from being applied. In the current study, we found that elevated preoperative γ-GT was associated with worse OS and DFS, and was also correlated with aggressive tumor characteristics and increasing risk of intraoperative transfusion. In addition, PA-TACE could prolong the median OS and DFS of patients with elevated γ-GT before and after PSM, which was also an independent risk factor of both OS and DFS. Hence, γ-GT could be taken as an alternative biomarker to guide the management of PA-TACE.

PA-TACE is often conducted to eradicate the microscopic tumor sites [20, 27], which are either independent from primary tumor size or are not removed completely by hepatectomy, but it remains controversial whether PA-TACE could benefit patients with HCC after radical resection. In the current study, no significant differences were observed in terms of OS and DFS between groups of receiving PA-TACE or not (both P > 0.05), which was similar with previous reports [27‐29]. Reasons are mainly because most of the published results are retrospective and patients receiving PA-TACE are typically present with more aggressive tumor characteristics and worse performance status [29, 30]. Hence, PA-TACE should be recommended with cautious to patients with “high risk factors”, but the key is to identify those who would be benefited from PA-TACE.

γ-GT is reported to improve tumor development and progression [31, 32], which could be regarded as an alternative biomarker of HCC diagnosis, especially for those with clinically negative AFP [33]. γ-GT is also found to be correlated with clinicopathological characteristics and prognosis of HCC. In the current study, elevated γ-GT was found to be associated with the incidence of rising TBil, HBV infection, intraoperative transfusion, multiple tumors, tumor diameter, satellite, and advanced stages (BCLC staging B, AJCC staging IIIa, and CNLC staging II), which indicated that it could be considered to be an noninvasive predictor of prognosis [34, 35]. In addition, γ-GT levels was found to be an independent risk factor of both OS and DFS as well as AFP (all P < 0.05), which indicated that γ-GT levels could also be taken as postoperative monitoring index. Hence, γ-GT might be taken as a promising biomarker to guide the performance of PA-TACE.

In fact, γ-GT has been identified to be associated with prognosis of patients receiving TACE as an initial treatment, and baseline γ-GT levels has also been found to be a significant prognostic factor for patients with intermediate HCC receiving TACE and conformal radiotherapy [15, 36]. But the clinical value of γ-GT levels to guide the performance of PA-TACE has rarely been explored. In the current study, patients with elevated γ-GT were much more likely to receive PA-TACE than those with normal γ-GT (P < 0.05), and only patients with elevated γ-GT but not normal γ-GT were found to be benefited from PA-TACE before and after PSM. In addition, PA-TACE was identified as independent protective factor of both OS and DFS (both P < 0.05), which indicated that our conclusion was robust. Hence, γ-GT could be taken as an alternative biomarker to guide the performance of PA-TACE, and patents with elevated γ-GT should be recommended to receive PA-TACE.

The mechanism of γ-GT levels to predict the efficacy of TACE, in our opinion, lies on its interaction with liver microenvironment. As a membrane-bound enzyme, γ-GT is an essential element for the production of intracellular glutathione (GSH), which could prevent the tumor cell from damage of reactive oxygen species (ROS) and free radicals [37]. Additionally, γ-GT could also induce the generation of the endogenous ROS, which might accelerate the tumor proliferation and survival via aberrant CpG island methylation, DNA damage and genome instability [38]. From the other hand, tumor microenvironment could influence the expression of γ-GT. As a part of the tumor microenvironment, oxidative stress such as ROS could up-regulate γ-GT via the redox regulation of many genes [38], Moreover, inflammatory cytokines such as interferon-α/β and tumor necrosis factor α could also stimulate the expression of γ-GT [37, 39]. Hence, γ-GT could not only be a biomarker of the inflamed liver microenvironment, but also a biomarker of the prognosis, which indicated that γ-GT might guide the management of PA-TCAE.

However, there were several limitations in this study. First, selection bias and recalling bias were hard to avoid in a retrospective study, although PSM and multivariate cox model were conducted to decrease potential confounding factors. Second, interactions of γ-GT and PA-TACE might exist, but mechanism needed to be explored further. Third, the cut-off value in this study was the upper limit of the normal values, which might be different from each manufacture. The last but not the least, there are apparent differences between the West and East in the epidemiology, tumor characteristics, and management of HCC, which indicated that the conclusion needs further validation in the western series.

Currently, we concluded that patients with more advanced HCC also have more elevated γ-GT, and these patients with elevated γ-GT would be benefited more from PA-TACE after radical resection. However, the conclusion needs further validation.