The development of tumor is closely linked to inflammation. Therefore, targeting molecules involved in inflammation may be effective in predicting cancer prognosis. Transarterial chemoembolization (TACE) holds significant therapeutic significance in addressing hepatocellular carcinoma (HCC). At present, no studies have evaluated the predictive value of γ-glutamyl transferase to albumin ratio (GAR) on the prognosis of HCC undergoing TACE.

To explore the potential prognostic significance of the GAR in individuals undergoing TACE for HCC.

A total of 1231 patients from seven hospitals in China were randomized into a training cohort (n = 862) and a validation cohort (n = 369). To establish independent prognostic factors for overall survival (OS), we utilized multivariate and univariate Cox regression models. The best cut-off value of the GAR was determined with the X-tile software, with OS as the basis. Validations were performed using dual therapy cohort and triple therapy cohort.

X-tile software revealed a GAR threshold of 4.75 as optimal. Both pre- and post-propensity score matching analyses demonstrated that the median OS in the low-GAR group (< 4.75) was notably longer compared to the high-GAR group (≥ 4.75), showing results of 26.9 vs 9.8 months (P < 0.001) initially, and 18.1 vs 11.3 months (P < 0.001) after match. Furthermore, multivariate analysis identified GAR ≥ 4.75 as an independent prognostic factor (P < 0.001). The receiver operating characteristic curves for the nomogram showed area under receiver operating characteristic curves of 0.741, 0.747, and 0.708 for predicting 1-, 2-, and 3-year survival, respectively. Consistent findings were reiterated in the two cohorts involving TACE in combination with targeted therapy and TACE in combination with targeted therapy and immunotherapy. Calibration curve and decision curve analyses substantiated the model’s relatively robust predictive capabilities.

Our study validates the effective prognostic capacity of the GAR-based nomogram for HCC patients undergoing TACE or TACE in combination with systemic therapy.

Hepatocellular carcinoma (HCC) is prevalent worldwide and is a life-threatening malignancy, witnessing an escalating incidence that represents a large proportion of deaths related to cancer. Projections indicate that the annual HCC incidence will exceed one million individuals by the year 2025[1]. Sadly, patients devoid of effective therapeutic interventions succumb to an abysmal median overall survival (mOS) of merely four months[2].

The latest guidelines released by the National Comprehensive Cancer Network advocate for the combined employment of atezolizumab and bevacizumab as the prime systemic therapy option for individuals affected by advanced HCC. Additionally, in cases of unresectable or inoperable HCC exceeding 5 centimeters, transarterial chemoembolization (TACE) may merit consideration to extend patient survival. Following the established staging system of Barcelona Clinical Liver Cancer (BCLC), TACE has become the mainstay of therapy for intermediate-stage HCC. Specifically, this encompasses patients boasting asymptomatic, multi-nodular tumors devoid of vascular invasion or extrahepatic spread[3]. Indeed, TACE has also yielded surprising results for some early patients who were not suitable for surgery or ablation[4-6]. In some series of studies, the majority of patients treated with TACE were in the early stages of disease, with more than 40% being solitary nodules[7,8]. Importantly, TACE has also garnered favorable treatment responses in advanced-stage HCC cases. An extensive longitudinal cohort study across 14 countries discovered that TACE served as the primary treatment for nearly 50% of individuals afflicted with BCLC-C-stage HCC[9]. This assertion is further supported by the findings of two prospective non-randomized trials[10,11], which confirmed the superiority of conventional TACE over basic supportive care.

Scientific investigations have illuminated the intricate relationship between long-standing inflammatory factors and the malignant transformation of tumors, highlighting the fundamental role of chronic inflammation and its associated factors in the emergence of tumorigenesis[12]. Inflammatory factors are important players in the regulation of the tumor microenvironment. They possess the capacity to instigate tumor epithelial-mesenchymal transition, generate reactive oxygen species, and thereby facilitate tumor cell proliferation, angiogenesis, invasion, and metastasis[12,13]. γ-glutamyl transferase (GGT) is a kind of glycoprotein secreted by Kupffer cells and bile duct endothelial cells. Elevated GGT levels are a marker of liver dysfunction and alcohol intake, and can be used to measure the severity of liver inflammation and cellular damage[14]. GGT’s main role is to mediate the hydrolysis of extracellular glutathione, which produces large amounts of hydrogen peroxide and reactive oxygen species and other free radicals, leading to oxidative stress in tissues[15]. Many experimental studies have also shown that the expression of GGT makes cancer cells more invasive and even leads to the emergence of anticancer drug resistance[16].

Albumin (ALB) is the most important protein in humans, synthesized by liver cells. It has a wide range of important physiological functions, such as regulating immunity, stabilizing endothelium, and binding to various drugs and toxins[17]. In addition, ALB binds to a series of inflammatory mediators and interacts with nitric oxide, playing anti-inflammatory and antioxidant roles[18]. Serum ALB levels reflect liver reserve function and nutritional status of the body. In cases of malnutrition, hepatitis, and cirrhosis, the concentration of ALB in the human body will significantly decrease[19]. Therefore, ALB is frequently utilized in the assessment of liver function prior to hepatic resection[20]. Recent research has confirmed that ALB can also exert a protective influence after a variety of radical surgeries[21]. Although some studies have shown that GAR can predict the outcome of HCC[22,23], these studies only focused on hepatectomy, and their sample sizes were small. In this study, we developed a predictive model for HCC based on a convenient and inexpensive liquid biopsy technique, which can effectively predict not only survival after TACE alone, but also outcomes of dual therapy or triple therapy.

TACE has become an important treatment method in the era of tumor precision therapy[24]. Although some studies have shown that GAR can be applied for the prediction of HCC prognosis, the study sample is generally small, and the study objects are all surgical resection. At present, no study has confirmed the predictive value of GAR in TACE. Therefore, we initiated a large-sample, multicenter TACE cohort study and established a nomogram model of HCC patient survival based on GAR. In this study, the patients with GAR ≥ 4.75 had lower mOS than those with GAR < 4.75(P < 0.001). High predictive accuracy of GAR was also found in both the dual and triple therapy cohorts for the first time.

At present, TACE-based prognostic models have been gradually established. The neutrophil-lymphocyte ratio model and platelet-to-lymphocyte ratio have been demonstrated to predict survival prognosis and metastasis in HCC patients treated with TACE[25,26]. However, there is no prognostic marker for patients suffering from HCC after TACE in conjugation with immunotherapy or targeted therapy. TACE was once the first-line therapy for stage B BCLC patients, and recent prospective clinical studies have shown that TACE is also a novel ideal treatment option for patients with early-stage (solitary nodules) and some advanced-stage HCC[27]. More and more HCC patients are expected to benefit from TACE treatment, so it is of great clinical significance to search for an effective prognostic marker for TACE treatment.

The role of inflammation in cancer has long been the focus of researchers. Inflammation promotes tumor development through a multi-faceted process, including angiogenesis, extracellular matrix remodeling, immunosuppression, invasion, and distant infiltration[28,29]. Various inflammatory cells create a favorable environment for tumor growth, thus exacerbating the development of this pathological process[30]. High levels of serum GGT are often a marker of severe hepatitis, cirrhosis, and advanced cancer. There is evidence that it mediates the hydrolysis of glutathione, which can lead to the formation of free radicals, lipid peroxidation and induce malignant transformation of cells. GGT is also thought to promote rapid growth and turnover of tumor cells[16]. A number of published prospective studies have shown a positive correlation between the levels of GGT and a number of cancers, including liver, breast, and prostate cancer[31,32].

In contrast, ALB plays a vital role in counteracting oxidative stress, enhancing microcirculation, and inhibiting inflammatory responses. It has been demonstrated that ALB exerts DNA replication stabilization and immune response potentiation, thus impeding tumor progression[33]. Furthermore, hypoalbuminemia has been consistently linked to unfavorable prognoses in cancer patients[34,35]. McMillan et al[35] found that individuals with advanced lung or gastrointestinal malignancies exhibit a persistent systemic inflammatory response, which results in a continuous reduction in ALB concentration. To some extent, serum GGT levels can reflect tumor load, whereas liver metabolic ability and immune function are determined by ALB levels. Consequently, in comparison with other biomarkers, the GAR value more accurately reflects the relative tumor burden and liver function, thus affording a more effective prognostic tool for predicting the survival outcomes of patients diagnosed with HCC.

In preceding investigations, the prognostic outcome of HCC has been linked to factors such as GAR, PVTT, tumor number, tumor size, and Child grade[23,36]. The present study further corroborates this finding. Furthermore, we extended the nomogram model, demonstrating its commendable performance for prediction in the validation set. This has enhanced the GAR’s practical application in clinical settings. Particularly for patients with elevated GAR, vigilance and proactive management should be emphasized.

The strength of the current research is the large sample size, which improves the reliability of results. We performed a PSM analysis, which reduced the effect of bias and confounding variables in the study and could more truthfully reflect the association of GAR with OS. Post-PSM survival analysis reaffirmed the prognostic value of GAR, with the low-GAR group demonstrating superior mOS. Further statistical scrutiny of the matched cohort, including both univariate and multivariate models, consistently highlighted GAR as a pivotal, independent determinant of OS outcomes. GAR was not only internally validated by the test data set, but also validated TACE in conjunction with targeted cohorts and TACE in conjunction with immunotherapy and targeted therapy. Therefore, it further improves the clinical applicability in the future treatment of HCC.

This study does, however, have some limitations. In the first place, this was a retrospective study, so selection bias was inevitable. Second, GGT and ALB levels can be influenced by different laboratory hematologic techniques, which may lead to some deviations. Third, although the predictive performance of GAR in dual and triple therapy cohorts has been verified, the number of patients was small, which may compromise the reliability of the conclusion. Therefore, multicenter, a large population, and prospective studies are expected to confirm and update the findings of this study in the future.

Our study validates the effective prognostic capacity of the GAR-based nomogram for HCC patients undergoing TACE or TACE in combination with systemic therapy.

The authors would like to thank all the reviewers who participated in the review.