Urological malignancies, which comprise urothelial carcinoma (UCa), renal cell carcinoma (RCC), and prostate cancer (PCa), constitute a significant proportion of global cancer incidence, representing 12.6% of newly diagnosed cases in 2022 (1). These malignancies rank among the most frequently diagnosed cancers in the United States in 2024 (2). Recent advancements in targeted therapies, immunotherapies, and multimodal treatments have led to improvements in survival outcomes. However, the prognosis for individuals with advanced-stage conditions is still grim, primarily due to the high rates of recurrence and metastasis. ​​Notably, the 5-year survival rate associated with metastatic prostate cancer is a mere 31%, and in the case of advanced bladder cancer, the corresponding 5-year survival rate is as low as 14% (3). Additionally, among post-nephrectomy RCC patients, 74% of recurrences occur within 5 years after surgery (4). Given these challenges, identifying prognostic factors for survival and recurrence in urological malignancies are essential for guiding​​ personalized treatment strategies and optimizing patient outcomes.

Gamma-glutamyl transferase (GGT) plays a critical role in the metabolic pathway of glutathione (GSH), exerting appreciable influence on cellular redox homeostasis and oxidative stress responses, especially within cancer cells (5). Research indicates that elevated GGT levels are associated with increased all-cause mortality​​, ​​particularly cancer-related mortality (6). Moreover, there is a growing consensus that serum GGT may function as an autonomous prognostic indicator for multiple types of cancer, including breast cancer (7), hepatocellular carcinoma (8), pancreatic cancer (9), nasopharyngeal carcinoma (10), and ovarian cancer (11). Emerging studies have demonstrated ​​associations between serum GGT levels and clinical outcomes​​ in urological malignancies. However, the reported results were inconsistent. We intended to undertake a comprehensive analysis of the current literature to explore the predictive value of pretreatment serum GGT for urological malignancies.

Urological malignancies, such as UCa, RCC, and PCa, represent a major category of oncologic diseases with substantial global health impacts. PCa is the second most common cancer diagnosed globally and ranks fifth highest cancer-attributable deaths in males, with about 397,000 deaths documented in 2022. Bladder cancer, a principal subtype of UCa, ranks ninth in global cancer incidence, resulting in approximately 220,000 deaths annually. RCC has the 14th highest incidence and was estimated to contribute 15,600 deaths in 2022 (1). ​​The significant disease burden imposed by these malignancies, characterized by elevated incidence rates and considerable mortality​​, ​​underscores the critical need for identifying reliable prognostic factors. From our perspective, this research constitutes the inaugural full meta-analysis to ascertain the prognostic implication of serum GGT levels prior to therapy in urological malignancies.

The study was designed to methodically evaluate the function of serum GGT prior to therapy in the prognosis of urological malignancies by comprehensively reviewing the published studies on the subject and using meta-analysis. The meta-analysis on the basis of qualitative studies showed that the degree of pretreatment serum GGT elevation was considerably related to worse OS, CSS, and PFS of all the people who have UCa, worse OS and PFS of all the people who have RCC, and worse OS and PFS of all the people who have PCa. Subgroup analyses of OS based on different variables such as publication year, geographic region, sample size, tumor characteristics, treatment modalities, GGT cutoff values, and NOS score consistently maintained statistical significance under these subgroup variables. Our results were confirmed to be reliable and robust through publication bias assessments and sensitivity analysis. Serum GGT, a clinically utilized hematological marker, is straightforward and cost-effective to measure. Thus, serum GGT may operate as a valuable prognostic indicator in the management and clinical assessment of urological malignancies.

A recent systematic review investigated serum GGT as a prognostic factor for urological tumors. The authors included 8 articles and qualitatively concluded that elevated serum GGT levels were remarkably relevant to adverse prognosis in patients with urological malignancies (23). However, this study has several limitations. First, the search was restricted to PubMed and Cochrane, which likely resulted in an incomplete literature retrieval.​ Additionally, contradictory results among included studies may compromise the consistency and reliability of the conclusions. Second, most of the included studies focused on serum GGT levels, whereas Ramankulov et al. (24) investigated plasma osteopontin. Their study only briefly mentioned the relationship between serum GGT levels and survival without specifying survival endpoints. Therefore, our study did not include the work of Ramankulov et al. (24). To address these limitations, thorough searches were carried out across multiple databases, and the aggregated data were meta-analyzed to provide a quantitative conclusion. Consequently, our research offers the most current and comprehensive evidence regarding the prognostic significance of pretreatment serum GGT in urological malignancies.

While serum GGT is conventionally utilized to detect​​ hepatic abnormalities, biliary tract disorders, and impairment related to alcohol use, its role in tumor prognosis has garnered increasing attention (25). Recent studies propose​​ that GGT may have a key function in neoplasm development and resistance to anticancer drugs. Typically, patients with ​​elevated GGT levels exhibit significantly reduced survival durations across malignancies (26). Serum GGT is thus scientifically supported as a potential prognosis indicator in cancer patients. Nonetheless, the precise association between serum GGT levels and the clinical prognosis of urological malignancies remains to be elucidated, necessitating additional investigation. Emerging evidence indicates that GGT’s involvement in oxidative stress pathways substantially influences tumor metabolism in urological cancers. In highly metabolically active cancer cells, GGT levels are markedly upregulated under oxidative stress conditions (27). Tumor cells upregulate membrane-bound GGT to facilitate the absorption of GSH, a key antioxidant, from the bloodstream and surrounding tissues, thus acquiring extra cysteine and cystine to restore intracellular GSH levels (28). However, in certain specific cases, GGT may also promote oxidative reactions. Continuous oxidative stress contributes to genomic instability and regulates the regulation of tumor progression (29). Moreover, studies have shown that GGT induction can be triggered by inflammatory mediators, including tumor necrosis factor and interleukin (30, 31). GGT is crucial in the metabolic pathway involving the inflammatory mediator leukotriene C4 (32). In summary, elevated serum GGT levels may influence the progression and outcomes of urological malignancies by regulating redox homeostasis and participating in inflammatory processes.

While this study provides valuable insights, several limitations warrant acknowledgment. Firstly, the incorporated studies were exclusively single-center and retrospective in design, thus inherently vulnerable to recall bias and residual confounding. Furthermore, Some HRs and corresponding 95% CIs were derived from univariate analyses lacking covariate adjustment, potentially introducing uncontrolled confounding biases. Secondly, dependence solely on published literature may engender publication bias due to potential underrepresentation of studies with non-significant findings. Thirdly, despite comprehensive search strategies, the paucity of articles reporting PFS outcomes compromises the robustness of corresponding conclusions. Finally, the predominance of Asian studies and the lack of validation in multi-center, ethnically diverse populations may limit the generalizability of our findings.

Elevated pretreatment serum GGT levels constitute an independent prognostic factor for shorter OS, CSS, and PFS durations​​ in urological malignancies. Collectively, pretreatment serum GGT levels may be a valuable indicator for informing clinical management strategies in urological malignancies.