Nasopharyngeal carcinoma (NPC) poses a global health burden with the highest incidence rates in Southeast Asia, South China and North Africa. Based on the 2020 global cancer statistics, there were ~133,000 new cases of NPC worldwide, accounting for 0.7% of all newly diagnosed cancer cases, with 80,000 deaths, representing 0.8% of global cancer deaths (1). Both incidence and mortality rates have increased compared with 2018 statistics (129,079 new cases and 72,987 deaths), suggesting a potential upward trend (2). In 2022, China is estimated to have ~64,165 new cases of NPC and 36,315 deaths (3), despite advancements in diagnostic and therapeutic technologies, NPC incidence and mortality rates have not substantially declined. Common clinical manifestations of NPC include nasal congestion, epistaxis, otalgia or ear fullness, hearing loss, diplopia and headaches. Currently, a combination of chemotherapy and radiotherapy is a key strategy for treating advanced-stage NPC. Due to improvements in diagnostic imaging, early detection through large-scale screening, and the emergence of Intensity Modulated Radiation Therapy (IMRT), the survival rate of locally advanced NPC has increased (4,5). However, even after treatment, ~5-15% of patients with advanced NPC experience local recurrence, and clinical manifestations of distant metastasis are observed in 15-30% of patients (4). Distant metastasis is the most common post-treatment failure pattern (6). For locally advanced NPC, clinical trials have demonstrated that adjuvant chemotherapy after radiotherapy significantly improves the failure-free survival rate in patients with advanced NPC. It is not only manageable in terms of safety but also does not affect the quality of life (7).

Previous studies have explored the impact of clinical, histological and biochemical factors on patients with NPC. Among them, disease staging and plasma Epstein-Barr virus (EBV) DNA concentration have been considered routine prognostic factors in clinical practice (8,9). Baseline serum lactate dehydrogenase (LDH) levels are also associated with prognosis in patients with NPC undergoing radical IMRT treatment (10). However, even among patients with identical disease stages and pretreatment EBV DNA levels, NPC exhibits significant biological heterogeneity, making prognosis prediction challenging. Exploring new prognostic factors to guide clinical decisions and provide favorable and accurate treatment for NPC patients is urgently needed.

Serum uric acid (SUA) is the final product of purine metabolism, possessing dual functions of antioxidation and pro-oxidation (11). As a systemic antioxidant, it plays a crucial role in protecting cells from damage induced by free radicals. Previous studies on elevated SUA indicate a risk of poor survival in patients with advanced HCC (12). Furthermore, research has demonstrated a positive correlation between uric acid levels and the incidence of kidney cancer, especially in female subjects (13). Meanwhile, the latest studies suggest the practicality of UA as a clinical target for breast cancer prevention. The public and clinical significance of reducing SUA may help reduce the incidence of breast cancer in overweight postmenopausal women (14). Most previous studies have focused on pre-treatment SUA, observing its predictive role in diseases, with little exploration of post-chemotherapy SUA. The predictive value of SUA levels after the end of the treatment cycle in patients with advanced NPC has not been determined. The present study aimed to confirm whether post-chemotherapy SUA levels have prognostic significance for patients with advanced NPC, potentially informing optimal treatment selection.

The present study included 182 patients with locally advanced NPC who were admitted in January 2020, confirmed by pathological diagnosis and without distant metastasis at presentation. The cohort consisted of 119 male (65.4%) and 63 female (34.6%) patients. The median age was 50 years (range: 18-78 years). Inclusion criteria (all required): i) Patients initially diagnosed with NPC by the Department of Pathology of The Second Affiliated Hospital of Nanchang University (Nanchang, China); ii) exclusion of hyperuricemia or gout before treatment; iii) patients staged from III to IVb according to the 7th edition of AJCC staging criteria in 2010; iv) patients who have not undergone antitumor treatments such as radiotherapy and chemotherapy in other hospitals; and v) availability of complete clinical data. Exclusion criteria (any of the following): i) Patients with incomplete clinical data; ii) patients with contraindications to radiotherapy and chemotherapy; iii) patients with a history of diabetes, hypertension, rheumatic autoimmune diseases, or other conditions that may affect kidney function; iv) patients with a history of hyperuricemia, gout, renal insufficiency, or other conditions affecting SUA levels; v) patients with a history of malignant tumors; vi) patients concurrently suffering from malignant tumors in other organs; and vii) patients who did not complete intensity-modulated radiation therapy within the specified time. Pretreatment evaluation included blood biochemistry, fiberoptic nasopharyngoscopy, nasopharyngeal and neck magnetic resonance imaging (MRI), chest computed tomography (CT), abdominal ultrasonography and whole-body bone scan. All SUA measurements were performed in the same central laboratory of the Second Affiliated Hospital of Nanchang University following standardized clinical procedures. The flowchart for patient selection is shown in Fig. 1.

SUA, the end product of purine metabolism excreted by the kidneys and intestines, is a potent antioxidant that scavenges singlet oxygen and free radicals (15). Its role in tumor biology is complex and not fully understood, with elevated levels potentially inhibiting or promoting tumorigenesis. Numerous clinical studies have investigated the association between SUA and the prognosis of various cancers, reporting correlations with tumor incidence, mortality and metastatic potential. Theoretically, elevated SUA levels may prevent tumor occurrence by enhancing antioxidant effects. However, extensive research results suggest that elevated SUA levels are associated with increased tumor incidence, mortality rates (12-14,16-22) and promotion of tumor metastasis (23). Previously, an increasing body of research has confirmed that elevated SUA levels can have a protective effect, contributing to improved patient survival rates (24-27). Therefore, it was investigated whether SUA levels correlate with OS, PFS, DMFS and LRFS in patients with NPC following induction chemotherapy, IMRT and adjuvant chemotherapy.

In the present study, based on the median uric acid level in the plasma after adjuvant chemotherapy being 350.45 µmol/l, 182 patients with NPC who completed the full treatment course were divided into two groups, the high SUA group (SUA >350 µmol/l) and the low SUA group (SUA ≤350 µmol/l). The results showed that post-adjuvant chemotherapy SUA levels could serve as prognostic biomarkers for OS, PFS and DMFS. The OS, PFS and DMFS were significantly higher in the high SUA group than in the low SUA group (P=0.037, P<0.001 and P=0.001, respectively). However, the LRFS difference showed no statistical significance (P=0.424). Multifactorial analysis has revealed that the SUA level after adjuvant chemotherapy is an independent prognostic factor for patients with NPC. The high SUA group has an improved prognosis than the low SUA group, which is consistent with the conclusions of the aforementioned study. Consistent with the present findings, previous research reported increased SUA levels in patients with metastatic colorectal cancer (CRC) who responded favorably to bevacizumab chemotherapy (28). This is similar to the results of the present study, suggesting that chemotherapy drugs may be effective in preventing the formation of new microvascular beds in existing tumor tissues. This relative difference between tumor tissues and supplying vascular tissues leads to local ischemia and the subsequent hyperuricemia. Thus, hyperuricemia appears to serve as an alternative biomarker for the efficacy of bevacizumab in treating patients with metastatic CRC.

In the present longitudinal observational study, SUA levels were repeatedly measured at four time points (pretreatment, post-induction chemotherapy, post-radiotherapy and post-adjuvant chemotherapy) in these patients with NPC. Through in-depth analysis, a significant decrease was observed in SUA levels following radiotherapy. Patients were measured for uric acid pretreatment (Mean, 323.69; SD, 87.56), after induction chemotherapy (Mean, 400.40; SD, 104.45), after radiotherapy (Mean, 222.84; SD, 68.47), and after adjuvant chemotherapy (M, 346.24; SD, 104.05). According to repeated measures analysis of variance, uric acid after radiotherapy was significantly lower than uric acid pretreatment [t(543)=-19.10; P<0.001; d=-1.47], uric acid after induction chemotherapy [t(543)=-29.15; P<0.001; d=-2.59] and uric acid after adjuvant chemotherapy [t(543)=-18.5; P<0.001; d=-1.80]. While the present study was not designed to elucidate the precise mechanisms behind this decrease, several potential contributing factors could be hypothesize based on clinical observations. The observed decline may be attributed to a combination of factors, including the systemic side effects of IMRT (for example, damage to taste buds and salivary glands), which often lead to decreased appetite and swallowing difficulties, potentially resulting in reduced nutritional intake and lower purine consumption. Furthermore, the catabolic state associated with advanced cancer and gastrointestinal side effects from platinum-based chemotherapy may exacerbate nutritional deterioration. However, it is crucial to note that these explanations remain speculative, and the present study lacks direct biochemical or clinical data to confirm these specific mechanisms. This represents an important direction for future research.

The observed correlation between elevated post-adjuvant chemotherapy SUA and improved survival outcomes warrants mechanistic discussion: SUA exhibits potent antioxidant activity and is regarded as a major antioxidant in humans, which is considered to scavenge free radicals and contribute to the total antioxidant capacity of plasma. Studies have indicated that uric acid, by providing antioxidant defense, plays a protective role in red blood cells and nerve cells (29,30). In the context of antitumor therapy, Ames et al (31) initially hypothesized that uric acid, through its role as a scavenger of singlet oxygen and hydroxyl radicals (products of singlet oxygen conversion), provides a major defense against human cancer and inhibits lipid peroxidation in red blood cells. Another study supporting the antioxidant ability of uric acid is related to the link between extensive oxidative stress parameters and colon cancer survival. Their conclusion is that only higher levels of uric acid in plasma are associated with longer survival in patients with colon cancer. It was considered that uric acid acts as a major antioxidant by clearing free radicals and stabilizing ascorbic acid in human serum (32). This suggests that high SUA concentration may have a protective effect on patients with NPC after adjuvant chemotherapy, and elevated uric acid levels may be a result of tumor lysis syndrome. Furthermore, by scavenging reactive oxygen species (ROS) generated during radiotherapy and chemotherapy, SUA might help in preserving immune cell function, particularly that of T lymphocytes, thereby indirectly sustaining an effective anti-tumor immune response. It is crucial to note that these potential mechanisms-tumor lysis, immune activation and ROS scavenging-are not mutually exclusive and may operate concurrently. Future studies integrating serial immune monitoring and metabolic profiling are essential to validate these hypotheses and decipher the precise role of SUA in the context of NPC treatment.

As a head and neck malignancy, NPC is primarily treated with IMRT due to its unique biological characteristics (4). However, IMRT inevitably induces side effects, as the oral cavity, pharynx, larynx and adjacent esophagus are often exposed to substantial radiation doses. Early side effects include decreased appetite, taste disturbance and salivary gland dysfunction, and swallowing difficulties, often leading to impaired nutritional intake (33). It is advisable to adopt a low purine diet. Moreover, malignant tumors themselves are a wasting disease. As the tumor progresses, the patient s physical function declines, nutritional status deteriorates, and the body s consumption exceeds intake. Combined with the gastrointestinal reactions caused by the platinum-based chemotherapy drug cisplatin, the nutritional status of patients rapidly deteriorates after radiotherapy (34). This may be a major reason for the post-radiotherapy SUA levels being lower than those of pretreatment.

However, the present study has several limitations. First, this is a single-center, retrospective study, which may limit the generalizability of the present findings to other patient populations and clinical settings. Second, despite the authors  efforts to control for confounding variables via strict inclusion and exclusion criteria, selection bias and unmeasured confounders inherent in retrospective designs may still exist. Factors such as detailed nutritional status, precise renal function metrics (for example, estimated glomerular filtration rate) and the use of medications affecting uric acid levels (for example, diuretics and allopurinol) were not systematically accounted for and could influence the results. Third, the median follow-up duration is only 50 months, therefore extending the follow-up period to evaluate the long-term prognosis of patients with intermediate to locally advanced NPC is essential. Therefore, these findings need confirmation through larger-scale prospective studies, However, the cutoff value of 350 µmol/l for SUA, while based on the median of the current cohort and aligned with common clinical reference standards, was determined post-hoc. Future studies are needed to validate this threshold prospectively or to explore more granular risk stratification using SUA as a continuous variable. Furthermore, as all participants were recruited from a single center in Southern China, an endemic region for NPC, the generalizability of the present findings to other populations with different genetic backgrounds and NPC incidence rates requires careful consideration. Ethnic and genetic variations, such as differences in purine metabolism enzymes or the strong association between NPC and EBV in endemic populations, might influence both baseline SUA levels and the host-tumor interaction.

In this context, the current comparative analysis demonstrated that the prognostic value of post-adjuvant chemotherapy SUA is independent of and complementary to established markers such as EBV-DNA and baseline LDH. This suggests that SUA may reflect distinct pathophysiological processes, such as systemic oxidative stress or metabolic alterations during treatment, which are not fully captured by EBV-DNA or LDH. Therefore, incorporating SUA into existing prognostic models could enhance risk stratification and personalized management for patients with NPC. The findings of the present study have a guiding role in the personalized treatment and health management of patients with cancer. The role of hyperuricemia as an independent risk factor for the occurrence and progression of cancer remains controversial and may vary by sex. Elevated SUA levels may be a valuable long-term surrogate marker rather than an independent risk factor. However, it is worth noting that although our research reveals the impact of radiotherapy and chemotherapy on uric acid levels, which may be used to assess the prognosis of patients with NPC after adjuvant chemotherapy, the specific mechanism of uric acid on the efficacy of radiotherapy and chemotherapy needs further study and large-sample validation. Further biochemical experiments and molecular biology studies will help elucidate the molecular mechanisms behind these biochemical changes, providing a theoretical basis for the development of new drugs and treatment strategies. Incorporating detailed nutritional assessments, purine metabolic profiling and renal function monitoring are warranted to validate these hypotheses. In addition, as biomarker research advances, exploring more correlations between biochemical indicators and treatment outcomes is anticipated to achieve more personalized and precise treatment approaches.

In conclusion, the present study identified post-adjuvant chemotherapy SUA level as an independent prognostic factor for OS, PFS and DMFS in patients with locally advanced NPC. Future studies should perform mechanism-based preclinical investigations to enable targeted regulation of SUA levels without promoting tumor development and/or metastasis. This can predict the risk of disease recurrence in NPC patients and guide the development of effective treatment plans.