Abstract
Background/Aim: This study investigated the prognostic value of serum uric acid (SUA) levels after definitive radiotherapy (RT) in head and neck cancer (HNC).
Patients and Methods: This retrospective study included patients with HNC undergoing definitive RT between January 2008 and February 2019. SUA levels were measured pre- and post-RT. Survival outcomes were analyzed using the Kaplan-Meier method, log-rank tests, and multivariable Cox regression. The optimal post-RT SUA cut-off (4.6 mg/dl) was determined via ROC analysis.
Results: A total of 185 patients were analyzed, with a median follow-up of 63.3 months. The mean pre-treatment SUA level was 5.4 mg/dl, which decreased to 5.2 mg/dl post-treatment, though the difference was not statistically significant (p=0.326). A post-treatment SUA cut-off of 4.6 mg/dl demonstrated discriminatory ability for distant metastasis-free survival (DMFS) but was not predictive of overall survival or locoregional relapse-free survival (LRFS). Kaplan-Meier analysis showed that patients with post-treatment SUA ≥4.6 mg/dl had significantly poorer DMFS than those with lower levels [hazard ratio (HR)=1.25, 95% confidence interval (CI)=1.02-1.53; p=0.004]. Multivariable analysis confirmed post-treatment SUA ≥4.6 mg/dl (HR=5.01, p=0.010), HPV-negative oropharyngeal tumors (HR=5.68, p=0.025), and Stage IV disease (HR=4.10, p=0.020) as independent prognostic factors for DMFS.
Conclusion: Post-treatment SUA levels may serve as a potential marker for predicting metastasis following RT in HNC.
Introduction
Head and neck cancers (HNC) encompass a diverse group of malignancies arising in the oral cavity, pharynx, larynx, and related structures, collectively accounting for 4-5% of all cancer diagnoses and deaths (1-3). Radiotherapy (RT) has been a cornerstone in the treatment of patients with HNC, aiming to eradicate tumors while preserving functionality. Despite advances in RT, patient outcomes remain highly variable (3), highlighting the need for novel biomarkers to improve early prediction, treatment stratification, and prognostication.
Several potential factors predicting the prognosis after RT in HNC have been identified, including tumor stage, nodal involvement, human papillomavirus (HPV) status, smoking history, and comorbidities (4, 5). Additionally, biomarkers such as p16 expression, immune response, and systemic inflammation markers (e.g., neutrophil-to-lymphocyte ratio) have emerged as areas of interest (6). However, despite these various factors demonstrating potential prognostic value, efficiently utilizing clinical markers to predict diverse RT outcomes among patients with HNC remains challenging.
Serum uric acid (SUA) levels, as cost-effective and clinically accessible biomarker, have been recognized for their potential predictive value in assessing the prognosis of patients with cancer (7-12). At physiological concentrations, UA acts as an antioxidant, scavenging singlet oxygen and free radicals. However, high intracellular concentrations can promote oxidative stress and inflammation (13). Elevated SUA levels have been implicated in various cancers, influencing tumorigenesis, progression, and patient outcomes (14, 15). During tumor progression and regression, SUA levels can be influenced by de novo biosynthesis in cancer cells, inflammation associated with cancer progression, and treatment-induced cell death (16-23). Previous studies have examined the prognostic significance of SUA in nasopharyngeal carcinoma after RT (24, 25) and found their association with survival outcomes of patients. From a perspective on nasopharyngeal cancer, the prognostic value of SUA could extend to other HNC cancer subtypes.
Furthermore, the SUA level could be changed dynamically through radiotherapy, and the prognostic value could have also different implications on the prognostic prediction. Radiotherapy induces cancer cell death, leading to the release of intracellular contents, including purines, which are metabolized into UA (25). This process can transiently elevate SUA levels in the tumor microenvironment, influencing oxidative stress and inflammatory responses (26, 27). The dynamic changes in SUA levels post-radiotherapy may reflect tumor burden and metabolic shifts, highlighting the potential of SUA as a biomarker for treatment response and prognosis in patients with HNC.
This study aimed to retrospectively evaluate the prognostic value of SUA levels in predicting clinical outcomes in patients with HNC following definitive RT. By assessing SUA levels before and after RT, we aimed to determine whether pre-treatment and post-treatment SUA levels can serve as a reliable biomarker for predicting disease progression and metastasis in this patient population.
Patients and Methods
Patients. This was a retrospective study at the two tertiary institutions that received approval from the Seoul National Hospital’s Institutional Review Board (Number. IRB#H-2302-069-1405, IRB#B-2304-821-403). The requirement for patient consent was waived due to the retrospective nature of the study.
We included patients with HNC treated with definitive radiotherapy (RT) between January 2008 and February 2019. The inclusion criteria were as follows: 1) patients with histologically confirmed HNC, including oral cavity, pharyngeal, and laryngeal cancers; 2) availability of complete serum uric acid (SUA) measurements within 2-3 months prior to treatment and at the 1st follow-up after treatment; 3) at least six months of follow-up data, including survival status, disease recurrence, and treatment response. Exclusion criteria included: 1) patients whose primary management was surgery; 2) patients with other concurrent malignancies or severe metabolic disorders, such as gout; 3) severe renal impairment [estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2]; 4) incomplete clinical data or missing follow-up information.
A total of 185 eligible patients were included in the final analysis. The baseline and treatment characteristics of this group are presented in Table I. The collected data encompassed demographic characteristics (age, sex), clinical performance status [Eastern Cooperative Oncology Group performance status (ECOG PS)], tumor-related parameters [primary tumor site, clinical T-stage, and clinical N-stage based on the 8th edition of the tumor-node-metastasis (TNM) classification], treatment details (treatment modalities, RT dose, and RT fractions), and follow-up assessments, including treatment response evaluated by positron emission tomography (PET), and hospitalization records related to treatment-related toxicities.
Baseline characteristics of 185 patients with head and neck cancer.
Hemoglobin (Hb), white blood cell count (WBC), serum uric acid (SUA), and albumin levels were measured before and after treatment. The neutrophil-to-lymphocyte ratio (NLR) was calculated by dividing the total neutrophil count (/mm3) by the total lymphocyte count (/mm3). These hematological markers were assessed based on blood tests conducted within 2-3 months prior to treatment and at the first follow-up after treatment. For consistency, pretreatment markers were designated as pre-Hb, pre-WBC, pre-SUA, pre-Albumin, and pre-NLR, while posttreatment markers were referred to as post-Hb, post-WBC, post-SUA, post-Albumin, and post-NLR.
Treatment. In this study, all patients were treated with definitive radiotherapy with or without chemotherapy, as determined through multidisciplinary discussions following clinical guidelines for HNC. The treatment approach aimed to achieve maximum tumor control while minimizing toxicity. Radiotherapy was administered as a definitive treatment in patients with unresectable tumors or those ineligible for surgery due to medical contraindications. Tumor response was evaluated by two independent radiologists, blinded to each other’s results, using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). In cases of conflicting results, consensus was reached.
Follow-up. The follow-up duration was measured from the first day of diagnosis of HNC until death or the last follow-up. The survival endpoints included overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS). OS was defined as the time from the start of treatment to death or patient censoring; DMFS was defined as the time to distant metastasis, death, or patient censoring; and LRFS was defined as the time to local or regional failure, death, or patient censoring. Patients were followed up every 3 to 6 months, with intervals determined based on the predicted prognosis of the primary tumor and the patient’s overall condition (28). The median follow-up time was 63.3 months (range=10.2-181.5 months).
Statistical analysis. Basic descriptive statistics for patient and treatment characteristics are presented as frequencies and percentages, along with mean and ranges. Survival analyses were performed using the Kaplan-Meier method to estimate survival probabilities for OS, LRFS and DMFS. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the prognostic performance of SUA levels in predicting survival outcomes. The area under the ROC curve (AUC) was calculated to assess the discriminatory ability of both pre-treatment and post-treatment SUA levels in predicting OS, LRFS, and DMFS. The optimal cut-off value for post-treatment SUA was determined using the Youden index, which maximizes the sum of sensitivity and specificity. The log-rank test was used to compare survival between groups, including those with low and high post-treatment uric acid levels. Multivariable analysis was conducted using the Cox proportional hazards model to identify independent prognostic factors. All statistical tests were two-sided, with p-values less than 0.05 considered statistically significant. Variables with a p-value <0.1 were included in the multivariable analysis. Statistical analyses were conducted using STATA 18.0 (StataCorp, College Station, TX, USA).
Results
Patient characteristics. A total of 185 eligible patients were included in the final analysis (Table I). The majority were male (80.0%, 148/185), with a smaller proportion being female (20.0%, 37/185). The mean age at diagnosis was 56 years (range=18-80 years). Most patients (96.2%, 178/200) had an ECOG performance status of 0 or 1, with 63.2% (117/185) in status 0, 33.0% (61/185) in status 1, and only 3.8% (7/185) in status 2.
Regarding tumor classification, 57 patients (30.8%) were T2, 44 (23.8%) T4, 43 (23.2%) T3, and 41 (22.2%) T1. Nodal classification revealed that 48.1% (89/185) were N2, 32.4% (60/185) N1, 14.1% (26/185) N0, and 5.4% (10/185) N3. Overall, Stage II (33%, 61/185) was the most common TNM stage, followed by Stage III (31.9%, 59/185), Stage IV (28.6%, 53/185), and Stage I (6.5%, 12/185).
The primary tumor sites were predominantly located in the nasopharynx (n=87), followed by the oropharynx in HPV-positive cases (n=49). Hypopharyngeal tumors were observed in 13 patients. Additionally, 12 patients had HPV-negative oropharyngeal tumors, and 24 patients had laryngeal tumors.
Treatment regimens included 94 patients receiving concurrent chemoradiotherapy (CCRT), 90 undergoing induction chemotherapy combined with CCRT or additional chemotherapy, and one receiving radiotherapy alone. Treatment-related toxicity required hospitalization for 42 patients (22.7%). The standard protocol involved intensity-modulated radiotherapy (IMRT) with a mean dose of 67.5 Gy (55.0-70.0 Gy), delivered over 6-7 weeks in 11-35 fractions.
Survival outcomes. The median follow-up time was 63.3 months (range=10.2-181.5 months). The 3-year and 5-year survival rates of overall survival (OS) were 89.7% [95% confidence interval (CI)=84.4-93.3] and 80.9% (95%CI=74.5-85.9), respectively. The 3-year and 5-year survival rates of locoregional relapse-free survival (LRFS) were 79.2% (95%CI=79.2-89.6) and 77.8% (95%CI=77.8-88.6), respectively. The 3-year and 5-year survival rates of distant metastasis-free survival (DMFS) were 88.8% (95%CI=83.1-92.6) and 87.5% (95%CI=81.6-91.6), respectively.
A total of 43 patients (23.2%) experienced disease progression, predominantly locoregional (17.3%, 32/185), with distant progression in 23 patients (12.4%) and combined progression in 12 patients (6.5%). Progression subsites included the larynx (six cases), hypopharynx (seven cases), lung (nine cases), and 24 cases in other locations such as the neck, liver, and mediastinum. Post-treatment positron emission tomography (PET) analysis revealed a metabolic complete response (mCR) in 57.8% (107/185) and a metabolic partial response (mPR) in 42.2% (78/185).
Prognostic value and discriminatory ability of serum uric acid levels in HNC. The mean uric acid (pre-SUA) was 5.4 mg/dl (2.20-10.40) (Table II). After treatment, post-SUA decreased to 5.2 mg/dl (1.70-11.10), however, the differences were not significant (p=0.326). An SUA level of 4.6 mg/dl in post-SUA was the optimal cut-off, achieving an AUC of 0.636, indicating good discriminator ability for DMFS (Figure 1). However, post-SUA did not significantly predict the outcome of OS or LRFS. Similarly, pre-SUA did not achieve the optimal AUC value to discriminate OS, LRFS, and DMFS. The group with post-treatment SUA <4.6 mg/dl comprised 76 cases, while the group with post-treatment SUA ≥4.6 mg/dl included 109 cases.
Baseline characteristics of lab results in 185 patients with head and neck cancer.
ROC curve analysis of pre-treatment serum uric acid (pre-SUA) and post-treatment SUA (post-SUA) in patients with head and neck cancer. (A-B) ROC curve analysis of pre-SUA and post-SUA for overall survival (OS), and (C-D) for locoregional relapse-free survival (LRFS) and (E-F) for distant metastasis-free survival (DMFS).
Prognostic value of serum uric acid for DMFS. Kaplan-Meier survival curves for DMFS (Figure 2) showed that patients with high post-treatment SUA (≥4.6 mg/dl) had significantly poorer DMFS compared to those with low post-treatment SUA (<4.6 mg/dl). Notably, patients with post-treatment SUA levels below 4.6 mg/dl had significantly better DMFS than those with higher levels (HR=1.25, 95% CI=1.02-1.53; p=0.004). Univariate analysis identified post-treatment SUA level ≥4.6 mg/dl, Stage IV, and hypopharyngeal primary tumor site as adverse predictors of DMFS (Table III). Multivariable analysis confirmed post-treatment SUA ≥4.6 mg/dl (p=0.010; HR=5.01, 95%CI=1.47-17.02), oropharyngeal tumors that are HPV-negative (p=0.025; HR=5.68, 95%CI=1.25-25.85), and Stage IV disease (p=0.020; HR=4.10, 95%CI=1.25-13.48) as independent prognostic factors for DMFS.
Kaplan-Meier survival curves for distant metastasis-free survival in patients with head and neck cancer, stratified by post-serum uric acid (SUA) levels (<4.6 mg/dl vs. ≥4.6 mg/dl).
Univariate and multivariate analysis for risk factors for distant metastasis-free survival of patients.
Discussion
This study evaluated the prognostic significance of serum uric acid (SUA) levels in patients with HNC treated with definitive radiotherapy (RT). Although SUA has been associated with cancer prognosis, its role in HNC remains poorly understood. Our findings provide novel insights by examining the dynamic changes in SUA levels before and after RT and their association with clinical outcomes. Unlike previous studies that focused primarily on nasopharyngeal cancer (24, 25), our study extends the scope to a broader HNC population, emphasizing the importance of post-treatment SUA as a prognostic marker.
A key finding of this study is that pre-treatment SUA (pre-SUA) levels had no significant prognostic impact on OS, LRFS, or DMFS. In contrast, post-treatment SUA (post-SUA) was significantly associated with a higher risk of metastasis. Post-SUA levels were determined using a ROC curve analysis, achieving an AUC of 0.636. This value indicates a moderate discriminatory ability to distinguish between patients with different prognoses. Kaplan-Meier survival analysis further revealed that patients with post-SUA levels ≥4.6 mg/dl exhibited significantly poorer DMFS than those with lower SUA levels. These findings align with previous studies that have implicated hyperuricemia in the progression and metastasis of various cancers (29-32). Elevated SUA levels may reflect heightened systemic oxidative stress and inflammation, both of which are well-recognized contributors to cancer progression (31-33).
Distant metastasis poses a significant clinical challenge in HNC, given its association with poor prognosis and limited therapeutic options. In this study, 23.2% of patients (n=43) experienced disease progression, with distant progression in 23 patients (53.5%) and combined progression in 12 patients (27.9%). This highlights the significant risk posed by metastatic recurrence and underscores the need for reliable biomarkers to predict and monitor this outcome. Our findings suggest that post-treatment SUA levels are significantly associated with DMFS. The identification of SUA as an independent prognostic factor for DMFS further highlights its utility in stratifying patients for closer monitoring or adjunctive therapies post-radiotherapy.
Predictive markers of distant metastasis in HNC patients after RT have traditionally encompassed a wide range of clinical and pathological factors, including advanced T and N stages, primary tumor site (particularly hypopharynx), positive lymph node involvement (especially N3 status), poor tumor differentiation, extranodal extension, inadequate locoregional control and HPV negative status (34-36). While tumor size, site, and nodal involvement provide valuable prognostic information, they require imaging and histopathological evaluation, which may be resource-intensive. In contrast, our study highlights that elevated post-treatment SUA levels are significantly associated with poorer DMFS in patients with HNC undergoing RT. SUA measurement is simple, cost-effective, and widely accessible, making it a practical option for routine clinical use. Given its ease of implementation and prognostic relevance, incorporating SUA into prognostic models could help stratify patients by risk, enabling more personalized treatment and surveillance approaches.
Study limitations. First, it is retrospective in nature, which may introduce selection bias. Second, while SUA levels were evaluated as a prognostic marker, the underlying mechanisms linking SUA to cancer progression remain speculative. Future studies should investigate the molecular pathways involved in SUA-mediated tumor progression. Additionally, the moderate AUC value (0.634) suggests that while SUA is a significant marker, it should be used in conjunction with other clinical and biochemical parameters to improve prognostic accuracy. Further research is needed to validate these findings in larger, prospective cohorts and to explore the integration of SUA with other inflammatory or metabolic markers. Moreover, investigating therapeutic strategies to modulate SUA levels and their impact on patient outcomes may provide novel avenues for improving the prognosis of patients with HNC.
Conclusion
In conclusion, elevated post-treatment SUA levels are significantly associated with poorer DMFS in patients with HNC, underscoring their potential role as a prognostic biomarker. Incorporating SUA into clinical decision-making frameworks may enhance risk stratification and guide personalized treatment approaches. However, further research is warranted to elucidate the mechanisms underlying this association and to confirm these findings in prospective studies.
Footnotes
Authors’ Contributions
Conception and design: Joo Ho Lee, Sangmin Lee, Xue Li; Administrative support: Hong-Gyun Wu, Joo Ho Lee; Provision of study materials or patients: Jih Ho Kim, Keun Young Eom, Hong-Gyun Wu; Collection and assembly of data: All Authors; Data analysis and interpretation: Sangmin Lee, Xue Li; Manuscript writing: All Authors; Final approval of manuscript: All Authors.
Conflicts of Interest
The Authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (Grant Nos. NRF-2021R1A2C1095168 and RS-2023-00218623) and by the SNUH Research Fund (11-2022-5050), funded by Seoul National University Hospital, to Joo Ho Lee.
Artificial Intelligence (AI) Disclosure
During the preparation of this manuscript, a large language model (ChatGPT, OpenAI) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools.
- Received March 31, 2025.
- Revision received April 18, 2025.
- Accepted April 24, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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