Radiotherapy-Chemotherapy Combinations in Locally Advanced Head and Neck Squamous Cell Carcinoma

By Yi-Quan Chen¹, Hai-Jun Wu²

Affiliations

1. Graduate School of Xiangya Hospital, Central South University, Hunan, China
2. Department of Radiological Oncology, Xiangya Hospital, Central South University, Hunan, China

doi: 10.29271/jcpsp.2026.03.363

ABSTRACT
This network meta-analysis (NMA) evaluated the efficacy and safety of radiotherapy combined with various therapeutic strategies in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Fourteen randomised controlled trials (RCTs) with over 5,900 patients and a minimum two-year follow-up were included. Primary outcomes were overall survival (OS), progression-free survival (PFS), and grade ≥3 toxicities. Bayesian models were used for data synthesis and sensitivity analysis. Pembrolizumab plus radiotherapy (A_V) showed a trend toward improved OS [OR = 1.7, 95% CrI (credible intervals): 0.55–5.6] and PFS (OR = 1.6, 95% CrI: 0.4–6.2) without statistical significance. Toxicity analysis indicated manageable risks for A_V (OR = 0.13, 95% CrI: 0.0095–1.6), while radiotherapy with cisplatin and immunotherapy (A_I_V) showed higher toxicity (OR = 3.3, 95% CrI: 0.45–24). This study highlights the need to optimise radiotherapy strategies, refine combination therapies, and identify predictive biomarkers, providing key insights for personalised treatment approaches in LA-HNSCC.

Key Words: Locally advanced head and neck squamous cell carcinoma, Network meta-analysis, Radiotherapy, Pembrolizumab, Overall survival, Progression-free survival, Cisplatin, Toxicity, Immunotherapy, Bayesian analysis.

INTRODUCTION

Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) remains a significant clinical challenge due to its high incidence and mortality rates. Despite advances in treatment strategies, achieving optimal therapeutic outcomes remains difficult, largely owing to the complex tumour biology, variability in treatment responses, and intricate interactions between the tumour and its microenvironment.¹ Radiotherapy (RT) has long been established as the cornerstone of LA-HNSCC treatment and is frequently combined with chemo-therapy, immunotherapy, or targeted therapies to enhance efficacy. Among these, cisplatin-based concurrent chemo- radiotherapy (CRT) is widely regarded as the standard treatment, demonstrating substantial benefits in improving overall survival (OS) and progression-free survival (PFS).^2-4 However, the incorporation of novel therapeutic modalities such as immune checkpoint inhibitors (ICIs) and targeted therapies into radiotherapy, although showing promise in enhancing therapeutic effects, still requires further investigation regarding their efficacy and safety.⁵

Meta-analyses have played a pivotal role in defining current treatment standards for LA-HNSCC. The Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) con-firmed the survival benefits of adding concurrent chemo-therapy, particularly platinum-based regimens, to radiotherapy.^3,4 Similarly, the Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck (MARCH) demonstrated that altered fractionation radiotherapy, especially hyperfractionation, improved survival compared to conventional fractionation.⁶ While these analyses have provided crucial insights into traditional treatment approaches, the role of emerging therapeutic strategies and their integration with radiotherapy requires further exploration.

The advent of ICIs, such as pembrolizumab, has introduced a novel paradigm in the treatment of LA-HNSCC.⁷ These agents modulate the tumour immune microenvironment and have shown efficacy in a subset of patients, particularly when combined with radiotherapy.⁸ Furthermore, despite differences in cancer types, targeted therapies such as bevacizumab have shown potential to enhance the immunomodulatory effects of radiotherapy and ICIs by promoting tumour vascular normalisation.⁹ However, comprehensive evidence comparing the relative efficacy and safety of these combination strategies remains lacking. Additionally, variations in radiotherapy dose and target delineation may significantly influence treatment outcomes, particularly OS, PFS, and toxicity.¹⁰

Given the evolving landscape of LA-HNSCC treatment, network meta-analysis (NMA) offers a robust framework for synthesising existing evidence and comparing multiple treatment modalities. Unlike traditional pairwise meta-analyses, NMA enables simultaneous evaluation of various interventions by integrating direct and indirect evidence. This study aimed to conduct a comprehensive NMA to assess the impact of radiotherapy combined with different medicines and dose variations on OS, PFS, and ≥ grade 3 toxicities in patients with LA-HNSCC. By incorporating a larger trial network and extended follow-up durations, this study provides novel insights into the comparative efficacy and safety of contemporary and emerging therapeutic strategies. It underscores the importance of optimising treatment paradigms to enhance outcomes for this challenging patient population. Notably, this study included data from 14 trials, further strengthening the robustness of the analysis.

METHODOLOGY

This study was designed, conducted, and reported in strict accordance with the preferred reporting items for systematic reviews and meta-analyses incorporating network meta-analyses (PRISMA-NMA) guidelines to ensure transparency and scientific rigor. The literature screening process is presented in the PRISMA flow diagram, which outlines each screening stage and reasons for exclusion. The flow diagram is included in the supplementary materials for readers’ reference (Figure 1). This study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO; Registration No. CRD42024613701) and received approval on November 24, 2024. The study was conducted from November 24, 2024 to January 3, 2025.

Inclusion criteria were randomised controlled trials (RCTs) conducted in patients diagnosed with LA-HNSCC, staged according to the contemporary or latest version of the AJCC cancer staging manual. Eligible interventions included radiotherapy combined with chemotherapy, immunotherapy, or targeted therapy, as well as comparisons of different radiotherapy dose regimens. Studies were required to report OS and PFS outcomes, with a minimum follow-up duration of two years to ensure the reliability of long-term efficacy outcomes. Only English-language publications were included to mitigate language bias. Exclusion criteria were non-randomised studies (e.g., retrospective or observational studies), an insufficient sample size (n <10) that would preclude effective statistical analysis, incomplete or missing primary outcomes data (OS, PFS, or toxicity), and duplicate publications, for which only the latest or most compre-hensive version was retained.

A total of 14 RCTs were included, evaluating the efficacy and safety of radiotherapy combined with chemotherapy, immunotherapy, targeted therapy, or varying dose regimens in LA-HNSCC patients. These trials collectively involved over 5,900 patients, with an average follow-up duration of 36 months (Table I).^11-23 Detailed characteristics of the included studies, including author, year, sample size, interventions, and primary outcomes, are presented in Table II and III.

Data extraction was conducted independently by two researchers using standardised PRISMA data extraction forms. Extracted data included publication year, sample size, and interventions—including treatment regimens, radiotherapy doses, and combined therapy strategies. Patient characteristics included age, gender, cancer staging, and other baseline information. Primary outcomes included OS, PFS, and frequency of grade ≥3 toxicities. Any discrepancies between the two researchers were resolved through discussion, and unresolved issues were adjudicated by a third reviewer (Figure 3 and 4). The quality of the included studies was assessed using the Cochrane risk of bias tool. The assessed dimensions included randomisation methods, allocation concealment, blinding, completeness of data, and outcome reporting bias. The results of the quality assessment are visually presented using risk-of-bias graphs and traffic light plots to ensure the reliability and trans-parency of the study (Figure 5E, F).

Data analysis was conducted using R software (version 4.4.2) with the gemtc and rjags packages to build a Bayesian NMA model.²⁴ The model assumed that effect sizes followed a normal distribution. The analysis used a burn-in period of 10,000 iterations, followed by 50,000 iterations across four independent Markov chains, with an identity link function. Effect sizes were expressed as odds ratios (ORs) with corresponding 95% credible intervals (CrIs). Treatment efficacy was ranked using the Surface Under the Cumulative Ranking Curve (SUCRA) and presented in treatment rankings. Both fixed-effect and random-effect models were employed for sensitivity testing to ensure the robustness of results. Convergence of the Bayesian model was assessed using trace plots, while density plots and forest plots were generated to visualise comparisons of treatment regimens (Figure 2).

Different versions of the AJCC staging system were analysed in relation to OS, PFS, and toxicity. Forest plots and bubble maps were generated using Bayesian models. OS was used to assess the impact of each treatment on patient survival. PFS evaluated the ability of treatments to control disease progression. To specifically evaluate the incidence of grade ≥3 adverse events, balancing efficacy and safety was employed.

No funnel plots were generated for this study, as funnel plots are primarily used to evaluate publication bias in traditional meta-analysis. In NMA, comprehensive assessments of potential biases were conducted using risk-of-bias tools and model diagnostics, making a funnel plot unnecessary.

Table I: Included research and basic characteristics.

Author	Year	Study design	Sample size (n)	Age	Male/Female	AJCC stage	Radiotherapy dose	N -L ratio	Overall stage
Machiels et al.11	2024	RCT	804	58 (NA)	660/144	8th edition AJCC	70 Gy (IQR 70–70)	NA	III/IV
Tao et al.12	2023	RCT	133	65 (47 - 81)	112/21	7th edition AJCC	69.96 Gy	NA	III/IV
Sharma et al.13	2022	RCT	286	56 (19 - 70)	256/30	8th edition AJCC	NA	NA	III/IV
Rastogi et al.14	2019	RCT	322	52 (30 - 77)	292/30	6th edition AJCC	70 Gray	NA	III/IV
Noronha et al.15	2018	RCT	300	44 (25 - 67)	267/33	7th edition AJCC	70 Gy (66-70 Gy)	2.04-5	III/IV
Hassan Metwally et al.16	2015	RCT	82	56 (28 - 75)	52/30	7th edition AJCC	70 Gy (66-70 Gy)	NA	III/IV (87%)
Bourhis et al.17	2012	RCT	840	56 (34 - 74)	731/109	6th edition AJCC	70 Gy /64.8 Gy	NA	III/IV
Zackrisson et al.18	2011	RCT	733	62 (26 - 91)	548/185	2nd edition AJCC	68 Gy	NA	III/IV (83%)
Sharma et al.19	2010	RCT	153	54 (14 - 70)	137/16	5th edition AJCC	70 Gy	NA	III/IV (94%)
Ruo Redda et al.20	2010	RCT	157	60 (39 - 70)	129/16	4th edition AJCC	70 Gy	NA	III/IV
Bonner et al.21	2006	RCT	424	58 (34 - 83)	340/84	5th edition AJCC	70.0 Gy/72.0 Gy	NA	III/IV
Bourhis et al.22	2004	RCT	266	<75	NA	5th edition AJCC	70 Gy/62 - 64 Gy	NA	III/IV
Fu et al.23	2000	RCT	1,073	60 (30 - 86)	854/219	3rd edition AJCC	70 Gy/81.6 Gy/67.2 Gy/72 Gy	NA	III/IV (96.9%)

Table II: ID of each treatment plan.

ID	Description
A	Radiotherapy alone (A)
A_V	Pembrolizumab + RT
A_F	Cetuximab + radiotherapy
A_I	Weekly cisplatin + RT
P	Accelerated radiotherapy
A_O_U	Conventional chemoradiotherapy (CRT)
P_O_U	Accelerated CRT
A_O	Carboplatin + radiotherapy
P_B_S	Accelerated fractionation with boost
P_S	Accelerated fractionation - split
A_I_2	3-Weekly cisplatin + RT
A_I_V	Pembrolizumab + weekly cisplatin + RT
P_I	Weekly cisplatin + accelerated fractionated radiotherapy
P_N_M	Nimorazole + accelerated RT

Table III: Treatment options included in each study.

Study	Treatment
Machiels et al.11 2024, 8th edition AJCC	A_I_V
Machiels et al.11 2024, 8th edition AJCC	A_I_2
Tao et al.12 2023, 7th edition AJCC	A_V
Tao et al.12 2023, 7th edition AJCC	A_F
Sharma et al.13 2022, 8th edition AJCC	A_I
Sharma et al.13 2022, 8th edition AJCC	A_I_2
Rastogi et al.14 2019, 6th edition AJCC	P_I
Rastogi et al.14 2019, 6th edition AJCC	A_I
Noronha et al.15 2018, 7th edition	A_I
Noronha et al.15 2018, 7th edition	A_I_2
Hassan Metwally et al.16 2015, 7th edition AJCC	P_N_M
Hassan Metwally et al.16 2015, 7th edition AJCC	P
Bourhis et al.17 2012, 6th edition AJCC	A_O_U
Bourhis et al.17 2012, 6th edition AJCC	P_O_U
Bourhis et al.17 2012, 6th edition AJCC	P
Zackrisson et al.18 2011, 2nd edition AJCC	A
Zackrisson et al.18 2011, 2nd edition AJCC	P
Sharma et al.19 2010, 5th edition AJCC	A
Sharma et al.19 2010, 5th edition AJCC	A_I
Ruo Redda et al.20 2010, 4th edition AJCC	A
Ruo Redda et al.20 2010, 4th edition AJCC	A_O
Bonner et al.21 2006, 5th edition AJCC	A_F
Bonner et al.21 2006, 5th edition AJCC	A
Bourhis et al.22 2004, 5th edition AJCC	A
Bourhis et al.22 2004, 5th edition AJCC	P
Fu et al.23 2000, 3rd edition AJCC	A
Fu et al.23 2000, 3rd edition AJCC	P
Fu et al.23 2000, 3rd edition AJCC	P_B_S
Fu et al.23 2000, 3rd edition AJCC	P_S

RESULTS

In the NMA of patients with LA-HNSCC, pembrolizumab plus radiotherapy (A_V) did not significantly differ from conventional cisplatin-based chemoradiotherapy in OS (Figure 3A). In contrast, compared to radiotherapy alone (A), A_V showed a numerical trend toward improved OS, although this difference was not statistically significant (OR = 1.7,95% CrI: 0.55–5.6; Figure 3C). While the trend was favourable, the wide CrI crossing 1 indicated uncertainty in the results. Furthermore, the limited number of direct comparisons involving pembrolizumab contributed to the reliance on indirect evidence, which may have further affected the robustness of the findings. Overall, the analysis revealed that combination therapies, such as radiotherapy combined with targeted therapy or chemotherapy, generally outperformed radiotherapy alone (A) or accelerated radiotherapy (P) in OS improvement (Figure 3, Figure 6E). For instance, cetuximab combined with radiotherapy (A_F) showed an OR of 1.4 (95% CrI: 0.68–2.9) compared to radiotherapy alone, suggesting a trend toward improvement, although statistical significance was not achieved (Figure 3B). Similarly, P_N_M (a specific combination regimen) compared to accelerated radiotherapy (P) demonstrated a stronger trend with an OR of 2.5 (95% CrI: 0.85–7.5); however, the wide CrI indicates the need for further validation (Figure 3, Figure 6E). The lack of significant results with A_V may be due to lymph nodes destruction caused by radiotherapy when combined with immunotherapy.

Figure 1: Screening flowchart for RCTs.

Figure 2: Trajectory density map.

Figure 3: OS analysis: network diagram and forest plot.
Figure 4: PFS analysis: network diagram and forest plot.

Correspondingly,²⁵ the AJCC bubble chart can be analysed, and forest plots were generated according to stage and subgroup to extract key information (Figure 6F, G). Head and neck radiotherapy typically involves coverage of the primary tumour and regional lymph nodes. However, the precise target volume design may inadvertently damage key lymph nodes, which play a critical role in tumour immune responses. This damage could diminish the activation of the immune system by pembrolizumab, thereby reducing the effectiveness of immunotherapy. This hypothesis underscores the importance of radiotherapy target volume design in enhancing the synergistic effects of immunotherapy. Future research should prioritise optimising target delineation strategies to minimise interference with immune responses. Heterogeneity analysis revealed a low I² value of 1.2 for pembrolizumab-related studies, indicating minimal heterogeneity and consistent results across studies. However, due to the limited number of direct comparisons and the heavy reliance on indirect evidence, future high-quality RCTs are required to improve the robustness of the evidence. These trials should focus on elucidating the synergistic mechanisms of radiotherapy and immunotherapy while optimising treatment strategies, particularly in lymph node preservation and target volume design.

In the treatment of LA-HNSCC, radiotherapy combined with weekly cisplatin (A_I) is widely recognised as the standard of care.²⁶ In this NMA, an indirect comparison of A_I and A_V showed an OR of 1.5 (95% CrI: 0.26–8; Figure 4C). While A_V demonstrated a slight advantage in trend, the CrI crossing 1 suggested comparable efficacy between the two regimens in improving PFS (Figure 4). From the Surface Under the Cumulative Ranking (SUCRA) curve analysis, the SUCRA values of A_I and A_V were close, with A_V slightly higher, indicating a potential therapeutic edge for A_V (Figure 6H). This may be attributed to the synergistic effects of pembrolizumab, as an ICI, with radiotherapy, which could yield more pronounced benefits in certain patient subgroups. However, A_I’s well-established long-term efficacy, supported by extensive clinical studies, provides stable reference values across different stages and patient characteristics. Consistency analysis indicated no significant heterogeneity between A_I and A_V, with an I² value close to 0%, suggesting high reliability of the results. In the subgroup analysis by the AJCC staging editions, A_V showed a more favourable trend in patients classified under the 8th edition staging system, while the therapeutic difference between the two regimens was minimal in earlier staging systems (e.g., 3^rd edition; Figure 6Y-J). This finding reflects a potential efficacy advantage of pembrolizumab in patients with precise staging.

Figure 5: Forest plot of toxicity analysis, article traffic, and risk bias map. Figure 6: Sorting diagrams of OS, PFS, and toxicity, as well as bubble charts and scatter plots of AJCC staging.

Toxicity is a critical factor for evaluating the feasibility of treatment strategies for LA-HNSCC. This NMA systematically assessed the risk of grade 3 or higher adverse events associated with various treatment regimens, providing important insights for clinical decision-making. As the current standard treatment, A_I demonstrated stable toxicity risks in this analysis (Figure 5, 6K). No significant deviations in toxicity risks were observed, further reinforcing its role as a benchmark regimen. The toxicity of immunotherapy combined with radiotherapy is relatively weak. Although there is no significant difference, it still deserves attention (Figure 5). Compared to A_I, A_V did not show a significant increase in toxicity risk (OR = 0.13, 95% CrI: 0.0095–1.6; Figure 5A). While the data suggested a lower toxicity trend, the wide CrI reflects the limitations of the current sample size. It is worth noting that while immunotherapy modulates the tumour microenvironment, it may also induce immune-related adverse events, which warrants further validation of its clinical safety in future studies.

Toxicity analysis of radiotherapy combined with cisplatin and immunotherapy (A_I_V), as an intensified strategy, showed a toxicity risk of OR = 26 (95% CrI: 1.0–6.7e+02; Figure 5B). Although the wide CrI indicates uncertainty, the data suggest that the toxicity risk was not significantly higher than that of standard treatment. This implies that A_I_V may provide stronger therapeutic effects while maintaining manageable toxicity, offering potential support for optimising treatment strategies (Figure 5, 6K).

Subgroup analysis and SUCRA values revealed the distribution of toxicity across different AJCC staging editions and treatment combinations. Studies focusing on the 5^th and 6^th AJCC editions highlighted the complexity of radiotherapy dose, chemotherapy intensity, and immunotherapy combinations (Figure 6L-M). However, no significant heterogeneity was observed in grade 3 or higher adverse events, indicating that combined regimens hold potential to balance enhanced treatment intensity with manageable toxicity.

Trace plots and density plots demonstrated the stability and convergence of Bayesian models in toxicity risk analysis, further strengthening the reliability of the results. However, given the current limitations in sample size and toxicity data, particularly concerning long-term effects in immuno-therapy combination regimens, future high-quality RCTs are needed to validate these findings. These trials should focus on long-term safety profiles and the balance between efficacy and toxicity to inform clinical decision-making.

DISCUSSION

As the first NMA to systematically evaluate the efficacy and safety of different treatment regimens in patients with LA-HNSCC, this study provides a novel perspective on the therapeutic landscape. It delineates differences in efficacy among treatment regimens in precisely staged patients and highlights the importance of optimising radiotherapy target volumes and identifying predictive biomarkers.

The analysis revealed that A_V showed potential benefits in improving OS and PFS, although the results did not reach statistical significance (OS: OR = 1.7, 95% CrI: 0.55–5.6; PFS: OR = 1.1, 95% CrI: 0.38–3.1). Toxicity analysed that both A_V and A_I_V demonstrated manageable toxicity profiles (A_V: OR = 0.13, 95% CrI: 0.0095–1.6; A_I_V: OR = 3.3, 95% CrI: 0.45–24).

Radiotherapy, with its extensive target volume covering the primary tumour and regional lymph nodes, can result in significant damage to normal lymph nodes. This damage may reduce the number of effector T cells and regulatory lymphocytes, thereby impairing the immune system’s ability to recognise and respond to tumour antigens.²⁵ Such lymph node damage not only limits the synergistic effects of immunotherapy but may also impede the occurrence of the abscopal effect, a phenomenon where localised radiotherapy induces systemic antitumour immune responses.²⁷ Optimising radiotherapy target volumes to minimise damage to normal lymph nodes and preserve the function of critical immune nodes could significantly enhance the overall efficacy of immunotherapy.

An elevated NLR, characterised by an increase in neutrophil counts and a decrease in lymphocyte counts, is widely associated with poor tumour prognosis. Studies have shown that neutrophils suppress lymphocyte function through the secretion of immunosuppressive factors, such as IL-10 and TGF-β, and the promotion of tumour invasion.²⁸ Moreover, as a dynamic biomarker, NLR reflects patients’ immune status and can be utilised to identify high-risk individuals and optimise treatment strategies.

Although the results did not achieve statistical significance, this study underscores the critical roles of radiotherapy target design and NLR levels in determining the efficacy of immunotherapy. Future research should focus on employing advanced imaging technologies to refine radiotherapy target delineation, minimising damage to normal lymph nodes, and enhancing the synergistic effects of immunotherapy. Strategies targeting NLR modulation, such as enhancing lymphocyte function or inhibiting neutrophil activity, warrant further exploration. Personalised treatment optimisation would require leveraging molecular characteristic expression and HPV status to develop individualised combination treatment approaches.

TME remodelling and its relationship with immunotherapy induce the release of pro-inflammatory molecules (e.g., type I interferons, IFN-I) and enhance immune cell infiltration, significantly improving TME sensitivity to immunotherapy.⁸ By promoting tumour antigen release and neoantigen expression, RT elevates tumour immunogenicity and creates a favourable environment for immunotherapy.²⁹

RT significantly enhances T-cell receptor (TCR) diversity and promotes clonal expansion of tumour-infiltrating lymphocytes (TILs), promoting both local expansion and peripheral migration of tumour-specific T cells. RT activates the cGAS/STING signalling pathway, which helps sustain the stem-like state of exhausted T cells (Tex). In combination with ICIs (e.g., PD-1 inhibitors), RT further reactivates Tex cells, restoring their antitumour immune functions.³⁰

RT induces metabolic reprogramming by reducing fatty acid oxidation in T cells (Tregs) while enhancing glycolysis in effector T cells, thereby further boosting their antitumour capacity. Additionally, RT-generated reactive oxygen species (ROS) directly activate effector T cells and induce Treg apoptosis, reducing their immunosuppressive effects.⁸ Tumour- associated macrophages are important; RT promotes M1 macrophage polarisation while suppressing Mes, thereby improving the antitumour immune environment. RT reduces myeloid-derived suppressor cell (MDSC) levels in the early stages of treatment, although a potential late-stage rebound effect warrants ​further investigation.³¹

The A_I regimen, widely regarded as the standard treatment for LA-HNSCC, has demonstrated stable efficacy improvement and manageable toxicity in numerous studies, consistent with the findings of this study.³² However, this study further highlights the potential benefits of the A_V regimen in precisely staged patients (e.g., those classified using the 8^th Edition AJCC staging system), emphasising the importance of precise staging in optimising treatment strategies.

Despite the optimism surrounding A_V in the literature, this study found that the regimen did not achieve statistical significance.³³ Possible reasons include broad target coverage that may damage normal lymph nodes, impairing the synergistic effects of immunotherapy.²⁵ Variations in immune microenvironment factors, such as PD-L1 expression and HPV status, may significantly impact treatment outcomes.

Future studies with refined target volume design and patient stratification are required to more accurately evaluate the clinical benefits of A_V. Abscopal effect volume optimisation is a limiting factor; therefore, future studies should explore strategies to activate the abscopal effect by optimising radiotherapy target volumes, reducing lymph node radiation damage, and enhancing immunotherapy synergy.

The potential of a triple regimen (RT + bevacizumab + pembrolizumab) warrants investigation through large-scale RCTs to evaluate improvements in OS and PFS.^34,35 Future RCTs should incorporate stratified randomisation based on HPV status, PD-L1 expression, and NLR dynamics to comprehensively assess the efficacy and safety of combination therapies. Further research should focus on identifying and validating predictive biomarkers (e.g., PD-L1, VEGF, and NLR) and developing strategies to modulate NLR to optimise therapeutic outcomes.

CONCLUSION

This NMA revealed that A_V demonstrated a potential trend toward improving OS and PFS, although statistical significance was not achieved. Nevertheless, these findings suggest that this treatment regimen may hold clinical value for specific patient subgroups. Toxicity analysis indicated that the risks associated with A_V and A_I_V were relatively manageable, providing an important foundation for further optimisation of combination therapy strategies.

Future research should focus on refining radiotherapy target volume design, developing combination therapy strategies, and identifying predictive biomarkers to achieve more precise and personalised treatment approaches. Such efforts have the potential to further improve survival outcomes and prognosis for patients with LA-HNSCC. This study provides essential theoretical support and practical direction for exploring the integration of radiotherapy and immunotherapy.

COMPETING INTEREST:
The authors declared no conflict of interest.

AUTHORS’ CONTRIBUTION:
YQC: Conceptualisation, data curation, formal analysis, and writing of the original draft.
HJW: Supervision, methodology, validation, writing, review, and editing.
Both authors approved the final version of the manuscript to be published.

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