Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor originating from the mucosal epithelium of the oral cavity, pharynx, larynx, and other regions of the upper digestive tract (Jiang et al., 2025). With an annual incidence exceeding 600,000 cases worldwide, HNSCC demonstrates significant geographical variations in disease prevalence (Wang and Anderson, 2022). HNSCC remains a major global health concern, with an estimated 946,456 new cases and 482,001 deaths reported annually worldwide (Bray et al., 2024). Despite advancements in diagnostic imaging and multimodal therapies, the 5-year survival rate for HNSCC remains relatively low, with fewer than 50% of patients surviving beyond this period (Ferlay et al., 2019). The incidence is generally higher in males than in females, likely due to higher rates of tobacco and alcohol consumption among men (Jiang et al., 2024). A similar sex-based disparity is observed in mortality rates. The treatment of HNSCC typically requires multidisciplinary comprehensive therapy, including surgery, radiotherapy, and chemotherapy (Cao et al., 2024). These treatment methods not only cause physical suffering to patients but also impose a heavy economic burden. The direct medical costs associated with HNSCC include hospitalization, surgery, chemoradiotherapy, and various diagnostic procedures. Indirect costs arise from productivity loss due to illness and treatment, as well as caregiving-related expenses borne by family members (Haddad et al., 2019). Moreover, the high recurrence rate of HNSCC further increases treatment complexity and economic burden (Umbreit et al., 2016). A deeper understanding of the therapeutic landscape, associated adverse events is therefore essential to guide clinical decision-making and improve outcomes in HNSCC management.

In the treatment landscape of HNSCC, five major systemic agents—cetuximab, pembrolizumab, nivolumab, atezolizumab, and durvalumab—have received clinical approval based on their demonstrated efficacy and safety profiles. These drugs fall into two main therapeutic categories: targeted therapy and immune checkpoint inhibitors. Cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR), has historically played a key role in the EXTREME regimen (cetuximab + platinum + 5-fluorouracil), which was considered the first-line standard of care for recurrent/metastatic (R/M) HNSCC prior to the introduction of immunotherapy (Vasiliadou et al., 2021). The standard cetuximab dosing protocol consists of an initial loading dose of 400 mg/m² followed by 250 mg/m² weekly (Chen et al., 2013). With the advent of immune checkpoint inhibitors, particularly anti-PD-1 antibodies, treatment strategies have evolved significantly. Pembrolizumab, as demonstrated in the KEYNOTE-048 trial, has become a first-line standard for R/M HNSCC either as monotherapy in patients with PD-L1 Combined Positive Score ≥1, or combination with platinum-based chemotherapy in those with more aggressive disease (Fan et al., 2020). The recommended dosage of pembrolizumab is either 200 mg every 3 weeks or 400 mg every 6 weeks (Haas et al., 2023). Nivolumab is approved for patients with R/M HNSCC who experience disease progression on or after platinum-based therapy, typically administered at 240 mg every 2 weeks or 480 mg every 4 weeks (Cohen et al., 2019). Although atezolizumab and durvalumab are not yet standard treatments for HNSCC, they have received regulatory approval in other solid tumors such as non-small cell lung cancer and urothelial carcinoma, and are currently being explored in head and neck cancers through ongoing clinical trials (Sodji et al., 2017). Atezolizumab is typically dosed at 1200 mg every 3 weeks, while durvalumab is administered at 10 mg/kg every 2 weeks (Prelaj et al., 2022). Treatment decisions for HNSCC are influenced by a variety of clinical and demographic factors, including patient age, performance status, comorbidities, and prior treatment history (Klinghammer et al., 2022). Understanding the mechanism of action, approved indications, dosing regimens, and real-world application of these agents is essential for optimizing individualized treatment strategies.

The utilization of real-world data (RWD) and spontaneous reporting systems (SRS) constitutes a validated approach for pharmacovigilance assessment (Jo et al., 2021). Since the 1960s, SRS has served as the cornerstone of pharmacovigilance, enabling early detection of adverse drug reactions and population-level safety evaluation (Srba et al., 2012). The WHO Collaborating Centre for International Drug Monitoring (Uppsala Monitoring Centre) maintains a global adverse drug reactions (ADRs) database critical for comparative drug safety analytics (Shetti et al., 2011). These data repositories play pivotal roles in enhancing HNSCC drug safety profiles and refining therapeutic protocols. Expanded therapeutic applications necessitate intensified safety surveillance.

This study evaluates five FDA-approved anti-HNSCC agents: cetuximab, pembrolizumab, nivolumab, atezolizumab, and durvalumab. These therapeutics demonstrate validated efficacy in advanced/recurrent HNSCC through multicenter clinical trials. However, treatment tolerance diminishes in elderly patients due to tumor progression, physiological decline, and immunosenescence (Song et al., 2024). Age-related pharmacodynamic alterations increase vulnerability to immunotherapy/targeted therapy toxicities, exacerbated by tumor heterogeneity and therapeutic complexity (Su et al., 2023). Geriatric treatment disparities manifest as reduced therapeutic response, amplified adverse effects, and compromised disease management (Schupack et al., 2022). Therapeutic efficacy in advanced disease is constrained by immune evasion mechanisms, tumor microenvironment dynamics, and patient performance status. This necessitates personalized therapeutic regimens tailored to individual patient profiles. We conducted a descriptive analysis of the spontaneously reported adverse events recorded in the VigiAccess database, aiming to compare the differences in adverse reactions associated with the five anti-HNSCC drugs. By analyzing the types and frequencies of adverse events, we sought to identify key safety concerns that may impact drug use, providing valuable insights for future clinical practice.

The global health burden of HNSCC continues to rise, particularly among high-risk groups associated with smoking and alcohol consumption. If left untreated, HNSCC can lead to severe health consequences, including death (Chintala et al., 2022).In recent years, novel immunotherapies and targeted treatments have offered more options for patients, but the potential ADRs of these therapies remain a major challenge in clinical application.his study analyzes data from the WHO-VigiAccess database, with a particular focus on ADRs associated with five promising anti-HNSCC drugs—cetuximab, pembrolizumab, nivolumab, atezolizumab, and durvalumab—highlighting their overall ADR profiles, distribution across different SOCs, and disproportionality in immune-related ADRs.The results show that different drugs exhibit significantly heterogeneous safety profiles due to differences in mechanisms of action and indications, underscoring the need for personalized monitoring strategies. These findings not only reveal the challenges in anti-HNSCC drug therapies but also provide important reference points for clinical practice.

Global ADR data analysis reveals a significant number of ADR reports associated with these five anti-HNSCC drugs, totaling 145,678 reports. In terms of gender distribution, ADRs reported by male patients are dominant, which could be linked to male patients’ treatment needs and pharmacokinetic differences. Studies have shown that male patients often experience more significant treatment responses and ADRs than female patients across many types of cancer, possibly due to differences in hormone levels, immune responses, and drug metabolism (Dai et al., 2025). For example, males generally have a higher drug clearance rate, which may lead to fluctuations in drug concentrations in the body, thereby increasing the risk of ADRs (Venturini et al., 2011). For instance, the activity of certain cytochrome P450 enzymes might be higher in males than in females, accelerating drug metabolism and thereby affecting drug efficacy (Tran et al., 1998). Additionally, smoking and alcohol consumption are major risk factors for HNSCC, with males typically having higher rates of these behaviors than females (Johnson et al., 2020). These lifestyle factors may influence drug metabolism and efficacy, increasing the risk of ADRs.The age distribution shows that the 45–64 age group has the highest proportion of ADRs. Patients in this age group are typically middle-aged and elderly, often with comorbid conditions, and long-term exposure to carcinogenic environmental factors (such as smoking and drinking) further increases their risk of HNSCC. Elderly populations, in particular, are more likely to experience immune-related adverse events when undergoing immune checkpoint inhibitor therapy, which is associated with age-related immune system decline and enhanced autoimmune responses (Wang et al., 2021). Additionally, older patients may experience more drug interactions due to comorbidities or polypharmacy, thereby increasing the risk of ADRs (Yadesa et al., 2021). The immune system ages with increasing age, leading to a decline in immune function, which may affect the efficacy and toxicity of immune checkpoint inhibitors (Baik et al., 2017). Furthermore, geographic distribution data show that the highest ADR reports come from the Americas and Europe. This phenomenon may reflect differences in drug availability, healthcare systems, and pharmacovigilance practices. The disparities in drug accessibility across regions may lead to patients being exposed to different treatment regimens, which can influence ADR reporting. For example, in the Americas and Europe, regulatory systems for drugs are relatively well-established, and pharmacovigilance measures are effectively implemented, resulting in a higher number of ADR reports (Valinciute-Jankauskiene and Kubiliene, 2021). In contrast, in some low-income countries and regions, the limited availability of drugs and insufficient resources may lead to fewer ADR reports, potentially underestimating the actual incidence (Onyije et al., 2024). These geographic differences and patient population characteristics provide a more comprehensive understanding of the safety and tolerability of anti-HNSCC drugs, helping further optimize treatment strategies and pharmacovigilance practices.

The five anti-HNSCC drugs evaluated in this study exhibit distinct safety profiles influenced by their pharmacological mechanisms, treatment settings, and patient characteristics. Cetuximab, as an EGFR inhibitor, has been used for a long time in the treatment of HNSCC (Elmusrati et al., 2021). It can be used alone or in combination with chemotherapy drugs to enhance treatment efficacy, especially for tumors with high EGFR expression (Pirker, 2015). However, despite its good effectiveness in treating HNSCC, Cetuximab’s ADRs related to skin and subcutaneous tissue diseases account for as much as 20.88%, mainly manifested as rash (5.74%), pruritus (2.21%), and acneiform dermatitis (1.87%). Skin toxicities such as rash and mucositis are common treatment-related side effects and typically manifest as rashes on the face, neck, and upper chest, closely related to the pharmacological effects of the drug (Puthenpurail et al., 2021). These ADRs are closely related to the abnormal differentiation of keratinocytes caused by EGFR signaling blockade, reflecting the typical skin toxicity of EGFR inhibitors (Nowaczyk et al., 2023). By inhibiting the EGFR signaling pathway, Cetuximab blocks the proliferation and repair of these cells, leading to skin cell damage and adverse reactions (Parikh et al., 2014). Clinically, preventive use of moisturizers and close monitoring of skin reactions is essential. Pembrolizumab, as a PD-1 inhibitor, blocks the interaction between PD-1 and its ligand PD-L1, restoring T-cell function and enhancing the immune system’s ability to recognize and eliminate cancer cells (Gu et al., 2024). ICIs—including Pembrolizumab, Nivolumab, Atezolizumab, and Durvalumab—achieve anti-tumor effects by enhancing T-cell activity through PD-1/PD-L1 pathway inhibition (Zhong et al., 2020; Tekiki et al., 2021; Schomberg, 2019). In this study, gastrointestinal disorders (GI) emerged as a common category of ADRs across all five drugs. The relatively high prevalence of GI-related ADRs is consistent with known toxicities such as mucositis, diarrhea, colitis, and nausea. For Cetuximab, mucositis and diarrhea may result from EGFR inhibition in the GI epithelium, which impairs mucosal repair and absorption (Hintelmann et al., 2020). For ICIs, colitis and diarrhea are well-documented irAEs resulting from loss of immune tolerance in the intestinal mucosa, likely mediated by T-cell overactivation and cytokine release (Lau et al., 2021). In addition to GI toxicity, Pembrolizumab was linked to elevated risks of surgical and medical complications (RoR: 4.56; PRR: 4.48), possibly due to its impact on wound healing and infection control in the post-surgical setting (Xu et al., 2023). Nivolumab was associated with a significantly increased risk of pregnancy-related disorders (RoR: 3.80; PRR: 3.79), suggesting potential disruption of maternal-fetal immune tolerance via enhanced T-cell activity. Atezolizumab demonstrated a notable risk in the hematologic system, with 5.51% of ADRs affecting blood and lymphatic tissues (RoR: 1.79; PRR: 1.75). This may reflect immune-mediated bone marrow suppression or autoimmunity targeting hematopoietic cells (Falette Puisieux et al., 2022). Immune checkpoint inhibitors may activate autoimmune responses, leading to attacks on normal blood cells, especially when the patient’s immune function is activated, causing immune cells to mistakenly attack normal hematopoietic tissue or blood cells, leading to hematologic adverse reactions (Zhang et al., 2021). Durvalumab, in contrast, showed the highest respiratory system toxicity (18.53%), primarily pneumonia (8.28%) and radiation pneumonitis (2.44%). These effects are likely enhanced by its use in post-chemoradiation consolidation therapy for NSCLC, where radiotherapy exacerbates lung tissue susceptibility. Routine pulmonary evaluation and radiographic monitoring are critical during treatment. Finally, both Pembrolizumab and Nivolumab—commonly used in advanced or refractory HNSCC—showed the highest rates of malignant neoplasm progression reports (Pembrolizumab: 5.83%, Nivolumab: 4.23%). This may reflect the drugs’ widespread use in late-stage disease, where tumor immune escape mechanisms can evolve in response to prolonged immune activation. Immune reprogramming of the tumor microenvironment might enable cancer cells to resist immune surveillance and promote progression or metastasis.

ICIs have demonstrated significant efficacy in the treatment of various malignancies, particularly HNSCC. The occurrence of specific irAEs may be related to the expression patterns of immune checkpoints and the immunological microenvironment in affected organs. For example, PD-1/PD-L1 expression in pulmonary tissue may lead to excessive T-cell activation, resulting in pneumonitis (Ebinama et al., 2023). Similarly, in the gastrointestinal tract, ICIs may disrupt immune tolerance and induce colitis. Endocrine organs are also susceptible, with irAEs manifesting as thyroiditis, hypophysitis, or type 1 diabetes (Takada et al., 2020). Pre-existing immune status may influence the likelihood of irAEs. Elevated levels of autoantibodies or inflammatory cytokines have been associated with increased risk (Basnet et al., 2024). In addition, the gut microbiome plays a crucial role in regulating immune responses. Studies have indicated that specific microbial compositions may be linked to irAE risk. For instance, the presence of certain bacterial strains may enhance immune activation and thereby increase susceptibility to irAEs (Naqash et al., 2021).

Although the overall incidence of SAEs—including mortality, hospitalization, and life-threatening complications—was relatively low across the five agents, their clinical significance should not be underestimated. Each drug exhibited a distinct adverse event profile. Previous studies have suggested that the risk of SAEs may be influenced by cumulative dosage and duration of treatment (Llopis-Salvia et al., 2010). However, there is currently a lack of robust data analyzing the specific causes leading to SAE outcomes. Therefore, it is essential to implement effective monitoring strategies in clinical practice. These include early recognition of symptoms and timely administration of immunosuppressive agents such as corticosteroids when indicated. Furthermore, stratifying patients based on comorbidities, PD-L1 expression, and prior treatment history may help reduce the likelihood of severe complications and improve treatment safety.

This study is limited by the inherent biases of spontaneous reporting systems. First, underreporting may disproportionately affect lower-grade toxicities, potentially underestimating their true incidence. Secondly, the lack of clinical variables such as treatment duration and dosing plan can hinder risk stratification and confuse ADR attribution. To address these limitations, future research should integrate existing adverse reaction reporting systems with hospital electronic medical record systems for analysis, to capture underreported low-level ADRs and clinical confounding factors. Additionally, the pharmacovigilance database lacked consistent data on whether ADRs occurred with monotherapy or combination regimens, limiting the assessment of each drug’s independent safety profile. Importantly, while HNSCC comprises clinically distinct subtypes (e.g., oropharyngeal, hypopharyngeal, laryngeal carcinomas) with potential variations in tumor biology and treatment response, the WHO-VigiAccess database lacks subtype-specific ADR data. Future research should integrate electronic health records and real-world evidence platforms to dynamically track the impact of dosage, treatment duration, and concomitant medications on ADRs, while also exploring the correlation between biomarkers (e.g., PD-L1 expression levels) and toxicity risks. Despite these limitations, new immunotherapies continue to evolve, demonstrating promising prospects. For instance, ongoing research on anti-PD-1 drugs and combination immunotherapies has shown high efficacy and good tolerability in early clinical trial results. While these immunotherapy drugs show broad potential for clinical application, more Phase III clinical trials and long-term safety evaluations are still needed.

This study analyzed ADRs associated with five major anti-HNSCC drugs based on data from the WHO-VigiAccess database, revealing the distinct safety profiles of these drugs in treating HNSCC. Ongoing long-term safety monitoring of these drugs, along with adjustments to clinical practice based on real-world data, will be crucial for the success of future HNSCC treatments.