Colorectal cancer (CRC) remains one of the most common malignancies worldwide. According to the most recent global cancer statistics from GLOBOCAN 2022, there were approximately 1.9 million new CRC cases and 0.9 million CRC-related deaths globally, making CRC the third most frequently diagnosed cancer and the second leading cause of cancer death worldwide. By 2040, global CRC cases are projected to increase further, potentially exceeding 3.2 million new cases annually (1). Historically, the identification of CRC has relied heavily on histopathological analysis (2), while the main clinical symptoms include alterations in bowel patterns, abdominal pain, and rectal hemorrhage (3). Notably, 20% of patients present with metastatic disease at the time of their initial diagnosis. Recently, significant advancements have been made in improving the prognosis for metastatic colorectal cancer (mCRC), largely due to the introduction of new molecular targeted therapies. Notably, agents targeting epidermal growth factor receptor (EGFR) have demonstrated considerable clinical efficacy (4). Elevated levels of EGFR are observed in various epithelial tumors, including those of the prostate, breast, head and neck, as well as gastrointestinal cancers (4–7). In CRC, the expression of EGFR is significantly higher than that in normal colorectal mucosa (8, 9). In 2004, the U.S. Food and Drug Administration approved cetuximab, an IgG1 monoclonal antibody that specifically targets EGFR, for the treatment of CRC.

Cetuximab is a chimeric monoclonal antibody composed of both human and murine components that competitively binds to the extracellular domain of EGFR (10). This binding inhibits dimerization, thereby disrupting intracellular signaling pathways. Consequently, several effects occur, including the inhibition of cancer cell proliferation, enhancement of apoptosis, and reduction in the production of matrix metalloproteinases (11). In recent years, significant advancements have been made in the management of mCRC through the use of cetuximab in conjunction with chemotherapy (12). Moreover, research has explored the use of cetuximab in treating various malignant tumors, including breast cancer, pancreatic cancer, head and neck squamous cell carcinoma (13), and esophageal squamous cell carcinoma (14). Consequently, the widespread application of cetuximab underscores the necessity of understanding its associated adverse effects, which may include mucosal inflammation, rash, myelosuppression, gastrointestinal issues (such as nausea, vomiting, diarrhea, and constipation), and interstitial pneumonia (15–17). While clinical studies (18) have indicated that skin reactions are the most common adverse effects, there remains a significant lack of comprehensive real-world research to thoroughly evaluate the cutaneous safety profile of cetuximab.

The FDA Adverse Event Reporting System (FAERS) and VigiAccess are two primary databases for spontaneous reporting, providing essential real-world evidence for pharmacovigilance in the post-marketing phase (19). Managed by the U.S. Food and Drug Administration, FAERS plays a critical role in identifying safety signals related to adverse events (AEs) associated with approved pharmaceuticals and biological products (20). VigiAccess, developed and maintained by the Uppsala Monitoring Centre on behalf of the World Health Organization (WHO), serves as a global database for suspected adverse drug reactions, facilitating the timely identification of safety issues across diverse populations and therapeutic contexts (21, 22). As cetuximab becomes more widely used in clinical settings, it is essential to comprehend its adverse effect profile in detail, especially regarding cutaneous toxicity, to improve patient safety and guide treatment approaches. This study employs two reputable datasets, FAERS and VigiAccess, to assess the potential for cutaneous adverse events linked to cetuximab, with the goal of enhancing its safety profile and offering evidence-based recommendations for healthcare providers and policymakers in the management of these occurrences.

At present, there is a notable lack of research centered on pharmacovigilance regarding skin AEs related to cetuximab. This study is, to our knowledge, the first in-depth evaluation of skin toxicity linked to cetuximab in a real-world context, leveraging data sourced from the FAERS and VigiAccess databases. Through performing disproportionality analyses across two distinct international reporting systems, we identified strong and consistent safety signals for multiple skin-related PTs, including rash, nail fold inflammation, and acneiform dermatitis. Furthermore, our subgroup analysis indicated that these AEs primarily impact older adults (those over 45 years) and males, highlighting the importance of prompt clinical monitoring. These findings offer fresh insights into the specific skin safety profile of cetuximab and bear significant consequences for pharmacovigilance practices and strategies for managing clinical risks.

It has been noted that there is a positive correlation between the severity of rash and the effectiveness of its treatment (25). Regulatory authorities in North America and Europe have granted approval for cetuximab for the treatment of advanced CRC (12) and head and neck squamous cell carcinoma (26). Nevertheless, the prevalence of these dermatological effects has not been comprehensively assessed in post-marketing surveillance. This research seeks to fill this void by investigating the association between cetuximab and skin AEs through data obtained from two large pharmacovigilance databases. Our findings highlight the importance of establishing routine skin monitoring in the clinical management of patients receiving cetuximab.

Table 1 illustrates that AEs from cetuximab were reported more frequently in male patients (59.13% in FAERS; 62.56% in VigiAccess) compared to female patients (27.18% in FAERS; 30.81% in VigiAccess). This disparity between sexes may be associated with the higher incidence and mortality rates observed in males diagnosed with CRC (27), leading to increased exposure to cetuximab within this demographic.

Our analysis of the FAERS and VigiAccess databases indicates a notable correlation between cetuximab and a range of inflammatory skin reactions, such as acneiform dermatitis, erythema, and dermatitis. In addition, we identified robust disproportionality signals for less frequently reported conditions like exfoliative dermatitis, seborrheic dermatitis, and allergic dermatitis. Moreover, both databases show that rashes are the most common issues impacting the skin and subcutaneous tissues. These research results align with those from a prior multicenter investigation into cetuximab’s efficacy and toxicity for treating head and neck squamous cell carcinoma (HNSCC), which found that skin rash occurred as the most commonly reported adverse event linked to this therapy, with an incidence of 49% (28). Although skin and subcutaneous tissue disorders were the most commonly reported adverse effects, only a small fraction of patients needed adjustments to their dosages because of serious symptoms. Nevertheless, even mild to moderate skin issues can lead to ongoing itching, worsening of the skin, or a higher likelihood of infections, which can greatly affect the quality of life for patients (29). Expert recommendations suggest that diffuse rashes or worsened acneiform dermatitis might indicate significant mucocutaneous inflammatory reactions. This highlights the importance of careful monitoring for possible secondary infections or scarring. Patients should be encouraged to avoid scratching the affected regions, steer clear of irritating skincare products, and quickly communicate any new or deteriorating skin issues (30). These findings underscore the vital necessity of diligently observing the dermatological condition of patients, commencing early interventions, and delivering focused health education during the entire course of cetuximab treatment.

Skin and subcutaneous tissue disorders linked to cetuximab might occur due to the disturbance of signaling in the EGFR pathway. Such disturbances can lead to various effects, which manifest as the typical clinical symptoms of skin toxicity caused by EGFR inhibitors. The EGFR is essential for the proper differentiation and development of epidermal keratinocytes, as it aids in epidermal growth, hinders differentiation, offers protection from ultraviolet (UV) radiation damage, lessens inflammation, and supports wound healing (31, 32). A study employing immunohistochemistry in the context of pharmacological inhibition of EGFR has demonstrated notable changes in the expression of crucial markers within the skin. The inhibition of EGFR resulted in the removal of cells that showed phosphorylated EGFR, along with diminished MAPK expression levels (33, 34). This modification subsequently impacted the behavior of keratinocytes, affecting aspects such as proliferation, differentiation, migration, and adhesion. This led to a range of skin responses, including rash, erythema, and dryness. Up until now, the majority of investigations into the mechanisms that drive acneiform eruptions triggered by EGFR inhibitors have primarily focused on their influence on keratinocyte proliferation and differentiation, ultimately leading to secondary inflammation. Nevertheless, a recent study shows that therapies aimed at targeting EGFR may have a more immediate effect on the immune response by reducing the inhibition of skin chemokine production, thereby promoting the chemotaxis and infiltration of leukocytes into the skin. This indicates that the role of skin EGFR is associated with the inhibition of chemokine synthesis (35). In summary, these findings support a biologically plausible mechanism underlying the cutaneous adverse effects associated with cetuximab, driven by interference in EGFR pathway signaling.

Given the important function of EGFR signaling in the skin, the considerable physical and psychological distress that may occur could require modifications in the dosage of anticancer drugs or possibly their cessation. We suggest that active skin monitoring be included in the clinical protocols for patients receiving treatment with cetuximab. Specialists from Italy concur that a team-based management strategy can alleviate skin-related toxicities, lower the incidence of severe symptoms, boost patient compliance, avert changes in prescribed treatments (such as radiotherapy and/or EGFR inhibitors), and ultimately enhance overall results (36). A proactive and cooperative approach to preventing and managing skin toxicity can greatly decrease the occurrence of serious symptoms, improve patient comfort during treatments, enhance the overall quality of life, and optimize the therapeutic advantages of EGFR-targeted monoclonal antibodies by reducing the necessity for dosage adjustments or early termination of therapy. Additionally, specifically trained nursing personnel can proficiently handle minor skin reactions. As a result, in the consensus guidelines focused on managing skin toxicity due to radiation in head and neck cancer, the involvement of nurses is vital for situations identified as low-grade (37). Recent studies have highlighted the potential of topical vitamin K3 (menadione) in inhibiting EGFR phosphatase, thereby restoring disrupted EGFR-mediated signaling in the skin following systemic administration of the EGFR inhibitor cetuximab (38). Although additional rigorously designed prospective research is necessary to confirm best practices, instruments like this algorithm can assist healthcare providers and inform patients, thereby improving the efficacy of cetuximab treatment. With the growing application of these drugs in early-stage and adjuvant therapy contexts, developing evidence-backed methods to manage cutaneous toxicity will become ever more important.

Despite the strengths of this study, several limitations inherent to spontaneous reporting systems should be acknowledged. First, both FAERS and VigiAccess lack reliable denominator data, such as the total number of patients exposed to cetuximab, which precludes the estimation of true incidence rates or absolute risks. Second, underreporting and reporting bias are well-recognized issues in pharmacovigilance databases, particularly for mild or transient adverse events, which may lead to an underestimation of the overall burden or an overrepresentation of well-known or expected reactions. Third, although FAERS provides outcome-related information (e.g., hospitalization, life-threatening events, or death), neither FAERS nor VigiAccess systematically captures standardized clinical severity grading, such as Common Terminology Criteria for Adverse Events (CTCAE) grades. As a result, the severity spectrum of cetuximab-associated skin adverse events cannot be reliably assessed in the present analysis. In addition, important clinical details, including exact onset time, cumulative drug exposure, concomitant medications, and detailed dermatological assessments, are often incomplete or missing, limiting causal inference. Moreover, disproportionality analyses are designed for signal detection rather than causal confirmation and should therefore be interpreted as hypothesis-generating.

Nevertheless, the use of two independent and complementary pharmacovigilance databases strengthens the robustness of our findings and reduces potential source-specific bias. Although spontaneous reporting data cannot replace prospective clinical studies, our results provide valuable real-world evidence that skin and subcutaneous tissue disorders represent the most prominent adverse events associated with cetuximab. Future well-designed observational studies, prospective cohorts, or dermatology-specific registries incorporating standardized severity assessments are warranted to better define incidence rates, severity distribution, underlying mechanisms, and long-term clinical implications.

Analyses of pharmacovigilance utilizing the FAERS and VigiAccess databases have revealed consistent disproportionality signals regarding cutaneous adverse events linked to cetuximab. Skin toxicities, notably including rash, acneiform dermatitis, erythema, acne, and dermatitis, were reported more frequently among middle-aged and older patients, particularly in males. Additionally, several events that were less commonly documented in clinical trials, such as exfoliative dermatitis, seborrheic dermatitis, and allergic dermatitis, have surfaced as significant safety signals in real-world settings. Although spontaneous reporting systems have inherent limitations, these results underscore the necessity for heightened clinical awareness. More prospective and mechanistic investigations are needed to validate these associations and elucidate the underlying mechanisms behind cetuximab-induced cutaneous toxicity.