A Case of Severe Skin Adverse Reactions Caused by Cetuximab

Summary

This case report describes severe cetuximab-induced skin toxicity in a rectal cancer patient, outlining diagnosis, management, and recovery. The paper provides a reproducible protocol, including dermatologic evaluation, biopsy, immunosuppressive therapy, and follow-up, demonstrating successful treatment and transition to alternative chemotherapy.

Abstract

Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is associated with various adverse reactions, among which skin-related adverse events (AEs) are common. This case report details a patient who developed severe skin AEs after cetuximab administration and outlines a reproducible management protocol. The patient, a 44-year-old man with KRAS wild-type metastatic rectal cancer, was undergoing cetuximab-based chemotherapy. Approximately 10 days after initiating a cetuximab monotherapy cycle following prior combination regimens, he developed severe Grade 3-4 acneiform rash and erythema multiforme-like lesions with ulceration, exudation, crusting, scaling, and hyperpigmentation on the face and anterior chest. Evaluation included physical examination, dermatology consultation, skin biopsy for histopathology and direct immunofluorescence, and laboratory tests (including serum IgE, eosinophil count, C-reactive protein, HLA-A*31:01 genotyping, viral serologies, and bacterial cultures). Management involved permanent discontinuation of cetuximab, high-dose intravenous methylprednisolone (1.5 mg∙kg^-1∙day^-1), cyclosporine (3 mg∙kg^-1∙day^-1), supportive wound care in a burn unit, and topical ocular/oral care. Symptoms improved significantly within 72 h, with a 90% reduction in lesion severity by day 14. Therapy was successfully transitioned to bevacizumab plus FOLFOX after dermatologic recovery, with no rash recurrence during follow-up. This case highlights the importance of early recognition, multidisciplinary management, and protocol-driven intervention for severe cetuximab-induced skin toxicity to ensure patient safety and treatment continuity.

Introduction

Cetuximab, a chimeric immunoglobulin G1 monoclonal antibody, has significantly advanced the treatment landscape for several malignancies, particularly metastatic colorectal cancer (mCRC) and head and neck cancers, especially those with RAS wild-type status¹. By specifically targeting the epidermal growth factor receptor (EGFR), it inhibits ligand-induced receptor phosphorylation, thereby curbing downstream signaling pathways involved in tumor cell proliferation, angiogenesis, and metastasis^2,3.

Despite its therapeutic efficacy, cetuximab treatment is frequently accompanied by various adverse reactions. Skin-related AEs are the most prevalent, occurring in up to 80-90% of treated patients, compared to a lower incidence with non-EGFR targeting regimens like FOLFOX or bevacizumab alone^1,4. These effects range from mild acneiform rashes (Grade 1-2) to more severe manifestations (Grade 3-4), significantly impacting patients' quality of life and potentially leading to treatment interruptions, dose modifications, or discontinuation, thereby affecting clinical outcomes^4,5.

Case Presentation:

A 44-year-old male (height: 162 cm; weight: 47 kg; body surface area: 1.45 m²) with no significant past medical history, comorbidities, or relevant family history, and a non-smoker, was admitted in late August 2023, reporting fatigue, dysarthria, and melena. Abdominal computed tomography (CT) revealed significant irregular thickening of the rectal wall, a rough serosal surface, mesenteric haziness, and multiple lymphadenopathies (Figure 1). Colonoscopic biopsy on September 7, 2023, confirmed moderately differentiated rectal adenocarcinoma (Figure 2). Immunohistochemistry (IHC) revealed proficient mismatch repair (pMMR) status: MLH1 (+), MSH2 (+), MSH6 (+), PMS2 (+); HER2 negative (-); and a high proliferation index: Ki-67 (>75%+). Subsequent genetic testing at an external institution confirmed KRAS wild-type status.

First-line treatment initiated in September 2023 consisted of cetuximab (500 mg/m² intravenous [IV] infusion every 2 weeks) combined with oral capecitabine (1,000 mg/m² twice daily for 14 days every 3 weeks). After one cycle, the patient's melena resolved, and his performance status improved. From cycles 2 to 4, he received cetuximab (500 mg/m²) with the FOLFOX6 regimen (oxaliplatin 85 mg/m², leucovorin 400 mg/m², fluorouracil 400 mg/m² bolus followed by 2,400 mg/m² continuous infusion over 46 h, every 2 weeks). The fifth cycle involved cetuximab monotherapy (500 mg/m²) to evaluate maintenance feasibility. From early January 2024 (cycles 6-13), he resumed cetuximab (500 mg/m²) with FOLFOX6. Throughout these 13 cycles over approximately 7 months, treatment was well-tolerated with only Grade 1 skin dryness reported.

In mid-April 2024, approximately 10 days after receiving a scheduled cetuximab monotherapy infusion (cycle 14, dose 500 mg/m²), the patient developed severe dermatological toxicity. He presented with widespread, pruritic, painful erythematous papules and plaques rapidly progressing to involve >30% of his body surface area (BSA), including the face, anterior chest, back, and proximal limbs. Lesions exhibited central ulceration, serous exudation, crusting, scaling, and hyperpigmentation (Figure 3). Mucosal involvement included oral erosions and conjunctival injection. Systemic symptoms included mild fever (38.0 °C). Based on the Common Terminology Criteria for Adverse Events [CTCAE] v5.0, this was graded as Grade 3 skin rash and Grade 2 mucosal involvement. Other differential diagnoses, including reactions to other concurrent medications, were considered unlikely as the patient was only on cetuximab monotherapy at onset; previous combination chemotherapy had been well-tolerated for months without significant skin toxicity. The patient reported a brief trial of unspecified traditional Chinese medicine, which was ineffective. He was urgently referred for dermatological management.

Diagnosis, Assessment, and Plan

Most reported skin reactions are mild to moderate. However, severe cutaneous adverse reactions (SCARs), such as severe acneiform rash, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlap, or erythema multiforme majus (EM), although relatively rare (<5%), can be life-threatening and require immediate intervention^4,6. Understanding these severe reactions is crucial as they offer insights into the underlying pathophysiological mechanisms of cetuximab-induced toxicity and necessitate standardized management approaches.

Current literature on severe cetuximab-induced skin reactions remains limited, often focusing on milder presentations. This report details a case of life-threatening cutaneous reactions following cetuximab administration for rectal cancer, aiming to enhance clinician awareness, facilitate early identification using standardized protocols (e.g., CTCAE grading), and promote the implementation of effective, reproducible management strategies.

Protocol

Prior to the collection of clinical data (including but not limited to medical history, laboratory test results, and imaging findings) and the acquisition of skin lesion photographs (Figure 3), the participant was provided with a detailed informed consent form that explicitly stated the purpose, scope, and manner of using his personal medical information and images (i.e., for academic research, manuscript publication in peer-reviewed journals, and non-commercial academic communication). The form clearly distinguished between "de-identified data/image use" (all personal identifiers, such as name, hospital ID, and facial features in non-essential areas of photographs, were removed or anonymized) and "academic dissemination scope" (including online publication, print journals, and academic conferences). The patient fully understood the content of the consent form, raised no objections to the use of his de-identified data and photographs, and signed the written informed consent form voluntarily. This process complies with the requirements of the Declaration of Helsinki and the Ethics Approval No. 2025-356 issued by the Ethics Committee of Ordos Central Hospital, ensuring the legality and ethicality of data and image use in this manuscript. Safety and Waste Disposal: Standard precautions were used for handling biopsy specimens (disposable gloves, sharps container for blades). Immunosuppressants were prepared under a laminar flow hood. Culture waste was autoclaved before disposal. Formalin-fixed tissues were disposed of as biohazardous waste per hospital protocol. Immunofluorescence reagent waste was collected separately for appropriate chemical disposal.

1. Initial clinical assessment and baseline documentation

1. The patient was admitted with a confirmed diagnosis of KRAS wild-type metastatic colorectal cancer (mCRC). A comprehensive pretreatment evaluation included medical history review, dermatological examination, and documentation of prior hypersensitivity reactions. Baseline laboratory tests-complete blood count (CBC), liver function tests (LFTs: ALT, AST, ALP, bilirubin), renal function tests (RFTs: creatinine, BUN), and inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR])-were performed using standard automated analyzers. Vital signs were recorded.
2. Before cetuximab initiation, the patient was counseled on common dermatologic side effects (e.g., acneiform rash, xerosis, paronychia) using a structured information sheet and provided written instructions for daily symptom monitoring (patient diary). No prophylactic antibiotics or topical steroids were administered initially.

2. Diagnostic evaluation of cutaneous reaction

1. Upon presentation with generalized pruritic erythematous papules and plaques 10 days post cetuximab infusion, an urgent dermatology consult was obtained. Physical examination documented the extent of involvement (% BSA using the rule of nines), epidermal detachment (Nikolsky sign), and mucosal involvement (oral cavity, conjunctiva). Systemic signs (fever >38 °C, lymphadenopathy) were assessed. Photographic documentation was performed using a standardized protocol: a digital camera with consistent lighting, background, and scale reference was used to capture images of representative lesions from multiple angles.
2. A 4 mm punch biopsy was obtained under local anesthesia (1% lidocaine with epinephrine) from the edge of a fresh blister on the patient's trunk. The specimen was divided: one part was fixed in 10% neutral buffered formalin for 24 h at room temperature (RT), processed routinely, embedded in paraffin, sectioned at 4-5 µm thickness, and stained with hematoxylin and eosin (H&E) for histopathology. The other part was snap-frozen in optimal cutting temperature (OCT) compound and stored at -80 °C for direct immunofluorescence (DIF); 4 µm cryosections were incubated with fluorescein isothiocyanate (FITC)-conjugated antibodies against human IgG, IgA, IgM, C3, and fibrinogen (dilutions 1:20-1:50 in phosphate-buffered saline [PBS]) for 45 min at RT in a humidified chamber, washed, mounted, and examined using a fluorescence microscope.
3. Concurrent laboratory investigations included: serum IgE quantification, automated CBC with differential for eosinophil count, CRP (particle-enhanced immunoturbidimetry), and HLA-A31:01 genotyping via PCR-based sequence-specific oligonucleotide probing (SSOP) using a commercial kit according to the manufacturer's instructions. Viral serologies for herpes simplex virus (HSV) (IgM/IgG by ELISA) and human herpesvirus-6 (HHV-6) (IgG by IFA), and bacterial cultures from skin swabs (blood agar, chocolate agar, incubated at 35-37 °C for 24-48 h) were performed to exclude infectious triggers.

3. Multidisciplinary management protocol

1. Cetuximab was permanently discontinued following consensus between oncology, dermatology, and immunology. The patient was transferred to a specialized burn unit (equipped with air-fluidized beds, continuous hemodynamic monitoring, and strict aseptic protocols) for intensive wound care and monitoring.
2. High-dose methylprednisolone (1.5 mg∙kg^-1∙day^-1 IV, prepared as a 40 mg/mL solution in sterile water for injection) was initiated within 6 h of severe symptom onset. Due to rapid progression with >30% BSA epidermal detachment, cyclosporine (3 mg∙kg^-1∙day^-1 IV, diluted in 0.9% sodium chloride or 5% dextrose to 2.5 mg/mL) was added. Fluid resuscitation was titrated using crystalloids to maintain urine output >0.5 mL∙kg^-1∙h^-1. Serum albumin levels were monitored twice daily (bromocresol green method).
3. Ocular involvement was managed with hourly application of preservative-free artificial tears and nightly application of erythromycin ophthalmic ointment (2.5 mg/g). Oral mucosal erosions were treated with sucralfate rinses (1 g/10 mL suspension in water, four times daily) and viscous lidocaine (2% solution, swish and spit every 4 h as needed).

4. Outcome monitoring and longitudinal follow-up

1. Daily assessments of skin re-epithelialization were conducted using the SCORTEN severity-of-illness score, which incorporates age, heart rate, BSA detachment, serum bicarbonate, glucose, urea, and comorbidities. Immunosuppressive therapy was adjusted based on clinical response. Systemic corticosteroids were tapered by 20% weekly after complete cessation of new blister formation for 72 h.
2. After full dermatologic recovery (re-epithelialization >95%), oncology therapy was transitioned to bevacizumab (5 mg/kg IV every 2 weeks) plus FOLFOX6. Biweekly skin examinations were performed during subsequent cycles to detect early recurrence. Long-term follow-up included periodic oncology and dermatology visits.

Results

The patient's baseline CTCAE v5.0 skin toxicity score was 0 before the reaction onset. The severe cutaneous adverse reaction manifested acutely 10 days post cetuximab infusion (cycle 14). Key findings included:

Development of Grade 3 acneiform rash and erythema multiforme-like lesions, progressing to diffuse desquamation and erosive lesions involving >30% of BSA

SCO...

Discussion

This case illustrates a severe SCAR likely induced by cetuximab monotherapy, successfully managed using a structured multidisciplinary protocol. Cetuximab inhibits EGFR signaling, leading to impaired keratinocyte differentiation, increased apoptosis, abnormal keratin secretion, and subsequent release of pro-inflammatory mediators (e.g., cytokines, chemokines), provoking intense local inflammation and acneiform rashes^1,3,5,<...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
10% neutral buffered formalin	Sigma-Aldrich	#HT501128	Used for fixation of skin biopsy specimens (24 h at room temperature); equivalent neutral buffered formalin products from other manufacturers are acceptable
Canon EOS Rebel T7i	Canon Inc.		Digital camera; used for standardized photographic documentation of skin lesions (consistent lighting, white background, and 1 cm scale reference); any digital camera with ≥24.1 megapixels and manual exposure mode is suitable
Cobas 8000	Roche Diagnostics		Standard automated analyzer; used for complete blood count (CBC), liver function tests (LFTs), renal function tests (RFTs), and C-reactive protein (CRP) detection; other clinical-grade automated analyzers meeting ISO 15189 standards can be substituted
eosin	Sigma-Aldrich	#HT110232	Used for counterstaining of paraffin-embedded skin sections; compatible with hematoxylin #HHS32; equivalent eosin solutions (0.5%–1% concentration) from other suppliers are applicable
FITC-Conjugated Anti-Human C3 Antibody	Agilent	#ZA004	Used for DIF detection in skin biopsy specimens; dilution: 1:40 in PBS; specificity: human complement C3; other FITC-conjugated anti-human C3 antibodies with validated reactivity are applicable
FITC-Conjugated Anti-Human Fibrinogen Antibody	Agilent	#ZA005	Used for DIF detection in skin biopsy specimens; dilution: 1:50 in PBS; specificity: human fibrinogen; equivalent antibodies from other brands (e.g., Dako) can be used if they meet DIF experimental requirements
FITC-Conjugated Anti-Human IgA Antibody	Agilent	#ZA002	Used for DIF detection in skin biopsy specimens; dilution: 1:30 in PBS; specificity: human IgA; other FITC-conjugated anti-human IgA antibodies with cross-adsorption to avoid species interference are acceptable
FITC-Conjugated Anti-Human IgG Antibody	Agilent	#ZA001	Used for direct immunofluorescence (DIF) detection in skin biopsy specimens; dilution: 1:20 in PBS; specificity: human IgG; equivalent FITC-conjugated anti-human IgG antibodies from other brands (e.g., Jackson ImmunoResearch) are suitable
FITC-Conjugated Anti-Human IgM Antibody	Agilent	#ZA003	Used for DIF detection in skin biopsy specimens; dilution: 1:25 in PBS; specificity: human IgM; equivalent antibodies from other suppliers (e.g., Abcam) meeting DIF-grade standards can be substituted
hematoxylin	Sigma-Aldrich	#HHS32	Used for nuclear staining of paraffin-embedded skin sections; compatible with eosin #HT110232; Mayer's or Harris' hematoxylin solutions from other manufacturers are acceptable
HHV-6 IgG IFA Kit	Zeus Scientific	#Z-2200	Used for detection of human herpesvirus-6 (HHV-6) IgG antibodies; indirect immunofluorescence assay; positive control: HHV-6-infected T cells; equivalent IFA kits from other suppliers are suitable
HLA-A*31:01 Genotyping Kit	Thermo Fisher Scientific	#4488393	Used for PCR-based sequence-specific oligonucleotide probing (SSOP) of HLA-A31:01 allele; includes primers, probes, and reaction buffers; other FDA-approved HLA-A31:01 genotyping kits with equivalent accuracy can be substituted
HSV IgM/IgG ELISA Kit	Siemens Healthineers	#09606790	Used for detection of herpes simplex virus (HSV) IgM and IgG antibodies; sensitivity: ≥98%, specificity: ≥97%; other ELISA kits meeting CE IVDR standards are acceptable
ImmunoCAP, Phadia, Thermo Fisher Scientific	Phadia (Thermo Fisher Scientific)		Used for quantification of serum IgE; detects total IgE concentration (detection range: 0.1–5000 IU/mL); other certified immunoassay kits with equivalent sensitivity and specificity can be used
Nikon Eclipse Ni-U	Nikon Instruments		Fluorescence microscope; used for observation of direct immunofluorescence (DIF) slides; equipped with FITC filter (excitation wavelength: 490 nm, emission wavelength: 525 nm); any fluorescence microscope with ≥1000× magnification and FITC-compatible filters is suitable
optimal cutting temperature (OCT) compound	Tissue-Tek	#4583	Used for snap-freezing of skin biopsy specimens (stored at -80 °C); ensures tissue integrity during cryosectioning; equivalent OCT compounds from other brands (e.g., Sakura Finetek) are acceptable
Pain relief pump system	REHN(I)/REHH(11)-256	C14230120200002117850000005	Sterile, disposable; used for postoperative pain management; complies with ISO 13485 medical device standards; other sterile disposable pain relief pump systems with the same flow rate (2 mL/h) are applicable
Pre flushing syringe	Bidi Medical Equipment (Shanghai) Co., Ltd	C14281803900001071870000016	Sterile; used for pre-flushing of intravenous catheters; volume: 10 mL; other sterile syringes meeting GB 15810-2019 (China) or ISO 7886-1 standards can be substituted
Primary Antibody: Anti-HER2 (rabbit monoclonal)	Dako	#4B5	Used for IHC detection of HER2 protein in colorectal cancer tissue; dilution: 1:100; positive control: HER2-positive breast cancer tissue; equivalent anti-HER2 antibodies (clone: SP3) from other suppliers are acceptable
Primary Antibody: Anti-Ki-67 (mouse monoclonal)	Dako	#MIB-1	Used for IHC detection of Ki-67 proliferation index in colorectal cancer tissue; dilution: 1:200; positive control: tonsil tissue; other anti-Ki-67 antibodies (clone: MM1) with validated sensitivity can be substituted
Primary Antibody: Anti-MLH1 (mouse monoclonal)	Dako	#M7359	Used for immunohistochemistry (IHC) detection of MLH1 protein in colorectal cancer tissue; dilution: 1:100; specificity verified by positive control (normal colorectal mucosa); equivalent anti-MLH1 antibodies (clone: ES05) from other suppliers are acceptable
Primary Antibody: Anti-MSH2 (mouse monoclonal)	Dako	#M7324	Used for IHC detection of MSH2 protein in colorectal cancer tissue; dilution: 1:200; positive control: normal colorectal mucosa; equivalent anti-MSH2 antibodies (clone: FE11) from other brands are suitable
Primary Antibody: Anti-MSH6 (mouse monoclonal)	Dako	#M7457	Used for IHC detection of MSH6 protein in colorectal cancer tissue; dilution: 1:150; positive control: normal colorectal mucosa; other anti-MSH6 antibodies (clone: EP49) with validated specificity can be substituted
Primary Antibody: Anti-PMS2 (mouse monoclonal)	Dako	#M7437	Used for IHC detection of PMS2 protein in colorectal cancer tissue; dilution: 1:50; positive control: normal colorectal mucosa; equivalent anti-PMS2 antibodies (clone: A16-4) from other manufacturers are applicable