Introduction
Cetuximab is a recombinant, human/mouse chimeric monoclonal antibody that specifically targets the epidermal growth factor receptor (EGFR). It is classified as an EGFR inhibitor and represents a cornerstone of targeted therapy for certain EGFR-expressing cancers. Approved by the FDA in 2004, cetuximab has revolutionized the treatment landscape for head and neck and colorectal malignancies.
Mechanism of Action
Cetuximab binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR, HER1, c-ErbB-1). This binding competitively inhibits the activation of EGFR and subsequent downstream signaling pathways. The drug prevents receptor dimerization, inhibits tyrosine kinase activation, and attenuates EGFR-dependent signal transduction. This results in:
- Cell cycle arrest (G1 phase)
- Induction of apoptosis
- Inhibition of angiogenesis
- Inhibition of metastasis and invasion
- Enhanced chemotherapy and radiation sensitivity
Indications
FDA-approved indications:- Squamous cell carcinoma of the head and neck (SCCHN):
- First-line treatment of recurrent locoregional or metastatic SCCHN in combination with platinum-based therapy and fluorouracil - Monotherapy for recurrent or metastatic SCCHN after platinum-based therapy failure - In combination with radiation therapy for locally or regionally advanced SCCHN
- Colorectal cancer:
- KRAS wild-type, EGFR-expressing metastatic colorectal cancer (mCRC): - First-line treatment in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) - Second-line treatment after oxaliplatin- and fluoropyrimidine-regimen failure - Third-line monotherapy after irinotecan- and oxaliplatin-based regimen failure
Off-label uses (with supporting evidence):- Non-small cell lung cancer (NSCLC) with EGFR expression (limited evidence)
- Anal carcinoma (in combination with chemotherapy)
Dosage and Administration
Initial dose: 400 mg/m² administered as a 120-minute intravenous infusion Maintenance dose: 250 mg/m² administered weekly as a 60-minute IV infusion Alternative dosing schedule (every 2 weeks):- Loading dose: 500 mg/m² IV over 120 minutes
- Maintenance dose: 500 mg/m² IV every 2 weeks over 60 minutes
- Infusion reactions: Interrupt infusion and manage symptoms
- Dermatologic toxicity: Grade 3 or 4 acneiform rash may require dose delay or reduction
- Electrolyte abnormalities: Monitor and replace as needed
- Renal impairment: No dosage adjustment required
- Hepatic impairment: No specific recommendations; use with caution
- Elderly: No dosage adjustment required
- Pediatric: Safety and effectiveness not established
Pharmacokinetics
Absorption: Administered intravenously only; complete bioavailability Distribution: Volume of distribution approximates plasma volume (2-3 L/m²) Metabolism: Undergoes proteolytic catabolism via reticuloendothelial system Elimination: Half-life approximately 112 hours (range 63-230 hours) Clearance: Non-linear, dose-dependent clearance; approximately 0.08 L/h/m²Contraindications
- Known severe hypersensitivity to cetuximab or any component of the formulation
- Patients with known KRAS-mutant or BRAF-mutant metastatic colorectal cancer (in colorectal cancer indication)
Warnings and Precautions
Boxed Warning:- Severe infusion reactions requiring emergency treatment and permanent discontinuation
- Cardiopulmonary arrest: Monitor serum electrolytes during and for 8 weeks after therapy
- Pulmonary toxicity: Interstitial lung disease reported
- Dermatologic toxicity: Severe acneiform rash may occur
- Electrolyte depletion: Hypomagnesemia, hypocalcemia, hypokalemia
- Ocular disorders: Keratitis, ulcerative keratitis
- Embryo-fetal toxicity: Can cause fetal harm
Drug Interactions
- No formal drug interaction studies conducted
- Theoretical interactions: Increased risk of bleeding with anticoagulants
- Radiation therapy: Enhanced radiation toxicity (desired therapeutic effect but requires careful monitoring)
- CYP450 substrates: Unlikely to affect cytochrome P450 enzymes
Adverse Effects
Very common (≥10%):- Acneiform rash (90%)
- Fatigue (89%)
- Nausea (55%)
- Diarrhea (45%)
- Constipation (40%)
- Abdominal pain (35%)
- Fever (33%)
- Vomiting (30%)
- Infection (28%)
- Stomatitis (25%)
- Paronychia (20%)
- Hypomagnesemia (15%)
- Anorexia (15%)
- Infusion reactions (15-20%, severe in 3%)
- Cardiopulmonary arrest (2-3%)
- Pulmonary fibrosis (≤2%)
- Severe dermatologic toxicity (15%)
- Severe electrolyte abnormalities (10%)
- Ocular disorders (≤0.5%)
Monitoring Parameters
Baseline:- EGFR expression testing (for colorectal cancer)
- KRAS and NRAS mutation status (for colorectal cancer)
- Complete blood count
- Comprehensive metabolic panel (including magnesium, calcium, potassium)
- Cardiac assessment (especially in patients with cardiac risk factors)
- Vital signs during and after infusion
- Skin examination at each visit
- Serum electrolytes weekly for first month, then monthly
- Pulmonary symptoms assessment
- Signs of infection
- Nutritional status
- Periodic electrolyte monitoring for 8 weeks after discontinuation
- Dermatologic follow-up
- Pulmonary function if symptoms develop
Patient Education
Before treatment:- Understand the need for genetic testing (for colorectal cancer)
- Discuss potential side effects and management strategies
- Arrange for transportation after first infusion
- Report any infusion-related symptoms immediately (chills, fever, breathing difficulty)
- Implement proactive skin care regimen (moisturizers, sunscreen, gentle cleansers)
- Maintain adequate hydration and nutrition
- Report persistent diarrhea, nausea, or vomiting
- Monitor for fever or signs of infection
- Report any visual changes or eye discomfort
- Notify healthcare provider of muscle cramps or twitching (signs of electrolyte imbalance)
- Use effective contraception during and for 2 months after treatment
- Avoid sun exposure; use broad-spectrum sunscreen
- Maintain good hand and foot hygiene to prevent paronychia
- Stay hydrated and maintain balanced diet
References
1. Lynch TJ, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337-345. 2. Bonner JA, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578. 3. Jonker DJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040-2048. 4. Cetuximab prescribing information. FDA-approved labeling. Revised 2022. 5. NCCN Guidelines®: Colon Cancer and Head and Neck Cancers. Version 2.2023. 6. Van Cutsem E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408-1417. 7. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol. 2005;16(9):1425-1433.