Cetuximab

In patients with squamous cell head and neck cancer, cardiopulmonary arrest and/or sudden death has occurred in 2% of patients receiving radiation therapy in combination with cetuximab and in 3% of patients receiving combination chemotherapy (platinum and fluorouracil-based) with cetuximab. Closely monitor serum electrolytes (magnesium, potassium, calcium) during and after cetuximab treatment (monitor for at least 8 weeks after treatment). Use with caution in patients with a history of coronary artery disease, heart failure, and arrhythmias; fatalities have been reported.

Acneiform rash has been reported in 76% to 88% of patients (severe in 1% to 17%), usually developing within the first 2 weeks of therapy; may require dose modification; generally resolved after discontinuation in most patients, although persisted beyond 28 days in some patients. Acneiform rash should be treated with topical and/or oral antibiotics; topical corticosteroids are not recommended. In colorectal cancer, the presence of acneiform rash correlates with treatment response and prolonged survival (Cunningham, 2004). Life-threatening and fatal bullous mucocutaneous disease (with blisters, erosions, and skin sloughing) has been observed with cetuximab; etiology is not determined; may be due to epidermal growth factor receptor (EGFR) inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis). Other dermatologic toxicities, including dry skin, fissures, hypertrichosis, paronychial inflammation, and skin infections, have been reported; related ocular toxicities (blepharitis, conjunctivitis, keratitis, ulcerative keratitis with decreased visual acuity) may also occur. Monitor closely for dermatologic toxicities and potential infectious sequelae. Sunlight may exacerbate skin reactions (limit sun exposure).

Hypomagnesemia is common (may be severe); the onset of electrolyte disturbance may occur within days to months after initiation of treatment; monitor magnesium, calcium, and potassium during treatment and for at least 8 weeks after completion. May require electrolyte replacement.

In clinical trials, serious infusion reactions have been reported in approximately 3% of patients; fatal outcome has been reported rarely (less than 1 in 1,000); interrupt infusion promptly and permanently discontinue for serious infusion reactions. Reactions have included airway obstruction (bronchospasm, stridor, hoarseness), hypotension, loss of consciousness, shock, myocardial infarction (MI), and/or cardiac arrest. Premedicate with anintravenous (IV) H1 antagonist 30 to 60 minutes prior to the first dose; premedication for subsequent doses is based on clinical judgment and with consideration of prior reaction to the initial infusion. The use of nebulized albuterol-based premedication to prevent infusion reaction has been reported (Tra, 2008). Approximately 90% of reactions occur with the first infusion despite the use of prophylactic antihistamines. Immediate treatment for anaphylactic/anaphylactoid reactions should be available during administration. The manufacturer recommends monitoring patients for at least 1 hour following completion of infusion, or longer if a reaction occurs. Mild to moderate infusion reactions (chills, fever, dyspnea) are managed by slowing the infusion rate (by 50%) and administering antihistamines. Patients with preexisting IgE antibody against cetuximab (specific for galactose-α-1,3-galactose) are reported to have a higher incidence of severe hypersensitivity reaction. Severe hypersensitivity reaction has been reported more frequently in patie

Has been reported; use with caution in patients with preexisting lung disease. Interrupt treatment for acute onset or worsening of pulmonary symptoms. Permanently discontinue with confirmed interstitial lung disease. Disease-related concerns:

Cetuximab is only indicated for patients with EGFR-expressing metastatic colorectal cancer without RAS (KRAS or NRAS) mutations. Determine RAS mutation status prior to treatment (with an approved test). Patients with a codon 12 and 13 (exon 2), codon 59 and 61 (exon 3), and codon 117 and 146 (exon 4) RAS mutation are unlikely to benefit from EGFR inhibitor therapy (while experiencing toxicities) and should not receive cetuximab treatment; cetuximab is not effective for colorectal cancer with RAS mutations. Cetuximab is also reported to be ineffective in patients with BRAF V600E mutation (Di Nicolantonio, 2008). The American Society of Clinical Oncology (ASCO) provisional clinical opinion (Allegra, 2009) recommends genotyping tumor tissue for KRAS mutation in all patients with metastatic colorectal cancer (genotyping may be done on archived specimens).

In trials for colorectal cancer, evidence of EGFR expression was required, although the response rate did not correlate with either the percentage of cells positive for EGFR or the intensity of expression. EGFR expression has been detected in nearly all patients with head and neck cancer; therefore, laboratory evidence of EGFR expression is not necessary for head and neck cancers. Concurrent drug therapy issues:

In a study of radiation therapy and cisplatin with or without cetuximab in patients with squamous cell head and neck cancer, an increase in the incidence of adverse reactions (eg, grade 3/4 mucositis, radiation recall, acneiform rash, electrolyte abnormalities, and cardiac events including ischemia) was noted in patients receiving cetuximab, including fatal reactions. There was no improvement in the primary end point of progression-free survival. Other warnings/precautions:

Non-neutralizing anti-cetuximab antibodies were detected in 5% of evaluable patients. Relationship between the appearance of antibodies and the safety or antitumor activity of the molecule is unknown.