Continuing Education Activity
Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor with the following FDA-approved indications: colorectal cancer, metastatic, KRAS wild-type (without mutation), and head and neck cancer (squamous cell).
Non-FDA-approved uses include colorectal cancer, non-small cell lung cancer (NSCLC), EGFR-expressing, advanced, and squamous cell skin cancer. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of cetuximab, pertinent for members of the interprofessional team for the treatment of patients with malignancies for which it is indicated.
Objectives:
- Identify the approved and non-approved indications for therapy with cetuximab.
- Outline the mechanism of action of cetuximab.
- Describe the adverse effects and monitoring for cetuximab.
- Summarize the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with cetuximab.
Indications
Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor utilized to treat the following:
FDA-Approved Uses
- Colorectal cancer, metastatic, KRAS wild-type (without mutation) - Cetuximab improves both overall survival and progression-free survival and preserves quality-of-life measures for patients with colorectal cancer where other treatments have failed. There is a limitation of use. Patients with colorectal tumor-bearing mutated K-ras did not benefit from cetuximab, whereas patients with tumor-bearing wild-type K-ras benefited from cetuximab. If KRAS mutation in either codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy.
- Head and neck cancer (squamous cell) - Treatment for locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab demonstrates improvement of locoregional control and lowers mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. Cetuximab plus platinum-fluorouracil chemotherapy improved overall survival when given as first-line treatment for patients with recurrent or metastatic squamous-cell carcinoma of the head and neck.[1][2]
Non-FDA-Approved Uses[3][4]
- Colorectal cancer, advanced, biweekly administration
- Non-small cell lung cancer (NSCLC), EGFR-expressing, advanced
- Squamous cell skin cancer, unresectable
Benefits of Combined Therapy and Uses in Clinical Trials
EPIC trial: Cetuximab and irinotecan improved progression-free survival and response rate and resulted in a better quality of life than irinotecan alone.[3]
BOND trial: Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer.
CRYSTAL trial: First-line treatment with cetuximab plus FOLFIRI, compared with FOLFIRI alone, decreased the risk of progression of metastatic colorectal cancer. The benefit of cetuximab was limited to patients with KRAS wild-type tumors.
Adding cetuximab to FOLFIRI as first-line treatment also demonstrates improved survival in patients with KRAS wild-type mCRC. BRAF tumor mutation would be an indicator of a poor prognosis.
Mechanism of Action
Cetuximab is a recombinant chimeric human/mouse IgG1 monoclonal antibody which binds to epidermal growth factor receptor (EGFR) and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands. EGFR is a member of the ErbB family of receptors. When inactive, EGFR is a monomer, but when bound by epidermal growth factor or transforming growth factor-alpha (TGF-alpha), it forms homodimers or heterodimers with another member of the ErbB family of receptors. Dimerization activates the intracellular tyrosine kinase region of EGFR, resulting in autophosphorylation and initiating a cascade of intracellular events. The EGFR signaling pathway regulates cell differentiation, proliferation, migration, angiogenesis, and apoptosis, all of which become deregulated in cancer cells. Cetuximab binds to EGFR with high specificity and a higher affinity than either epidermal growth factor or TGF-alpha, thus blocking the ligand-induced phosphorylation of EGFR. Also, cetuximab enhances the effects of irinotecan and radiotherapy in experimental systems. K-ras, a small G-protein downstream of EGFR and a vital component of the EGFR signaling cascade, can acquire activating mutations in exon 2, thus isolating the pathway from the effect of EGFR and rendering EGFR inhibitors ineffective.[5][2][4]
Administration
The administration of the drug is via IV infusion with a loading dose lasting over 2 hours, weekly maintenance dose over 1 hour. Do not administer as an IV push or bolus. Do not shake or dilute. Administer via infusion pump or syringe pump. Following the infusion, an observation period of 1 hour is recommended; a longer observation time following an infusion reaction may be necessary. Premedication with an antihistamine alone is acceptable, although the addition of a glucocorticoid (with or without an H2 receptor antagonist) is reasonable for those living in high-incidence areas. Dosing prescribed as initial loading dose 400 mg/m^2 infused over 120 minutes and a maintenance dose of 250 mg/m^2 infused over 60 minutes for colorectal cancer, metastatic, KRAS wild-type (without mutation), and head and neck cancer (squamous cell).[5][1]
Adverse Effects
Adverse effects include the following based on body systems:
Central nervous system: Fatigue (91%), malaise (73% or less), pain (59%), peripheral sensory neuropathy (45%; grades 3/4: 1%), headache (19% to 38%), insomnia (27%), confusion (18%), chills (16% or less), rigors (16%or less), anxiety (14%), depression (14%)
Dermatologic: Desquamation (95%), acneiform eruption (15% to 88%; grades 3/4: 1% to 18%), radiodermatitis (86%), xeroderma (14% to 57%), pruritus (14% to 47%), skin rash (28% to 44%), changes in nails (31%), acne vulgaris (14% to 22%), paronychia (20%), palmar-plantar erythrodysesthesia (19%), skin fissure (19%), alopecia (12%)
Endocrine & metabolic: Weight loss (15% to 84%), hypomagnesemia (6% to 55%), dehydration (13% to 25%), hypocalcemia (12%), hypokalemia (12%)
Gastrointestinal: Diarrhea (19% to 72%), nausea (49% to 64%), abdominal pain (59%), constipation (53%), vomiting (40%), stomatitis (31% to 32%), anorexia (25% to 30%), dyspepsia (14% to 16%), xerostomia (12%)
Hematologic and oncologic: Neutropenia (49%; grades 3/4: 31%), leukopenia (grades 3/4: 17%)
Hepatic: Increased serum ALT (43%), increased serum AST (38%), increased serum alkaline phosphatase (33%)
Infection: Infection (13% to 44%), infection without neutropenia (38%)
Local: Application site reaction (18%)
Neuromuscular and skeletal: Weakness (73% or less), ostealgia (15%), arthralgia (14%)
Ophthalmic: Conjunctivitis (10% to 18%)
Respiratory: Dyspnea (49%), cough (30%), pharyngitis (26%)
Miscellaneous: Fever (22% to 29%), infusion related reaction (10% to 18%; grades 3/4: 2% to 5%[5][6]
Contraindications
- United States labeling: No contraindications listed
- Canadian labeling: Known severe hypersensitivity to cetuximab or any component of the formulation
Monitoring
Vital signs during infusion and observe for at least 1-hour post-infusion. Patients developing dermatologic toxicities should be monitored for the development of complications. Periodic monitoring of serum magnesium, calcium, and potassium are recommended to continue over an interval consistent with the half-life (8 weeks); monitor closely (during and after treatment) for cetuximab plus radiation therapy. KRAS genotyping of tumor tissue in patients with colorectal cancer.[1][6]
Toxicity
Cardiopulmonary arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients. Use with caution in patients with a history of coronary artery disease, heart failure, and arrhythmias.
Infusion reactions: Serious infusion reactions occurred with the administration of cetuximab in approximately 3% of patients in clinical trials, with fatal outcomes reported in less than 1 in 1000. Immediately interrupt and permanently discontinue cetuximab infusion for serious infusion reactions. In most subjects with a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose alpha-1,3-galactose. The presence of this oligosaccharide is related to the production of cetuximab in a murine cell line. Anaphylaxis in response to cetuximab is a significant clinical problem in the Southeastern United States, with a grade 3/4 infusion reaction rate of 14%.[6]
Dermatologic toxicity: An acne-like or maculopapular rash, a characteristic side effect of EGFR blockade, is due to the role of EGFR in maintaining the integrity of the skin. There are reports of acneiform rash in 76% to 88% of patients (severe in 1% to 17%), usually developing within the first two weeks of therapy, may require dose modification, generally resolved after discontinuation in most patients, although persisted beyond 28 days in some patients. The acneiform rash should have treatment with topical and/or oral antibiotics; topical corticosteroids are not recommended.
Interstitial lung disease: use with caution in patients with preexisting lung disease.
Electrolyte abnormality: Hypomagnesemia is common (may be severe). Because EGFR strongly expresses in the kidney, particularly in the ascending limb of the loop of Henle, where 70% of filtered magnesium gets reabsorbed, EGFR blockade may interfere with magnesium transport. Because symptoms may ameliorate rapidly with supplementation, when fatigue or hypocalcemia occurs during cetuximab therapy, serum magnesium levels should be measured, with repletion as necessary. 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 eight weeks after completion.[2]
Enhancing Healthcare Team Outcomes
Cetuximab is an inhibitor of epidermal growth factor receptor (EGFR) utilized for the treatment of several malignancies. Its administration and management require the effort of an interprofessional healthcare team. The drug is usually administered only by the oncologist, but a board-certified oncology pharmacist should play a role in dosing, administration, scheduling, and educating the patient on the potential adverse effects. Also, oncology nurses should be aware of the possible complications that can occur during the infusion and report these to the oncologist when encountered.[7][8][9]
The team should monitor vital signs during infusion and observe the patient for at least 1-hour post-infusion. Patients developing dermatologic toxicities should be monitored for the development of complications. It is recommended to continue periodic monitoring of serum magnesium, calcium, and potassium over an interval consistent with the half-life (8 weeks); monitor closely (during and after treatment) for cetuximab plus radiation therapy, and obtain KRAS genotyping of tumor tissue in patients with colorectal cancer.[1][6]
This type of interprofessional team approach is necessary to achieve optimal patient outcomes with cetuximab therapy. [Level 5]
Cetuximab