A Patient on Targeted Therapy: Cetuximab

Jeff is a 47-year-old white male who presented to his primary care provider complaining of having had swollen lymph nodes in the right neck for 2 months. He also complained of nasal stuffiness and sore throat. Physical exam found lymphadenopathy in the left cervical triangle less than 2 cm in diameter. He smokes about 2 packs of cigarettes a day and has a 60 pack-year history of smoking. He has been a cabinet-maker for almost 20 years. He has no other significant medical history and is not on any regular medications. He is a social drinker and denies any illicit drug use. He was treated with an antibiotic for 10 days, but on return the lymphadenopathy appeared slightly enlarged. He was sent to an ear, nose, and throat specialist who biopsied the nodal mass. Following an extensive workup, he was diagnosed with stage III (T2, N1, M0) squamous cell carcinoma of the nasopharynx.

History

Jeff was treated with chemotherapy and radiation therapy. He received cisplatin at 100 mg/m² on days 1, 22, and 43 with concomitant radiation therapy to the tumor site and bilateral neck. Following completion of radiation therapy, he continued on cisplatin at 80 mg/m² on day 1 with 4 days of a continuous infusion of fluorouracil (5-FU) at 1,000 mg/m² for three cycles. He had a complete response and then underwent a period of observation every 3 months.

Approximately 9 months after Jeff's initial treatment, a computed tomography (CT) scan showed mediastinal lymph nodes consistent with metastatic disease from his head and neck primary cancer. He elected to undergo treatment with cetuximab (Erbitux) as a single agent. His treatment plan was 400 mg/m² of cetuximab as a loading dose over 2 hours, then 250 mg/m² over 1 hour as a weekly maintenance dose. The patient was premedicated with IV diphenhydramine at 50 mg. A 1-hour observation period following each treatment was also ordered.

During his third weekly maintenance infusion, Jeff complained of itching around the neck and arms. The oncology nurse immediately stopped the cetuximab infusion and performed a physical assessment. His vital signs had not changed and there was nothing unusual noted on physical exam other than slight facial and neck flushing. The treating oncologist ordered a 30-minute observation; if the patient remained stable the nurse was to administer another 50 mg of diphenhydramine, then restart the infusion at a 50% slower rate. This was done and Jeff finished the infusion without further incident. He was sent home with orders to take diphenhydramine at 25 mg every 6 hours by mouth and to call if he had any signs of allergic reaction. There were none. Cetuximab was subsequently ordered to be given at a permanent 50% infusion rate reduction with a 2-hour postinfusion observation period.

During his sixth weekly maintenance infusion, Jeff complained of itching and tightness in his chest. The oncology nurse immediately stopped the cetuximab infusion and performed a physical assessment. The nurse noted the patient sounded slightly hoarse; she auscultated some wheezes bilaterally. The patient's pulse rate was elevated slightly as was his blood pressure.

The oncology nurse kept an open line of fluids and immediately administered IV hydrocortisone at 100 mg, as per institution protocol. Oxygen was begun at 2 L/min. The treating oncologist was paged. The patient improved within a couple of minutes. However, within 10 minutes, the patient began developing hives on his neck and arms and the wheezing and hoarseness recurred. His blood pressure began to fall. The oncologist ordered epinephrine at 0.3 mg subcutaneously and the patient was sent to the emergency room. Cetuximab was permanently discontinued.

Discussion

Nasopharyngeal cancer accounts for about 2% of all head and neck cancers, usually occurring between the ages of 30 and 50.[1] Ninety percent of head and neck cancers have squamous cell pathology. Nasopharyngeal cancer risk factors include Epstein-Barr virus; routine inhalation of nitrosamines, such as are found in salt-cured, steamy foods; and inhalation of toxic chemicals, such as those found in woodworking occupations.[1]

Patients with nasopharyngeal cancers often present with epistaxis, nasal obstruction, and impaired eighth cranial nerve function.[1] The risk of distant metastasis is increased if multiple lymph nodes in the neck (especially the lower neck) are involved. The nasopharyngeal area has a rich capillary lymphatic system, with spread occurring initially in the cervical triangle, jugular chains, or supraclavicular nodes. Because of this metastatic potential, treatment for nasopharyngeal cancer is complex.

Surgery is usually not recommended due to anatomic inaccessibility. Radiation therapy, the treatment of choice for small nasopharyngeal cancers, generally offers an 80% to 90% survival rate. Both sides of the neck are treated with radiation because of the risk of contralateral lymph node metastasis. For larger tumors, chemoradiotherapy followed by adjuvant therapy is generally recommended.[2] Chemotherapy consists of cisplatin given concurrently with radiation therapy followed by cisplatin and 5-FU.

Combination Therapy

Recurrent disease may be treated with combination chemotherapy if the patient has a good performance status. Combination chemotherapy should be platinum-based, given with a taxane, 5-FU, or cetuximab. Single-agent chemotherapy could be employed for a patient with a poorer performance status.[2] Single-agent therapy could consist of platinum, a taxane, methotrexate, 5-FU, ifosfamide (Ifex), gemcitabine (Gemzar), bleomycin (Blenoxane), or cetuximab.[2]

Cetuximab is an IgG1 human-mouse chimeric monoclonal antibody that targets epidermal growth factor receptors (EGFRs). It is indicated for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy or as a single agent for recurrent or metastatic squamous cell carcinoma of the head and neck in patients for whom prior platinum-based therapy has failed.[3] Cetuximab is considered a targeted cancer therapy.

The EGFR is a transmembrane receptor tyrosine kinase. It is normally expressed in many normal epithelial cells and epithelial-derived tissues, such as skin, hair follicles, and the gastrointestinal and respiratory tract linings.[4] Activating EGFR triggers several downstream signaling pathways that control normal biologic functions such as cell proliferation and survival, cellular motility, and gene transcription.[5,6] In tumor cells, when EGFR is overexpressed or malfunctions, tumor growth occurs by stimulation of cell division, inhibition of apoptosis, stimulation of angiogenesis, and/or increased cell motility (metastasis). Epidermal growth factor receptor is overexpressed or mutated in many cancers, including approximately 78% of colorectal cancers, almost all of head and neck cancers, and in pancreatic, non-small-cell lung, ovarian, esophageal, gastric, breast, prostate, bladder. and renal cancers.[6]

The most common side effect of cetuximab is an acneform rash.[3,7] Other common side effects include asthenia, fever, weight loss, and pain. Rare side effects include severe infusion reactions, interstitial lung disease (ILD), and hypomagnesemia.

One of the most serious potential adverse reactions of cetuximab, like most monoclonal antibodies, is a severe infusion reaction. About 3% of patients who receive cetuximab will have a grade III or IV infusion reaction.[3] This incidence is similar to that seen with chemotherapy agents such as paclitaxel and oxaliplatin (Eloxatin) and other monoclonal antibodies such as trastuzumab (Herceptin) and rituximab (Rituxan).[8] Premedication with an H₁ antagonist (IV diphenhydramine at 50 mg) is recommended for prevention of a severe infusion reaction.

According to the Common Terminology Criteria for Adverse Events (CTCAE),[9] a grade 3 allergic reaction consists of symptomatic bronchospasm, with or without urticaria. Parenteral medications are indicated. Allergy-related edema or angioedema and hypotension may occur. Anaphylaxis is considered a grade 4 adverse event. Emergency medication such as epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen should be available whenever cetuximab or other targeted therapies are administered. Standing orders are recommended. While infusion reactions usually occur with the first infusion, it is possible to occur with any infusion.[3]

An infusion reaction will begin with changes in the cardiac, respiratory, or integumentary systems.[8] Respirations may become more labored and short. Wheezing, stridor, and tightness of the chest may follow. The heartbeat will increase and the blood pressure will change. The patient may complain of chest pain, heart palpitations, itching, flushing, or dizziness. The nurse may auscultate irregularities and/or distant or extra heart sounds. One might also observe erythema or angioedema of the face, eye area, earlobes, hands, and feet. Other signs might include nasal congestion or rhinitis, sneezing, or tearing of the eyes. Severe reactions will lead to rapid onset of airway obstruction with bronchospasm, stridor hoarseness, urticaria, and hypotension.

Less severe infusion reactions (grade 1 or 2) occur in 19% of patients treated with cetuximab alone.[10] These can usually be successfully treated by slowing the infusion rate. CTCAE grade 1 consists of transient flushing or rash and drug fever less than 100.4°F. Grade 2 may consist of a rash, flushing, urticaria, dyspnea, and drug fever greater than 100.4°F. Most patients may be rechallenged following a grade 1 or 2 adverse event by slowing the infusion rate and aggressive premedications.

Besides premedicating with diphenhydramine, the patient should be closely monitored during the first and every infusion.[8] Vital signs should be checked every 5 to 15 minutes throughout the infusion as well as after the infusion. The patient should be monitored for 1 hour after the infusion-longer if there has been a previous infusion reaction.

References:

1. Carr E: Head and neck malignancies, in Yarbro C, Frogge M, Goodman M (eds): Cancer Nursing Principles and Practice, 6th ed, pp 1294-1329. Sudbury, Massachusetts, Jones & Bartlett Publishers, 2005.

2. National Comprehensive Cancer Network: Head and Neck Cancers, v 1.2006, in the NCCN Clinical Practice Guidelines in Oncology, 2006, accessed 6/25/06 at www.nccn.org

3. Erbitux (cetuximab) package insert, New York, ImClone Systems Inc; Princeton, NJ, Bristol-Myers Squibb, 2006.

4. Lenz H: Anti-EGFR mechanism of action. Oncology 20(4 suppl 2):5-13, 2006.

5. Wujcik D: EGFR as a target: Rationale for therapy. Semin Oncol Nurs 22(1 suppl 1):5-9, 2006.

6. Harari P: Anti-EGFR therapy update: Clinical experience and adverse event insights. Oncology 20(4 suppl 2):3-4, 2006.

7. Sipples R: Common side effects of anti-EGFR therapy: Acneform rash. Semin Oncol Nurs 22(1 suppl 1):28-34, 2006.

8. Sandler A: Nondermatologic adverse events associated with anti-EGFR therapy. Oncology 20(4 suppl 2):35-40, 2006.

9. National Cancer Institute: Common terminology criteria for adverse events, v 3.0. Bethesda, Md, 2003.

10. Saltz L, Meropol N, Loehrer P, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22(7):1201-1208, 2004.