Epidermal growth factor receptor (EGFR) is expressed in normal epithelial tissues.  Overexpression of EGFR is detected in many human cancers including colorectal and head and neck. This policy addresses the indications for Erbitux® (cetuximab), a recombinant human/mouse chimeric monoclonal antibody that binds specifically to the human EGFR.

Medically Necessary:

Erbitux® (cetuximab) is considered medically necessary for the following indications:

Colorectal Cancer Uses:

Erbitux® (cetuximab) is considered medically necessary for treatment of patients with metastatic colorectal carcinoma when all of the following criteria are met:

1. Disease progression on or following fluoropyrimidine, oxaliplatin, or irinotecan containing chemotherapy regimens; AND
2. Patient has not received prior treatment with panitumumab (Vectibix™); AND
3. Erbitux® is not used in combination with other monoclonal antibodies.

Head and Neck Cancer Uses:

Erbitux® (cetuximab) is considered medically necessary for any of the following:

1. In combination with radiation therapy, for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck; OR
2. As a single agent for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed.

Investigational/Not Medically Necessary:

Erbitux® (cetuximab) is considered investigational/not medically necessary when the above criteria are not met.
 

Erbitux® (cetuximab) is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular portion of the human epidermal growth factor receptor (EGFR). It is thought to interfere with the growth of cancer cells by blocking EGFR on their surface.

The patient selection criteria outlined above in the policy statement were derived from the Food and Drug Administration (FDA) approved prescribing information for Erbitux® (cetuximab), the studies presented to the FDA in support of the pre-market approval application, and studies in the peer-reviewed published medical literature.

Erbitux was first approved in February 2004, under the FDA's accelerated approval program, which allows the FDA to approve products for cancer and other serious or life-threatening diseases on the basis of early evidence of a product's effectiveness. At that time, it was approved as a combination treatment with irinotecan for the treatment of metastatic colorectal cancer or alone if the patient is unable to tolerate with irinotecan.

Erbitux® (cetuximab) is now FDA approved for multiple indications including the treatment of EGFR expressing, metastatic colorectal carcinoma used in combination with irinotecan, in patients who are refractory to irinotecan-based chemotherapy; as a single agent for the treatment of EGFR expressing, metastatic colorectal carcinoma in patients who are intolerant to irinotecan-based chemotherapy; in combination with radiation therapy, for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck and as a single agent for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed (FDA Product information, 2006).

Colorectal Carcinoma
Cunningham et al. (2004) compared the efficacy and safety of 329 patients whose disease had progressed during or within 3 months after treatment while on irinotecan. Patients received either irinotecan plus cetuximab versus the same dose of cetuximab alone. Those who received cetuximab alone had the option to switch to the combination treatment if the single agent failed. Combined therapy was associated with a significantly better objective response tumor shrinkage rate (23 versus 11 percent), and tumor progression was delayed a median of 4.1 months among those who received the two drugs compared with 1.5 months in those patients receiving cetuximab alone.

Although the survival time was also longer for the combination therapy group, the difference in median overall survival was not statistically significant (8.6 versus 6.9 months). Cunningham did note: “Toxic effects were more frequent in the combination therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone.” He concluded: “Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer.”

At this time, it is not known whether Erbitux® (cetuximab) will improve symptoms of EGFR- expressing colorectal cancer or help these patients to live longer. Currently, no data is available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux® (cetuximab) for the treatment of EGFR-expressing, metastatic colorectal carcinoma (Erbitux® Product information, 2006).

Head and Neck Carcinoma
Bonner and colleagues (2006) studied the safety and efficacy of Erbitux® in combination with radiation therapy in a randomized, controlled trial of 424 patients with locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN) versus radiation therapy alone. Bonner randomized 424 patients with Stage III/IV SCC of the oropharynx, hypopharynx, or larynx with no prior therapy in a phase III multicenter, controlled clinical trial. The patients received Erbitux ® plus radiation or radiation therapy alone for 6-7 weeks. At the end of treatment, the patients were followed by radiologic studies and physical examination. Bonner found the addition of Erbitux® to radiation (n=211) when compared to radiation alone (n=213) resulted in a survival time of 49 months versus 29.3 months on radiation therapy alone. In addition, delay in tumor growth was observed with the use of Erbitux and radiation, compared to radiation alone. Bonner concluded: “Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck.”

Since expression of EGFR has been detected in nearly all patients with head and neck cancer, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR expression prior to study entry (Erbitux® Product information, 2006).

According to the American Cancer Society (ACS), colorectal cancer is the third most common cancer in men and women. It is estimated there will be 106,680 new colon cancer and 41,930 new rectal cancer cases in the United States.

According to the National Institutes of Health, National Cancer Institute (2005), head and neck carcinomas account for approximately 3 to 5 percent of all cancers in the United States and are more common in men and in people over age fifty. 39,000 men and women in this country were expected to develop head and neck cancer in 2005. Head and neck cancer includes cancers of the tongue, mouth, salivary glands, pharynx, larynx, sinus, and other sites located in the head and neck area.

About 90 percent of head and neck cancers are of the squamous cell variety and almost 100 percent of these express EGFR, which is critical for tumor growth. Therefore, as noted in the Erbitux® product information (2006), and based on the entry criteria for patients enrolled in the head and neck cancer clinical trials, pretreatment assessment for evidence of EGFR expression was not required for patients with squamous cell carcinoma of the head and neck.

A monoclonal antibody is a protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells (National Cancer Institute). Erbitux® is a monoclonal antibody that binds specifically to the human Epidermal Growth Factor Receptor. As a result, Erbitux® may interfere the signals necessary for the cancer cells’ growth and survival.

Dosing information:
Initial dose: 400mg/m2 IV over 2 hours.
Maintenance dose:  250mg/m2 IV over 60 minutes weekly until disease progression or unacceptable toxicity.

Colorectal carcinoma [Dosage per Product Information, 2006]:
Standard dosing and maintenance infusion weekly until disease progression or unacceptable toxicity.

Head and Neck carcinoma [Dosage per Product Information, 2006]:
Single agent: Standard dosing and maintenance infusion weekly until disease progression or unacceptable toxicity.

Combined with radiation therapy: Initial dose given one week prior to initiation of radiation therapy. Subsequent weekly maintenance dose for the duration of the radiation therapy (6-7 weeks).

Possible Risks:
Erbitux® carries a black box warning regarding severe infusion reactions characterized by rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, hypotension, and/or cardiac arrest. It is recommended that severe infusion reactions require immediate and permanent discontinuation of Erbitux® therapy. These severe reactions can happen with any Erbitux infusion, but have happened more often the first time Erbitux® is given. Those having severe infusion reactions with Erbitux® should have their infusion stopped immediately and should not be re-treated with Erbitux®. Appropriate medical therapy, including epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen should be available for use in the treatment of such reactions. In clinical trials, mild to moderate infusion reactions were managed by slowing the infusion rate of Erbitux® and by continued use of premedication with antihistamine medications (eg, 50mg of diphenhydramine) in subsequent doses. Most reactions (90%) were associated with the first infusion of Erbitux® (cetuximab) despite the use of prophylactic antihistamines. Caution needs to be taken with every Erbitux® (cetuximab) infusion as there were patients who experienced their first severe infusion reaction during later infusions. A 1-hour observation period is recommended following the Erbitux® (cetuximab) infusion. Longer observation periods may be required in patients who experience infusion reactions. (Erbitux® product information, 2006).

A further black box warning indicates Erbitux® in combination with radiation therapy should be used with caution in head and neck cancer patients with known coronary artery disease, congestive heart failure, and arrhythmias. Although the etiology of these events is unknown, close monitoring of serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux® therapy is recommended (Erbitux® product information, 2006).

Additional FDA warnings include: Erbitux® (cetuximab) in combination with radiation treatment may increase the chance of cardiac arrest and death. Patients with cardiac conditions including, but not limited to, coronary artery disease, congestive heart failure, and arrhythmias should inform their physician and be followed closely during and after treatment. The FDA also warned the safety of Erbitux® (cetuximab) in combination with radiation therapy and cisplatin has not been established in patients with squamous cell carcinoma of the head and neck. Further, pulmonary toxicity as evidenced by interstitial lung disease (ILD) has been reported in patients treated with Erbitux® (cetuximab).  However it is difficult to determine if Erbitux® (cetuximab) caused ILD since there are many other factors involved.  (ILD occurs when the lung becomes stiff due to scarring of the tissue between the air sacs of the lungs.) Erbitux® (cetuximab) dermatologic toxicity can include skin reactions such as an acne-like rash, drying, cracking, inflammation, and infections (eg, blepharitis, cellulitis, cyst).  These reactions may be worsened by sun exposure.

Erbitux® (cetuximab) has not been studied in pediatric populations.

Monoclonal antibody: a protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells

The following codes for treatments and procedures applicable to this policy are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

ICD-9 Diagnosis

When services are Investigational/Not Medically Necessary:

For the procedure and diagnosis codes listed above when criteria are not met, for all other diagnoses not listed; or when the code describes a procedure indicated in the Policy section as investigational/not medically necessary.

Peer Reviewed Publications:

1. Bonner J, Harari P, Giralt J, et al. Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck. N Engl J Med. 2006; 354: 567–578.
2. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004; 351:337-345.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Erbitux® (cetuximab) [Product Information]. Branchburg, NJ. ImClone Systems Incorporated. March 2006. Available at: http://www.fda.gov/cder/foi/label/2006/125084s046LBL.pdf. Accessed on December 11, 2006.
2. National Cancer Institute (NCI) – Colon and Rectal Cancer information. Available at: http://www.nci.nih.gov/cancertopics/types/colon-and-rectal. Accessed on December 11, 2006.
3. National Cancer Institute (NCI) – Drug information: Erbitux. Updated October 5, 2006. Available at: http://www.nci.nih.gov/cancertopics/druginfo/cetuximab. Accessed on December 11, 2006.
4. National Cancer Institute (NCI) - Head and Neck Cancer: Questions and Answers. March 9, 2005. Available at: http://www.cancer.gov/cancertopics/factsheet/Sites-Types/head-and-neck. Accessed on December 12, 2006.
5. U.S. Food and Drug Administration. Patient Information Sheet: Cetuximab (marketed as Erbitux). Updated: August 9, 2006. Available at: http://www.fda.gov/cder/drug/InfoSheets/patient/cetuximabPIS.htm. Accessed on December 11, 2006.

1. American Cancer Society. Cancer Facts and Figures 2006. Atlanta: American Cancer Society; 2006. Available at: http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf. Accessed on December 11, 2006.
2. National Cancer Institute. Dictionary of Cancer Terms. Available at: http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=46066. Accessed on December 11, 2006.
3. US National Library of Medicine. Medline Plus. Drug Information: Cetuximab (Systemic). Developed: 04/05/2004. Revised: 05/10/2006. Available at: http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500511.html.  Accessed on December 11, 2006.

Cetuximab
Epidermal Growth Factor Receptor (EGFR)
Erbitux®
Monoclonal Antibody
Vectibix™

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
 

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member's contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

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