This document addresses the treatment of oncologic conditions with cetuximab (Erbitux; Eli Lilly and Company, Indianapolis, IN), a recombinant human and mouse chimeric monoclonal IgG1 antibody that binds to and inhibits the biologic activity of the human epidermal growth factor receptor (EGFR).
Note: For additional information, please refer to the following related documents:
* A course of panitumumab discontinued because of adverse reaction, not progressive disease, is not considered prior treatment.
** If cetuximab is recommended as initial therapy, it should not be used in second or subsequent lines of therapy.
Investigational and Not Medically Necessary:
Cetuximab is considered investigational and not medically necessary when the above criteria are not met including, but not limited to:
Cetuximab is considered investigational and not medically necessary when used in combination with other monoclonal antibodies.
Cetuximab and panitumumab are currently two intravenous anti-EGFR therapies approved by the U.S. Food and Drug Administration (FDA) to treat malignancies. Cetuximab is thought to interfere with the growth of cancer cells by blocking the activation of receptor-associated kinases, inducing apoptosis and decreasing the production of vascular endothelial growth factor. Antibody-dependent cellular cytotoxicity (ADCC) against specific human tumor types may also be mediated by cetuximab. However, the specific mechanism of anti-tumor effect in vivo is unknown (Product Information Label, 2013).
Treatment of Metastatic Disease
Cetuximab is currently FDA approved for treatment of EGFR-expressing, metastatic colorectal carcinoma used in combination with irinotecan, in individuals who are refractory to both oxaliplatin- and irinotecan-based regimens and as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma in individuals who are intolerant to irinotecan-based chemotherapy; in combination with radiation therapy (Product information Label, 2015). The prescribing information notes that cetuximab is not indicated in Ras-mutant colorectal cancer or in those cases in which the Ras mutation status is unknown. KRAS testing is discussed further below.
The criteria in the Position Statement are based on the selection criteria in the pivotal trial as well as the expert view of medical practitioners practicing in the clinical area of oncology, who have familiarity with the available evidence at this time. While both cetuximab and panitumumab are used in the treatment of metastatic colorectal cancer, there are no published head-to-head comparisons between the drugs. In addition, there is no published peer-reviewed literature to support use of cetuximab in second or subsequent lines of therapy when cetuximab was used as initial therapy.
In 2017, the NCCN Clinical Practice Guidelines (CPGs) in Oncology® for advanced stage IV colon and rectal adenocarcinoma include off-label recommendations for cetuximab as a single agent and in combination therapy based on 2A category of evidence and uniform consensus. These guidelines do not recognize the use of cetuximab for treatment of squamous cell anal cancer.
Small bowel or appendix adenocarcinomas are rare and there is little to no high-level data regarding these conditions. The 2017 NCCN Colon Cancer CPG recommends that systemic chemotherapy of these conditions follow the NCCN colon cancer guidelines.
There are several recommended off-label uses of cetuximab in combination therapy for metastatic colorectal carcinoma. These regimens include the use of agents such as fluorouracil (5-FU), irinotecan and oxaliplatin. In some situations, the oral formulation of 5-FU, capecitabine, is recommended as equivalent to infused 5-FU (NCCN, 2017).
Primary Tumor Sidedness
Evidence exists that supports that the location of the primary tumor is an integral factor in predicting whether cetuximab will be effective. Little to no benefit was found in those tumors treated with cetuximab which originated on the right side (cecum to hepatic flexure). Conversely, cetuximab appears to offer benefit when used to treat tumors originating on the left side (splenic flexure to rectum). The 2017 NCCN CPG for colon cancer recommends that cetuximab be limited as a first-line treatment of metastatic disease to those with left-sided tumors. While the evidence suggests that sidedness might also be predictive of response on subsequent lines of therapy, further definitive studies are needed.
Cetuximab in Combination with Other Monoclonal Antibodies
In a phase III open-label trial, 732 individuals with metastatic, unresectable colon or rectal carcinoma were randomized to receive treatment with capecitabine-bevacizumab (CB) and oxaliplatin, or capecitabine-bevacizumab-cetuximab (CBC) with oxaliplatin (Tol, 2009). The CBC cohort had a significantly decreased median progression-free survival (PFS), quality of life and health status compared to the CB group. The authors concluded that the addition of cetuximab to capecitabine, oxaliplatin and bevacizumab "resulted in a significant decrease in progression-free survival and a poorer quality of life." This was supported by a second phase III study (Hecht, 2009).
The 2017 NCCN CPG® notes that the panel "strongly recommends against the use of therapy involving concurrent combination of an anti-EGFR agent (cetuximab or panitumumab) and an anti-VEGF agent (bevacizumab).
Alberts and colleagues (2012) reported results from a phase III randomized trial investigating the addition of cetuximab to adjuvant chemotherapy for individuals with stage III disease. The trial was halted when data from the second interim analysis did not demonstrate improved disease-free survival (DFS) probabilities in comparison to the control group (74.6% compared to 71.5%) respectively. The investigators noted although cetuximab has demonstrated improved outcomes in the metastatic colorectal setting, additional studies are needed to determine the efficacy of cetuximab in the adjuvant setting. The 2017 NCCN CPG notes that cetuximab "has no role in the adjuvant treatment of colon cancer."
Studies of metastatic colorectal carcinoma treatment have shown there are subsets of individuals who are not as responsive to anti-EGFR monoclonal antibodies. Research into the KRAS gene has demonstrated that the absence of mutations in the KRAS gene (i.e. KRAS wild-type) is a predictive factor for a positive response to cetuximab therapy. Therefore the mutation status of the KRAS has emerged as an important selection criterion and is included in the FDA label. For example, in a systematic review and meta-analysis, Adelstein and colleagues (2011) analyzed data from 11 studies that included 8924 individuals treated with anti-EGFR therapy. Individuals with KRAS wild-type had a hazard ratio (HR) for progressive disease of 0.80 (4436 individuals 95% confidence interval [CI], 0.64, 0.99) compared to 1.11 (3119 individuals, 95% CI, 0.97, 1.27) in those with the mutant KRAS. The authors concluded the status of KRAS mutation modified the treatment effect of anti-EGFR therapy in the treatment of metastatic CRC. Van Cutsem (2011) reported updated results from a phase III randomized controlled trial (CRYSTAL) of cetuximab combined with irinotecan in first-line therapy for metastatic CRC. The KRAS status was determined in 1063 (89%) individuals of a total 1198 participants. In individuals with KRAS wild-type metastatic CRC treated with the cetuximab regimen, there were significant improvements in overall survival (OS) with a median survival of 23.5 months compared to 20.0 months, and improved response rates of 57.3% compared to 39.7% (p<0.001) in the control group. The authors concluded KRAS mutation status was a predictive biomarker for efficacy of cetuximab. Other studies have offered similar conclusions (De Roock, 2008; Karapetis, 2008; Messersmith, 2008).
The updated NCCN guidelines (2017) note "The panel believes that patients with any known KRAS mutation, including G13D, should not be treated with cetuximab or panitumumab". Use of cetuximab is indicated for individuals with tumors that express the wild-type KRAS gene. The American Society of Clinical Oncology (ASCO) (Allegra, 2009) issued a provisional, consensus clinical opinion based on systematic reviews of literature primarily from phase II and III clinical trials involving individuals with metastatic colorectal cancer:
All individuals with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then individuals with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment.
Unlike KRAS testing, EGFR testing of colorectal tumor cells has not demonstrated predictive value in determining the likelihood of a response to either cetuximab or panitumumab. Thus, this testing is not required to establish medical necessity for this indication for cetuximab. However, in 2015, the product label was updated to note the following for colorectal cancer "Determine EGFR-expression status using FDA-approved tests prior to initiating treatment."
BRAF V600E Mutations
The NCCN CPG was revised in 2017 to note that the presence of BRAF V600E mutation makes a response to cetuximab or panitumumab highly unlikely. However, the guideline does not explicitly state that individuals with a BRAF V600E should not be treated with these drugs. The guideline does include a 2A recommendation that the workup of a suspected or proven metastatic synchronous adenocarcinoma should include determination of tumor gene status for both RAS and BRAF.
Squamous cell anal cancer is the most common histologic form of anal cancer. Adenocarcinoma and melanoma of the anal canal represent infrequently occurring subtypes of anal carcinoma. The management of anal adenocarcinoma generally follows management strategies for rectal cancer according to the NCCN Anal Carcinoma CPG (NCCN, 2017). Specialty consensus opinion also supports the recommendations to treat stage IV anal adenocarcinoma similar to stage IV colorectal adenocarcinoma.
Head and Neck Carcinoma
In 2006, the FDA approved cetuximab in combination with radiation therapy, as treatment of locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN). An additional approval was given for use as a single agent for the treatment of individuals with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed. In 2011, the FDA approved cetuximab in combination with platinum-based therapy with 5-FU for the first-line treatment of individuals with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck (Product Information Label, 2015). The FDA based their approval, in part, on the results of randomized Phase III trials reporting that the addition of cetuximab to standard chemotherapy regimens improved response rates and survival (Burtness, 2005; Vermorken, 2008).
Since expression of EGFR has been detected in nearly all individuals with head and neck cancer, individuals enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR expression prior to study entry (Product Information Label, 2015).
Additional recommended off-label uses for cetuximab include single-agent, combination with chemotherapy, with or without radiation therapy for the treatment of recurrent, unresectable or metastatic squamous cell carcinoma of the head and neck (American Hospital Formulary Service® [AHFS® ], 2015). The 2017 NCCN CPG for Head and Neck Cancers includes the same recommendation when there is no surgery or radiotherapy option.
Squamous Cell Carcinoma of the Skin (SCCS)
The 2017 NCCN guidelines note the rarity of cutaneous squamous cell cancer with distant metastases, and the lack of systemic therapy information. Retrospective case reports have described responses to cetuximab treatment in individuals with metastatic, unresectable SCCS. In a phase II, multicenter, open-label study, cetuximab was used as first-line chemotherapy to treat individuals with metastatic, unresectable SCCS. The initial dose of cetuximab infusion was 400 mg/m2 , with subsequent weekly doses of 250 mg/m2 . The primary endpoint was disease control rate (DCR) after 6 weeks of treatment. Thirty-one participants were evaluable out of 36 enrolled individuals. Based on intent to treat analysis, the DCR was 69% (95% CI, 52% to 84%). The best overall response rate was 28% (95% CI, 14% to 45%) which included 2 individuals with complete response (CR) and 6 participants with partial response (PR). The most frequently occurring adverse event was grade 1 to grade 2 acne-like rash.
The efficacy of cetuximab as a treatment for squamous cell carcinoma was noted in limited but supportive published case series and specialty consensus opinion, including the NCCN Clinical Practice Guideline (2017) category 2A recommendation.
A phase II trial by Hasselbach and colleagues (2010) investigated the combination of cetuximab, bevacizumab and irinotecan to treat individuals with progressive primary glioblastoma multiforme (GBM) within 6 months of initial radiation and temozolomide therapy. The overall response rate based on intent to treat was 26% (95% CI: 14%-41%). When compared to data from other studies utilizing bevacizumab with or without irinotecan, the authors concluded the addition of cetuximab to the bevacizumab regimen was not supported as "the response rate does not appear to be superior with the addition of cetuximab."
Ménétrier's disease is a rare disorder characterized by a premalignant hyperproliferative disorder of epithelial cells and diffusely enlarged gastric folds (Fiske, 2009). The presenting signs and symptoms include abdominal pain, nausea, vomiting, anemia, hypochlorhydria and peripheral edema. Due to severe symptoms, lack of effective medical therapy and concern of transformation into gastric cancer, individuals with intractable symptoms require partial or total gastrectomy. A single-arm study of cetuximab treatment reported that in 7 of the 9 enrolled participants who completed the 4-week trial period, there was improvement in the predominant presenting symptoms; improved quality of life; and reduced Ki-67, a marker of cellular proliferation. The investigators noted due to the rarity of Ménétrier's disease, a randomized controlled study was not feasible, and this case series demonstrates resolution of severe predominant symptoms in some individuals is possible. However, further data is needed to determine the long-term efficacy of cetuximab treatment for Ménétrier's disease.
Non-Small Cell Lung Cancer (NSCLC)
The role of cetuximab in NSCLC has been controversial. The key pieces of data are the results of two randomized trials, the open-label FLEX trial and the BMS099 trial, both of which compared cetuximab with and without chemotherapy in individuals with advanced NSCLC.
The FLEX trial randomized 1125 participants to receive chemotherapy (cisplatin, vinorelbine) alone (n=568) or chemotherapy plus cetuximab (n=557). With a median follow-up of 23.8 months, there was a significantly prolonged OS in the chemotherapy plus cetuximab group versus chemotherapy alone (HR 0.871, 0.762-0.996; p=0.044). The median OS in the chemotherapy plus cetuximab group was 11.3 months (9.4-12.4) versus 10.1 months (9.1-10.9) in the group treated with chemotherapy (Pirker, 2009).
The BMS099 trial randomized 676 participants to receive chemotherapy (taxane/carboplatin [TC]) alone (n=338) or chemotherapy plus cetuximab (n=338). There was no significant difference in median progression-free survival (4.40 months for cetuximab/TC, 4.24 months for TC alone, p=0.236). The cetuximab/TC group had a slightly longer OS of 9.69 months, but it was not statistically significant versus 8.38 months for the TC group (HR=0.890; 95% CI, 0.754-1.051; p=0.169) (Lynch, 2010).
The clinical significance of these results has been questioned. In 2009, the American Society of Clinical Oncology (ASCO) clinical guideline update on chemotherapy for stage IV NSCLC, recommendations for first-line chemotherapy included cetuximab with cisplatin and vinorelbine for individuals with EGFR-positive tumors. This guideline was updated in 2011, without any change to the recommendation for use of cetuximab (Azzoli, 2011).
Janjigian and colleagues (2014) evaluated the use of afatinib and cetuximab in individuals with advanced EGFR-mutant lung cancer who had been heavily pre-treated and had acquired resistance to erlotinib/gefitinib (n=126). Treatment continued until disease progression, intolerable adverse events withdrawal or death. Efficacy endpoints included objective response (OR) and progression-free survival (PFS). Within the treated population, 29% (37/126) had confirmed OR and of those, 18% (22/126) had at least a 50% shrinkage of the tumor size. The median duration of response lasted 5.7 months. None of the subjects showed a complete response to treatment. An additional 41% (52/126) were reported as having stable disease. The median PFS was 4.7 months (95% CI, 4.3–6.4). Treatment related adverse events (AEs) were reported in 99% of subjects. Grade 3 and 4 AEs were reported in 44% and 2% of the treated population respectively. Serious treatment related events were reported in 14% of individuals and 13% of individuals discontinued treatment due to treatment related AEs.
The 2017 NCCN CPG for NSCLC includes a 2A recommendation for the use of afatinib/cetuximab for those with sensitizing EGFR mutations who have progressed following EGFR tyrosine kinase inhibitors (TKIs) and chemotherapy. This was based on one phase Ib, open-label, uncontrolled, multicenter study (Janjigian 2014). Confirmatory trials are underway. In 2015, NCCN assigned a category 3 recommendation (i.e., denoting significant disagreement that the intervention is appropriate) for the use of cetuximab in the treatment of advanced NSCLC citing concerns of toxicity with the regimen containing cetuximab, cisplatin and vinorelbine. This regimen was removed from the treatment algorithms and recommended chemotherapy lists. The guidelines concluded, "Some clinicians feel that although the FLEX trial results were statistically significant they were not clinically significant."
In 2013, the American College of Chest Physicians (ACCP) published guidelines regarding the treatment of Stage IV NSCLC (Socinski, 2013) which assigned a 2B recommendation to cetuximab regimens and suggested that the drug should not be used outside of a clinical trial. The document summarizes the data as follows:
In summary, the data are conflicting with regard to the impact of adding cetuximab to platinum-based chemotherapy in the first-line setting of advanced NSCLC. There appears to be an improvement in response rates as a result of adding cetuximab, but no effect on PFS and no consistent effect on overall survival. In the trials in which there has been a survival benefit, the magnitude of the benefit is very modest and not felt to be clinically robust, particularly relative to the toxicity….
Casino and colleagues (2008) reported results from a phase II trial that randomized 84 individuals with advanced pancreatic carcinoma to receive either chemotherapy with gemcitabine and cisplatin with and without cetuximab. At a median follow-up of 11.8 months, there was no significant difference for the primary endpoint of objective response. The investigators concluded that the addition of cetuximab did not have a significantly positive effect and therefore, "should not be further assessed in phase III trials."
The NCCN CPG (2017) for pancreatic cancer does not recommend the addition of cetuximab to chemotherapy as an off-label indication to treat pancreatic adenocarcinoma. The guidelines note a phase III trial reported a lack of improvement in OS with the addition of cetuximab.
Penile Squamous Cell Cancer
Carthon and colleagues (2014) reported results from a retrospective analysis of 23 men with metastatic penile squamous cell cancer and 1 individual with metastatic scrotal cancer. All men received an EGFR-targeted agent after a prior line of therapy in a majority (22/24) of the men and after 2 lines of therapy in a third (8/24). Three men in this cohort were treated with EGFR-targeted therapy other than cetuximab. PR was observed in 1/5 men treated with cetuximab alone. PR was reported in 5/15 individuals who received cetuximab in combination with other chemotherapy. The most common (71%) adverse event was grade I/II skin rash. With a median follow-up of 207 days (14-1441 days), the median overall time to progression (TTP) for the cohort was 79 days (range, 11-281 days). The median overall survival (OS) was 207 days (range 14-1441 days). The authors reported OS and TTP were worse in men with visceral, soft tissue or bone metastases. The authors noted limitations to this study include the retrospective nature and the non-standardized chemotherapy regimens used to treat the men. The authors concluded the study demonstrated tolerable therapy with EGFR-targeted agents and recommended further prospective studies are needed.
The 2017 NCCN CPG for penile cancer recommends cetuximab as a 2A off-label indication as a second line of therapy, particularly if not previously treated with a similar class or agent. However, the literature is based primarily on case reports and retrospective non-randomized studies. Data from prospective studies are recommended.
There are ongoing trials studying additional indications such as multiple myeloma, solid tumors (including breast cancer, ovarian, esophageal, GBM, urothelial and pancreatic cancers), and at different stages of various diseases (e.g., early stage colorectal cancer). The use of cetuximab in combination with a variety of chemotherapy or other biologic agents is also under investigation. However, further data is needed to determine the efficacy and safety of cetuximab therapy for these indications.
Colorectal cancer refers to malignancies originating from the large intestine (colon) or the rectum. The term colorectal cancer does not include anal cancer. Anal cancer refers to malignancies developing from anal tissue (e.g., anus, anal canal or anorectum) which include the opening of the rectum to the outer body. Anal cancer occurs infrequently and represents 3% of all cancers of the lower gastrointestinal tract (National Cancer Institute [NCI], 2016; NCCN, 2017).
According to the NCI (2017), head and neck carcinomas account for approximately 4% of all cancers in the United States and are twice as common in men compared to women. People over age 50 are diagnosed more often than younger people. Head and neck cancer usually originates in the squamous cells that line the moist, mucosal surfaces within the head and neck. Cancers that are included in the head and neck category include tongue, mouth, pharynx, larynx, nasal cavity, sinus, salivary glands, and other sites located in the head and neck area.
About 90% of head and neck cancers are of the squamous cell variety and almost 100% of these express EGFR, which is critical for tumor growth. Therefore, as noted in the cetuximab product information (2015), and based on the entry criteria for individuals enrolled in the head and neck cancer clinical trials, pretreatment assessment for evidence of EGFR expression was not required for individuals with squamous cell carcinoma of the head and neck.
Non-melanoma skin cancer is the most common type of cancer in the United States. Subtypes of non-melanoma skin cancer include basal cell and squamous cell skin cancer. According to the American Cancer Society (ACS), approximately 3.3 million non-melanoma cell skin cancers are diagnosed annually, and about 80% of the cases are basal cell cancers. The precise incidence is unclear as skin cancers are not reported to cancer registries. Risk factors for skin cancer include exposure to ultraviolet (UV) radiation; fair skin complexion; exposure to chemicals or radiation therapy; reduced immunity; human papilloma virus (HPV) infection and smoking. Primary treatment for squamous cell carcinoma typically involves surgery or radiation. Individuals with increased risk of the cancer spreading or recurring may be treated with radiation or chemotherapy (ACS, 2017; NCI, 2015).
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. Cetuximab is a monoclonal antibody that binds specifically to the human EGFR. As a result, Cetuximab may interrupt the signals necessary for the cancer cells' growth and survival.
Adverse Events and Warnings:
Black box warnings from the FDA Product Information Label (2015) include the following serious infusion reactions and cardiopulmonary arrest:
Additional Warnings from the FDA Product Information Label (2015) include:
Pulmonary toxicity as evidenced by interstitial lung disease (ILD) has been reported in individuals with squamous cell carcinoma of the head and neck treated with cetuximab. ILD, including 1 fatality, occurred in 4 of 1570 (<0.5%) individuals receiving cetuximab in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt cetuximab for acute onset or worsening of pulmonary symptoms. Permanently discontinue cetuximab for confirmed ILD.
Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving cetuximab therapy. Acneiform rash occurred in 76–88% of 1373 individuals receiving cetuximab in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1–17% of patients.
Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Erbitux. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Monitor individuals receiving cetuximab for dermatologic toxicities and infectious sequelae. Individuals should limit sun exposure during cetuximab therapy.
In individuals evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 participants receiving cetuximab in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI Common Toxicity Criteria Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of cetuximab. Periodically monitor individuals for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of cetuximab. Replete electrolytes as necessary.
Adenocarcinoma: Cancer originating in cells that line specific internal organs and that have gland-like (secretory) properties.
Anal cancer: Cancer originating in the tissues of the anus; the anus is the opening of the rectum (last part of the large intestine) to the outside of the body.
Apoptosis: A series of molecular steps resulting in a type of cell death. The body's normal way of getting rid of unneeded or abnormal cells; programmed cell death.
Colon cancer: Cancer originating in the tissues of the colon (the longest part of the large intestine). Most colon cancers are adenocarcinomas that begin in cells that make and release mucus and other fluids.
Colorectal cancer: Cancer originating in the colon (the longest part of the large intestine) or the rectum (the last several inches of the large intestine before the anus).
Head and neck cancer: Cancer that arises in the head or neck region (in the nasal cavity, sinuses, lips, mouth, salivary glands, throat, or larynx [voice box]).
KRAS wild-type: The normal or typical form of the KRAS gene, as distinguished from any mutant forms of KRAS; KRAS lacking mutation.
Line of therapy:
Metastasis: The spread of cancer from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.
Monoclonal antibody: A protein developed in the laboratory that can locate and bind to a specific substance in the body.
Non-small cell lung cancer: A group of lung cancers that are named for the kinds of cells found in the cancer and how the cells look under a microscope. The three main types of non-small cell lung cancer are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Non-small cell lung cancer is the most common kind of lung cancer.
Off-label: Utilization of a United States Food and Drug Administration (FDA) approved drug for uses other than those listed in the FDA approved labeling.
Partial response: A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment; also called partial remission.
Rectal cancer: Cancer originating in tissues of the rectum (the last several inches of the large intestine closest to the anus).
Vascular endothelial growth factor (VEGF): A substance made by cells that stimulates new blood vessel formation.
The following codes for treatments and procedures applicable to this document 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:
|J9055||Injection, cetuximab, 10 mg [Erbitux]|
|C00.0-C14.8||Malignant neoplasm of lip, oral cavity and pharynx|
|C17.0-C17.9||Malignant neoplasm of small intestine|
|C18.0-C20||Malignant neoplasm of colon, rectosigmoid junction, rectum|
|C21.0-C21.8||Malignant neoplasm of anus and anal canal|
|C30.0-C32.9||Malignant neoplasm of nasal cavities, ear, sinuses, larynx|
|C39.0||Malignant neoplasm of upper respiratory tract, part unspecified|
|C44.02||Squamous cell carcinoma of skin of lip|
|C44.121-C44.129||Squamous cell carcinoma of skin of eyelid, including canthus|
|C44.221-C44.229||Squamous cell carcinoma of skin of ear and external auricular canal|
|C44.320-C44.329||Squamous cell carcinoma of skin of nose and other/unspecified parts of face|
|C44.42||Squamous cell carcinoma of skin of scalp and neck|
|C44.520-C44.529||Squamous cell carcinoma of anal skin, skin of breast and other part of trunk|
|C44.621-C44.629||Squamous cell carcinoma of skin of upper limb, including shoulder|
|C44.721-C44.729||Squamous cell carcinoma of skin of lower limb, including hip|
|C44.82||Squamous cell carcinoma of overlapping sites of skin|
|C44.92||Squamous cell carcinoma of skin, unspecified|
|C49.0||Malignant neoplasm of connective and soft tissue of head, face and neck|
|C76.0||Malignant neoplasm of head, face and neck|
|C77.0||Secondary and unspecified malignant neoplasm of lymph nodes of head, face and neck|
|C78.5||Secondary malignant neoplasm of large intestine and rectum|
|C79.2||Secondary malignant neoplasm of skin|
|D00.00-D00.08||Carcinoma in situ of lip, oral cavity and pharynx|
|D02.0||Carcinoma in situ of larynx|
|Z51.11-Z51.12||Encounter for antineoplastic chemotherapy and immunotherapy|
|Z85.038||Personal history of other malignant neoplasm of large intestine|
|Z85.048||Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus|
|Z85.810-Z85.819||Personal history of malignant neoplasm of lip, oral cavity and pharynx|
When services are Investigational and 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 Position Statement section as investigational and not medically necessary.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
Epidermal Growth Factor Receptor (EGFR)
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.
|Revised||05/04/2017||Medical Policy & Technology Assessment Committee (MPTAC) review.|
|Revised||05/03/2017||Hematology/Oncology Subcommittee review. Added appendicular to the Colorectal and Anal Adenocarcinoma medically necessary statement. Updated Rationale, References and Website sections.|
|Reviewed||05/04/2016||Hematology/Oncology Subcommittee review. Updated Rationale, Background, Websites and References sections. Removed ICD-9 codes from Coding section.|
|Reviewed||05/06/2015||Hematology/Oncology Subcommittee review. Updated Rationale, Background, Websites and References sections|
|Revised||05/14/2014||Hematology/Oncology Subcommittee review. Removed treatment of non-small cell lung cancer from the medically necessary indication and added as an investigational and not medically necessary indication. Updated Rationale, Background, Coding, Websites and References sections.|
|Revised||11/13/2013||Hematology/Oncology Subcommittee review. Added small bowel adenocarcinoma as medically necessary indication. Updated Rationale, Background, Coding, Websites and References sections.|
|Revised||05/08/2013||Hematology/Oncology Subcommittee review. Clarification of existing criteria. Integrated medically necessary criteria A-C into each specific clinical indication. Additional medically necessary indication for NSCLC – single agent maintenance therapy if used as part of first-line combination regimen (vinorelbine and cisplatin). Updated Rationale, Background, Websites and References.|
|Revised||05/09/2012||Hematology/Oncology Subcommittee review. Clarified KRAS wild-type in medically necessary Position Statement. Added clarifying note to Position Statement. Updated Rationale, Background, Coding, Websites and References.|
|Revised||11/16/2011||Hematology/Oncology Subcommittee review. Added medically necessary indication to reflect FDA approval for treatment of squamous cell carcinoma of the head and neck. Added medically necessary indication for squamous cell carcinoma of the skin with criteria. Updated Rationale, Background, Coding, Websites and References.|
|10/01/2011||Updated Coding section with 10/01/2011 ICD-9 changes.|
|Reviewed||05/18/2011||Hematology/Oncology Subcommittee review. Updated Rationale, Background, Websites and References.|
|Revised||05/12/2010||Hematology/Oncology Subcommittee review. Reformatted off-label indications. Removed CapeOx combination from off-label medical necessity criteria. Clarified criteria for head and neck carcinoma and NSCLC. Updated rationale, background, websites and references.|
|Revised||05/20/2009||Hematology/Oncology Subcommittee review. Updated rationale, background, coding, websites and references. Added medically necessary criteria for metastatic colorectal carcinoma- neoadjuvant, initial therapy, and single agent for progressive disease. Added medically necessary criteria for combination therapy for head and neck carcinoma. Added medically necessary indication for non-small cell lung cancer with criteria.|
|Revised||02/26/2009||MPTAC review. Additional medical necessity criteria for metastatic anal adenocarcinoma. Clarified definitions. Background, websites and coding updated.|
|Revised||11/19/2008||Hematology/Oncology Subcommittee review. Clarified medically necessary indications for metastatic colorectal carcinoma. Added new tumor expression of KRAS wild-type criteria. Clarified the combined use with other monoclonal antibodies is considered investigational and not medically necessary. Updated rationale, references and websites.|
|Revised||05/14/2008||Hematology/Oncology Subcommittee review. Replaced USP DI reference information with DrugPoints information. Clarified the medically necessary criteria for head and neck cancer excluded the combination with other monoclonal antibodies and after panitumumab treatment. Added criteria for use in only one line of therapy. Added "including but not limited to use as adjuvant therapy after resection" to the investigational and not medically necessary head and neck criteria. Updated rationale, references and websites.|
|Reviewed||11/28/2007||Hematology/Oncology Subcommittee review. Title changed. Rationale, references, coding and websites updated. The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary."|
|04/20/2007||Coding updated with ICD-9 Diagnosis codes 153.0-154.8 and V10.05-V10.06.|
|New||12/06/2006||Hematology/Oncology Subcommittee review. Initial document development.|