The contribution of cetuximab in the treatment of recurrent and/or metastatic head and neck cancer

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Abstract

Recurrent and/or metastatic squamous cell carcinoma of the head and neck (HNSCC) continues to be a source of significant morbidity and mortality worldwide. Agents that target the epidermal growth factor receptor (EGFR) have demonstrated beneficial effects in this setting. Cetuximab, a monoclonal antibody against the EGFR, improves locoregional control and overall survival when used as a radiation sensitizer in patients with locoregionally advanced HNSCC undergoing definitive radiation therapy with curative intent. Cetuximab is also active as monotherapy in patients whose cancer has progressed on platinum-containing therapy. In the first-line setting for incurable HNSCC, cetuximab added to platinum-based chemotherapy significantly improves overall survival compared with standard chemotherapy alone. These positive results have had a significant impact on the standard of care for advanced HNSCC. In this review, we will discuss the mechanism of action, clinical data and common toxicities that pertain to the use of cetuximab in the treatment of advanced incurable HNSCC.

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Most cited references 68

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EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

W Pao, V. Miller, M Zakowski … (2004)

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.

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Cancer statistics, 2007.

Ahmedin Jemal, Rebecca Siegel, Elizabeth Ward … (2007)

Each year, the American Cancer Society (ACS) estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. This report considers incidence data through 2003 and mortality data through 2004. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,444,920 new cancer cases and 559,650 deaths for cancers are projected to occur in the United States in 2007. Notable trends in cancer incidence and mortality rates include stabilization of the age-standardized, delay-adjusted incidence rates for all cancers combined in men from 1995 through 2003; a continuing increase in the incidence rate by 0.3% per year in women; and a 13.6% total decrease in age-standardized cancer death rates among men and women combined between 1991 and 2004. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. While the absolute number of cancer deaths decreased for the second consecutive year in the United States (by more than 3,000 from 2003 to 2004) and much progress has been made in reducing mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population.

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Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy.

Jan B Vermorken, José Trigo, Ricardo Hitt … (2007)

To evaluate the efficacy and safety of the epidermal growth factor receptor-directed monoclonal antibody cetuximab administered as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) who experience disease progression on platinum therapy. An open-label multicenter study in which patients with disease progression on two to six cycles of platinum therapy received single-agent cetuximab (initial dose 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) for > or = 6 weeks (single-agent phase). Patients who experienced disease progression could receive salvage therapy with cetuximab plus platinum (combination-therapy phase). From June 2001 to December 2002, 103 patients were enrolled and treated with cetuximab, 53 of whom subsequently received combination therapy. In the single-agent phase, response rate was 13%, disease control rate (complete response/partial response/stable disease) was 46%, and median time to progression (TTP) was 70 days. During the combination-therapy phase, the objective response rate was zero, disease control rate was 26%, and TTP was 50 days. Median overall survival was 178 days. Treatment was well tolerated. The most common cetuximab-related adverse events in the single-agent phase were skin reactions, particularly rash (49% of patients, mainly grade 1 or 2). There was one treatment-related death due to an infusion-related reaction. Single-agent cetuximab was active and generally well tolerated in the treatment of recurrent and/or metastatic SCCHN that progressed on platinum therapy. Response was comparable to that seen with cetuximab plus platinum combination regimens in the same setting.

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Author and article information

Journal

Journal ID (nlm-ta): Biologics

Journal ID (publisher-id): Biologics: Targets & Therapy

Title: Biologics : Targets & Therapy

Publisher: Dove Medical Press

ISSN (Print): 1177-5475

ISSN (Electronic): 1177-5491

Publication date Collection: 2010

Publication date (Print): 2010

Publication date (Electronic): 9 August 2010

Volume: 4

Pages: 173-185

Affiliations

Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

Author notes

Correspondence: Ranee Mehra, 333 Cottman Ave., Philadelphia, PA 19111, USA, Tel +1 215-214-4297, Fax +1 215-728-3639, Email ranee.mehra@ 123456fccc.edu

Article

Publisher ID: btt-4-173

PMC ID: 2921255

PubMed ID: 20714355

SO-VID: 01640788-968f-49fe-b45a-2c1f18eabbb6

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This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

The contribution of cetuximab in the treatment of recurrent and/or metastatic head and neck cancer

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Network and Systems Medicine

Most cited references 68

EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

Cancer statistics, 2007.

Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy.

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