Cetuximab in the treatment of head and neck cancer

Approaches to the treatment of locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) have been limited by their toxicity. Effective, better tolerated approaches are urgently required. Cetuximab is an immunoglobulin G(1) monoclonal antibody that specifically targets the epidermal growth factor receptor (EGFR), which is commonly expressed in a number of solid tumors, including SCCHN, where it is associated with poor prognosis. Cetuximab is approved in 56 countries for use in the treatment of EGFR-expressing metastatic colorectal cancer that has progressed on irinotecan-containing therapy and has recently received approval in Europe and the USA for use in the treatment of SCCHN. A randomized Phase III study has demonstrated that cetuximab plus radiotherapy can significantly improve locoregional control and prolong overall survival compared with radiotherapy alone. Cetuximab has also been confirmed to be effective as monotherapy in recurrent and/or metastatic SCCHN that has progressed on platinum-containing therapy. Clinical studies have demonstrated that cetuximab is well tolerated and does not significantly increase the side effects associated with radiotherapy or chemotherapy. This article presents the rationale for EGFR inhibition in the management of head and neck cancers, and the preclinical and clinical evidence for the use of cetuximab in the treatment of SCCHN.     

Cetuximab in the treatment of head and neck cancer

Approaches to the treatment of locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) have been limited by their toxicity. Effective, better tolerated approaches are urgently required. Cetuximab is an immunoglobulin G₁ monoclonal antibody that specifically targets the epidermal growth factor receptor (EGFR), which is commonly expressed in a number of solid tumors, including SCCHN, where it is associated with poor prognosis. Cetuximab is approved in 56 countries for use in the treatment of EGFR-expressing metastatic colorectal cancer that has progressed on irinotecan-containing therapy and has recently received approval in Europe and the USA for use in the treatment of SCCHN. A randomized Phase III study has demonstrated that cetuximab plus radiotherapy can significantly improve locoregional control and prolong overall survival compared with radiotherapy alone. Cetuximab has also been confirmed to be effective as monotherapy in recurrent and/or metastatic SCCHN that has progressed on platinum-containing therapy. Clinical studies have demonstrated that cetuximab is well tolerated and does not significantly increase the side effects associated with radiotherapy or chemotherapy. This article presents the rationale for EGFR inhibition in the management of head and neck cancers, and the preclinical and clinical evidence for the use of cetuximab in the treatment of SCCHN.     

Effect of cetuximab in recurrent and refractory squamous cell carcinoma of the head and neck (SCCHN): a case report

The epidermal growth factor receptor (EGFR) is frequently overexpressed in squamous cell carcinoma of head and neck (SCCHN). Different strategies to target the activated EGFR have reached the clinic. Cetuximab is a monoclonal antibody that selectively binds to the extracellular domain of the EGFR on the tumor cell, thereby inhibiting receptor-associated tyrosine kinase activation. Two randomized phase III clinical trials have recently demonstrated that cetuximab increases the activity of radiotherapy in the treatment of locally advanced SCCHN and of platinum-based chemotherapy in the treatment of metastatic SCCHN. Here we report the clinical case of a long-lasting complete response in a 57-year-old male, who was a current smoker and had a history of alcohol abuse, affected by recurrent locally advanced SCCHN after failure of radiotherapy and of platinum-based chemotherapy.     

Targeted therapy in head and neck cancer: state of the art 2007 and review of clinical applications

In patients with squamous cell carcinoma of the head and neck (SCCHN), tumor recurrence, secondary tumors, and comorbidities contribute to therapy failure, and treatment approaches often are limited by their toxicity. With the incorporation of targeted therapies, the number of options available for patients with SCCHN is growing. The epidermal growth factor receptor (EGFR) is involved in the development and progression of SCCHN and is associated with a poor prognosis. The anti-EGFR monoclonal antibody (MoAb) cetuximab is the first targeted therapy to be developed for SCCHN. Recent data confirmed a survival advantage and enhanced locoregional control of SCCHN with cetuximab plus radiotherapy (RT) in patients with locally advanced (LA) SCCHN. Single-agent cetuximab conferred clinical benefits for patients with platinum-refractory metastatic disease, and a recent phase 3 trial demonstrated a survival benefit with cetuximab and standard platinum-based therapy in the front-line treatment of recurrent/metastatic disease. Cetuximab has a toxicity profile milder than that of cytoxic agents and does not exacerbate RT toxicity when it is used in combination. Small-molecule EGFR-tyrosine kinase inhibitors also have shown promise in combination with chemoradiotherapy or as single agents, although they are in earlier stages of developmental. Other targeted approaches (eg, antiangiogenics) are also under investigation. Ongoing clinical trials will further define targeted treatment roles in all stages of SCCHN.     

EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck

Squamous cell carcinoma of the head and neck (SCCHN) continues to be a source of significant morbidity and mortality. Agents that target the epidermal growth factor receptor (EGFR), including monoclonal antibodies and small molecule tyrosine kinase inhibitors, have demonstrated activity in this disease. The US Food and Drug Administration has approved the monoclonal antibody cetuximab in conjunction with radiation for locally advanced disease, and as a single agent for recurrent/metastatic disease. In addition, recent data have shown a survival benefit for patients with recurrent/metastatic disease who are treated with platinum, fluorouracil, and cetuximab. These promising results have prompted further study of EGFR inhibitors with radiation and cytotoxic chemotherapy to further increase the benefit of treatment for SCCHN.     

New approaches to EGFR inhibition for locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN)

Despite recent advances in radiotherapy and chemotherapy, survival rates for squamous cell carcinoma of the head and neck (SCCHN) have remained poor. The focus of SCCHN therapy has more recently shifted to the molecular level, particularly the epidermal growth factor receptor (EGFR/ErbB) pathway. Several agents that target the EGFR pathway, including monoclonal antibodies and tyrosine kinase inhibitors, are under investigation for SCCHN. Searches of PubMed and results of key oncology congresses were performed to identify relevant articles and abstracts. The EGFR-targeted monoclonal antibody cetuximab is approved for the treatment of locally advanced SCCHN in combination with radiotherapy, for first-line treatment of recurrent or metastatic SCCHN in combination with platinum-based chemotherapy and 5-fluorouracil, and for recurrent or metastatic SCCHN following progression with platinum-based chemotherapy. Other investigational EGFR-targeted monoclonal antibodies (e.g., panitumumab, nimotuzumab, zalutumumab) are in clinical development for SCCHN. Inhibition of the tyrosine kinase domain of EGFR has also been explored as a therapeutic approach in SCCHN using small-molecule reversible inhibitors, such as gefitinib and erlotinib. However, a key challenge in SCCHN is the development of resistance, and strategies are being pursued to delay or overcome resistance to EGFR-targeted agents. These strategies include development of agents that inhibit multiple ErbB receptors simultaneously (e.g., lapatinib) or that bind multiple ErbB family receptors irreversibly (e.g., afatinib, PF-00299804) and investigation of combinations of agents that target multiple pathways implicated in the pathogenesis of SCCHN. Ongoing large clinical trials are evaluating these emerging agents and combinations for the treatment of SCCHN.     

The role of inhibitors of the epidermal growth factor in management of head and neck cancer

Epidermal growth factor receptor (EGFR) is overexpressed in most head and neck cancers and correlates with poor prognosis. In the past few years, numerous clinical trials for head and neck cancer have tested monoclonal antibodies against EGFRs and small molecule inhibitors of EGFR tyrosine kinase. Results led to FDA approval of cetuximab with concomitant radiotherapy for treating locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN), and as a single agent in patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy failed. This article reviews the biology of EGFR as it pertains to head and neck cancer, including the important clinical trials of EGFR monoclonal antibodies and tyrosine kinase inhibitors in SCCHN, alone and with concomitant radiotherapy. Molecular and clinical markers of response and outcome are also discussed.     

Drug Insight: cetuximab in the treatment of recurrent and metastatic squamous cell carcinoma of the head and neck

Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) have a poor prognosis, particularly those whose disease has progressed on previous platinum-containing therapy. The epidermal growth factor receptor (EGFR) is expressed at very high levels in SCCHN and is associated with a poor prognosis. Several phase II-III studies have shown that the EGFR-targeting monoclonal antibody, cetuximab, offers clinical benefit for patients with SCCHN. Cetuximab monotherapy is active in patients whose cancer progresses on platinum-containing therapy. Tumor response and patient survival are in excess of what is achieved with commonly used therapies in this setting. Addition of a platinum regimen to cetuximab in patients with disease that progresses on platinum seems to confer no further benefit over cetuximab alone, either in terms of response rate or survival. In the first-line setting, cetuximab plus platinum and 5-fluorouracil significantly prolongs overall survival compared with platinum and 5-fluorouracil alone. The superior survival observed with cetuximab compared with platinum-based treatment demonstrates that cetuximab is the most active treatment for recurrent and/or metastatic SCCHN, and is of particular clinical significance.     

Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum-based therapies

BACKGROUND: The epidermal growth factor receptor (EGFR) inhibitor cetuximab is active in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The activity of cetuximab was compared with that of commonly used treatments in this setting. METHODS: All patients had recurrent and/or metastatic SCCHN and had progressed on cisplatin- or carboplatin-based chemotherapy. Efficacy data from 3 prospective studies (n=278 patients) that administered cetuximab as a single agent (n=103 patients) or combined with either cisplatin/carboplatin (n=96 patients) or cisplatin (n=79 patients) were compared with the results from a retrospective study of patients who received various second-line treatments (all treatments including best supportive care only, n=151 patients; chemotherapy, n=43 patients). Safety data considered were only those from the cetuximab studies. RESULTS: Over the 3 cetuximab trials, overall response rates from 10% to 13% and disease control rates from 46% to 56% were observed. The median time to disease progression ranged between 2.2 months and 2.8 months, and the median overall survival ranged between 5.2 months and 6.1 months. No patients who progressed on cetuximab alone responded to additional platinum. These survival data compared favorably with those from the retrospective study (median survival, 3.4 months [n=151 patients] and 3.6 months [n=43 patients]). Cetuximab-based treatments generally were tolerated well, and cetuximab did not increase the side effects associated with platinum therapy. CONCLUSIONS: Cetuximab has the potential to prolong survival in patients with recurrent and/or metastatic SCCHN who fail on platinum therapy compared with various second-line therapies. Cetuximab did not increase the toxicities associated with chemotherapy. The results obtained by treatment with cetuximab alone after platinum failure did not appear to differ from the results obtained by reintroducing platinum in combination with cetuximab.     

Cetuximab: a standard approach to the first-line treatment of recurrent and/or metastatic and locally advanced squamous cell carcinoma of the head and neck

The burden of squamous cell carcinoma of the head and neck (SCCHN) on healthcare systems is expected to rise in line with projected increases in population sizes in general, and the relative proportion of elderly individuals in particular, underlining the need for effective, well tolerated treatment strategies. The epidermal growth factor receptor (EGFR)-targeted IgG1 monoclonal antibody, cetuximab, is the only EGFR-targeted agent currently approved for use in the treatment of SCCHN. Adding cetuximab to standard first-line platinum-based chemotherapy in the treatment of recurrent and/or metastatic SCCHN significantly improved overall survival (hazard ratio [HR] 0.80; P = 0.04), progression-free survival (HR 0.54; P < 0.001) and response rates (odds ratio 2.33; P < 0.001), compared to platinum-based chemotherapy alone. This was the first time in 30 years that a significant increase in overall survival had been achieved over platinum-based therapy alone and established cetuximab plus platinum-based chemotherapy as the new standard first-line treatment approach for recurrent and/or metastatic disease. In locally advanced SCCHN, cetuximab plus radiotherapy significantly improved locoregional control (HR 0.68, P = 0.005) and overall survival (HR 0.74; P = 0.03) compared to radiotherapy alone. In both recurrent and/or metastatic disease and locally advanced disease, adding cetuximab to standard therapy was generally well tolerated and did not affect patients’ quality of life. The clinical benefits seen with the addition of cetuximab to standard chemotherapy or radiotherapy make it one of the most significant advances made in SCCHN treatment in recent years.     

Recent advances in molecular-targeted drugs in head and neck cancer

Recently, the integration of radiotherapy and chemotherapy has advanced the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN), allowing functional organ preservation while improving locoregional control and overall survival compared with radiotherapy alone. However, as recurrences remain inevitable, there is an absolute need for alternative modes of therapeutic intervention. Moreover, the use of chemotherapy and radiotherapy also increases the incidence of toxicities such as mucositis, myelosuppression, xerostomia, and dysphasia. More recently, the use of molecular-targeted drugs, which minimally adds to the existing toxicities, along with cytotoxic drugs and radiotherapy has been intensively investigated. Cetuximab is a chimeric IgG1 monoclonal antibody that specifically blocks the epidermal growth factor receptor. In a randomized trial of radiotherapy with or without cetuximab for locally advanced SCCHN, the addition of cetuximab significantly improved the locoregional control and overall survival without an increase in adverse events. Furthermore, a randomized trial of 5-FU and cisplatin with or without cetuximab for recurrent/metastatic SCCHN demonstrated a significant survival benefit for cetuximab combination arms compared with 5-FU and cisplatin arms alone. Based on these findings, many molecular-targeted drugs have been investigated in the treatment of the head and neck cancer to ensure better clinical outcomes in the near future.     

Place des thérapeutiques moléculaires ciblées dans les carcinomes épidermoïdes des voies aérodigestives supérieures

The development of molecular targeted therapies in oncology is currently experiencing rapid growth, focusing primarily on two large categories of molecules, monoclonal antibodies and tyrosine-kinase inhibitors. Their action is directed at different molecular targets, particularly receptors of the HER family such as the epidermal growth factor receptor (EGFR or HER1) and biological factors involved in the neoangiogenesis process such as VEGF. Cetuximab, an anti-EGFR monoclonal antibody, has been shown to be effective in the treatment of epidermoid carcinoma of the upper aerodigestive tract in association with radiotherapy (locally advanced tumors) or with conventional cytotoxic agents (recurrent or metastatic tumors). Intensive research efforts are currently ongoing to develop new molecules with original specific biological targets or able to interact with several molecular pathways, to combine these therapies either amongst themselves or with conventional therapeutic agents (radiotherapy and chemotherapy) and, above all, to determine the predictive factors of their efficacy and toxicity.     

Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck

BackgroundWe evaluated combined targeting with cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in squamous cell carcinoma of the head and neck (SCCHN).Patients and methodsThe combination was studied in human endothelial cells and head and neck and lung cancer xenograft model systems. Patients with recurrent or metastatic SCCHN were treated with weekly cetuximab and bevacizumab, 15 mg/kg on day 1 given intravenously every 21 days, until disease progression. Analysis of tumor biomarkers and related serum cytokines was performed.ResultsCetuximab plus bevacizumab enhanced growth inhibition both in vitro and in vivo, and resulted in potent reduction in tumor vascularization. In the clinical trial, 46 eligible patients were enrolled. The objective response rate was 16% and the disease control rate 73%. The median progression-free survival and overall survival were 2.8 and 7.5 months, respectively. Grade 3–4 adverse events were expected and occurred in less than 10% of patients. transforming growth factor alpha, placenta-derived growth factor, EGFR, VEGFR2 increased and VEGF decreased after treatment but did not correlate with treatment efficacy.ConclusionsCetuximab and bevacizumab are supported by preclinical observations and are well tolerated and active in previously treated patients with SCCHN.     

Cetuximab, a chimeric human mouse anti-epidermal growth factor receptor monoclonal antibody, in the treatment of human colorectal cancer

The recent successful development of monoclonal antibodies that target key components of biological pathways has expanded the armamentarium of treatment options for patients with colorectal cancer (CRC). In particular, the epidermal growth factor receptor (EGFR), a tyrosine kinase growth factor receptor involved in CRC development and progression, is exploited by the newest monoclonal antibody that is available for use in CRC patients. Cetuximab, the first chimeric monoclonal antibody, which has been generated against the EGFR, is currently registered in USA, Europe and worldwide, in combination with irinotecan in the treatment of metastatic CRC patients who have progressed on irinotecan containing chemotherapy. Cetuximab is well tolerated and does not exacerbate the toxicity of concomitant chemotherapy. Furthermore, a series of phase III clinical trials are currently evaluating the combination of cetuximab with standard chemotherapy regimens in the first-line treatment chemotherapy-na?ve patients with metastatic CRC.     

Advances in molecular diagnostics and therapeutics in head and neck cancer

Opinion statement Extensive treatment-related morbidities and stagnant survival rates over the past few decades for patients with squamous cell cancer of the head and neck (SCCHN) emphasize the need for novel diagnostics and therapeutics based on the molecular characteristics of the tumor. The development of an early detection test remains largely preliminary. Much attention has recently been given to saliva-based early detection assays that use accepted tumor markers such as p53 and DNA methylation. Most of these studies have focused on feasibility as opposed to prospective clinical trials. To date, early detection saliva assays have failed to yield a high enough sensitivity and specificity for broad population-based screening. The use of saliva as a noninvasive, inexpensive, and accessible diagnostic substrate remains desirable. Unlike SCCHN diagnostics, molecular-targeted therapies for SCCHN will soon be a reality, with many more compounds in the pipeline. The most promising of these drugs target the epidermal growth factor receptor (EGFR), which is known to be overexpressed in squamous cell carcinomas. Cetuximab, a monoclonal EGFR antibody, has shown efficacy in combination with radiotherapy in advanced SCCHN in a recent phase III trial and is currently being petitioned for US Food and Drug Administration approval. Likewise, erlotinib, an EGFR tyrosine kinase inhibitor, has shown favorable results in phase II trials as monotherapy and in combination with chemotherapy. Gefitinib, another EGFR tyrosine kinase inhibitor, has shown efficacy as monotherapy, in combination with chemotherapy, and with chemoradiotherapy. At least two phase III trials of gefitinib in patients with advanced SCCHN are ongoing. Such low-toxicity, tumor-specific targeting strategies will soon be available for patients with head and neck cancer. The challenge is to establish assays to determine which patients are most likely to benefit from these agents.     

Serum concentrations of interleukin-8, vascular endothelial growth factor, and epidermal growth factor receptor in patients with squamous cell cancer of the head and neck

Squamous cell cancer of the head and neck (SCCHN) is associated with production of pro-inflammatory and pro-angiogenic cytokines. We hypothesized that cytokine serum levels will correlate with tumor volume and aggressiveness. We investigated interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR) in SCCHN. The patient population consisted of normal and irradiated controls: patients with newly diagnosed SCCHN, and patients with recurrent or metastatic disease. Pretreatment sera were studied by ELISA. Serum IL-8 levels, as opposed to VEGF or EGFR, were consistently elevated in patients with recurrent or metastatic disease. The differences in mean serum IL-8, compared to controls, were significant (p=0.02). Serum levels of IL-8 are consistently elevated in patients with recurrent or metastatic SCCHN and elevated levels may correlate with advanced or aggressive disease. Further, more intensive, study of IL-8 as a biomarker in SCCHN is warranted.     

西妥昔单抗联合化疗在复发或转移头颈部鳞状细胞癌中的应用

复发或转移头颈部鳞状细胞癌(SCCHN)预后较差.西妥昔单抗是一种可抑制表皮生长因子(EGFR)的单克隆抗体,并可提高包括顺铂在内的多种化疗药物疗效.多项临床研究结果显示,西妥昔单抗联合化疗对复发或转移头颈部鳞癌有效,以其高疗效和低不良反应在治疗中显示出了优势.     

Therapeutic potential of tyrosine kinase inhibitors in breast cancer

Despite recent advances in the treatment of breast cancer, survival rates for patients with metastatic breast cancer remain poor, and new treatments are still required for both hormone-dependent and hormone-independent disease. The epidermal growth factor receptor (EGFR) is a promising new target for anticancer therapy because it is commonly highly expressed in breast cancer and is implicated in the control of many aspects of tumor biology. Because expression of EGFR is inversely related to expression of the estrogen receptor (ER) and is associated with resistance to currently available breast cancer therapies, EGFR-targeted therapies may be valuable in the treatment of ER-negative tumors and endocrine-resistant, ER-positive tumors. Furthermore, the novel mechanism of action of EGFR-targeted therapies may complement the antitumor activity of existing treatment with cytotoxic agents, radiotherapy, or hormones. In this article, the small-molecule inhibitors of the tyrosine kinase activity of EGFR are discussed, with particular emphasis on the potential use of such agents at each stage of breast cancer, including a potential role in chemoprevention.     

Exploring biomarkers in head and neck cancer

Personalized medicine based on predictive markers linked to drug response, it is hoped, will lead to improvements in outcomes and avoidance of unnecessary treatment in squamous cell carcinoma of the head and neck (SCCHN). Recent research has shown that expression of ERCC1 may predict resistance to treatment with platinum agents. Future testing for this marker may help select the optimal type of chemotherapy. Infection with human papillomavirus (HPV) is associated with less aggressive disease and better prognosis in locally advanced SCCHN treated with chemoradiation or radiation alone; HPV-positive patients may ultimately benefit from less intensive, less toxic therapy. K-RAS mutations, occurring in about 40% of colorectal cancers and associated with lack of benefit from epidermal growth factor receptor (EGFR) antibodies in this disease, are found in <5% of SCCHN patients, making routine testing for K-RAS mutations unwarranted at this time. Virtually all head and neck tumors overexpress EGFR, which limits the usefulness of EGFR expression as a marker for treatment selection. Although the incidence of EGFR tyrosine kinase domain mutations is very rare, a better understanding of the role of EGFR mutations, expression, amplification, and downstream effects in SCCHN may help define the role of EGFR in this setting. These observations caution against extrapolating results obtained with biomarkers in other types of cancer to SCCHN. Validation of each biomarker in the context of SCCHN clinical trials will be required before a specific marker can be incorporated into daily practice.     

Overview of the current status of human epidermal growth factor receptor inhibitors in lung cancer

Although chemotherapy remains the standard of care for lung cancer, new less toxic drugs are urgently needed. Targeted agents represent a new era in cancer therapy, and non-small-cell lung cancer (NSCLC) is at the forefront of many development programs. An exciting target is the human epidermal growth factor receptor (EGFR, ie, HER1), and agents targeting this receptor, including gefitinib, cetuximab, and erlotinib (OSI-774; Tarceva), are being investigated. These agents have antitumor activity and are less toxic than most therapies. Based on phase II data, gefitinib received US approval for third-line treatment of patients with locally advanced or metastatic NSCLC. Cetuximab is licensed in the United States for patients with metastatic colorectal carcinoma. However, erlotinib, recently approved in the United States for second- and third-line treatment of patients with locally advanced or metastatic NSCLC, is the only agent of this class to improve survival as monotherapy in patients with advanced, refractory NSCLC, as shown in a phase III placebo-controlled trial. Phase III trials of erlotinib and gefitinib combined with chemotherapy were disappointing, which could be the result of drug scheduling, chemotherapy combinations, or other factors. Patient characteristics may also affect outcome, and research is ongoing to identify predictive markers of response to enable patient selection and improve outcome. Recently identified mutations within the HER1/EGFR tyrosine kinase (TK) domain may provide insight into why some patients respond rapidly to HER1/EGFR tyrosine kinase inhibitors. Surrogate markers of efficacy are also being investigated, including rash, which could be used to monitor and optimize antitumor activity. Therefore, although more work is required, data indicate that HER1/EGFR inhibitors will play an important role in treating patients with NSCLC.