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.     

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.     

Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck

Despite significant advances in the use of surgery, chemotherapy and radiotherapy to treat squamous cell carcinoma of the head and neck (SCCHN), prognosis has improved little over the past 30 years. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of SCCHN disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. The epidermal growth factor receptor (EGFR) is expressed at much higher levels in SCCHN tumours than in normal epithelial tissue, and EGFR expression correlates with poor prognosis. Therefore, much effort is currently directed toward targeting aberrant EGFR activity (e.g. cell signalling) in SCCHN. This review discusses the efficacy of novel therapies targeting the EGFR (e.g. anti-EGFR antibodies and EGFR tyrosine kinase inhibitors) that are currently tested in SCCHN patients.     

Consensus guidelines for the management of radiation dermatitis and coexisting acne-like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck

Background: Radiation dermatitis occurs to some degree in mostpatients receiving radiotherapy, with or without chemotherapy.Patients with squamous cell carcinoma of the head and neck (SCCHN)who receive radiotherapy in combination with epidermal growthfactor receptor (EGFR) inhibitors, such as cetuximab, may developa characteristic acne-like rash in addition to dermatitis. Design: An advisory board of 11 experienced radiation oncologists,medical oncologists and dermatologists discussed the managementoptions for skin reactions in patients receiving EGFR inhibitorsand radiotherapy for SCCHN. Skin toxicity was categorised accordingto the National Cancer Institute—Common Terminology Criteriafor Adverse Events (version 3) grading. Results: Both general and grade-specific approaches for themanagement of dermatitis in this patient group are presented.It was concluded that where EGFR inhibitor-related acne-likerash and dermatitis coexist within irradiated fields, managementshould be based on the grade of dermatitis: for grade 1 (orno dermatitis), treatment recommendations for EGFR-related acne-likerash outside irradiated fields should be followed; for grades2 and above, treatment recommendations for dermatitis were proposed. Conclusions: This paper presents comprehensive consensus guidelinesfor the treatment of dermatitis in patients with SCCHN receivingEGFR inhibitors in combination with radiotherapy. Key words: cetuximab, EGFR inhibitors, radiation dermatitis, radiotherapy, skin reactions, squamous cell carcinoma of the head and neck Received for publication June 26, 2007. Revision received July 12, 2007. Accepted for publication July 12, 2007.     

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.     

Targeted therapies in head and neck cancer

Over the past decade, the important role of different growth factors and their receptors and signal transduction pathways in the genesis and progression of tumors has been well recognized and their mechanism of action and interactions is gradually being unraveled. Epidermal growth factor receptor (EGFR) overexpression is present in the vast majority of squamous cell head and neck cancers and carries a worse prognosis. EGFR is the target of multiple specifically targeted monoclonal antibodies and tyrosine kinases, which are in various stages of clinical development in squamous cell carcinoma of the head and neck (SCCHN). The search for EGFR mutations is an area of active investigation. The incidence and impact of EGFR mutations in SCCHN has yet to be determined. EGFR downstream signaling pathways are the target of farnesyltransferase inhibitors (FTIs) and mammalian target of rapamycin (mTOR) inhibitors. Cyclooxygenase-2 (COX-2) is overexpressed in premalignant lesions (oral leukoplakia) and in squamous cell carcinoma of the head and neck. EGFR and COX-2 signaling pathways form a positive feedback loop. As their toxicity profiles are non-overlapping, combination of COX-2 inhibitors and EGFR targeted therapies looks attractive. The majority of the studies, although not all, examining the prognostic significance of vascular endothelial growth factor (VEGF) expressing did observe a worse outcome in patients with SCCHN expressing VEGF and VEGF receptor 2 (VEGFR-2). Anti-VEGF strategies include neutralizing antibodies to VEGF or VEGFR and VEGFR tyrosine kinase inhibitors. Aurora kinase inhibitors, insulin like growth factor inhibitors, and histone acetylase inhibitors have recently gained interest as potential new promising ways of tackling tumors including SCCHN.     

Epidermal growth factor receptor inhibitor-related skin toxicity: mechanisms, treatment, and its potential role as a predictive marker

The human epidermal growth factor receptor (HER1/EGFR/ErbB1) signaling is aberrant and overexpressed in many solid malignancies making it an appealing target for biologic agents. Among the classes of drugs targeting EGFR are monoclonal antibodies and EGFR tyrosine kinase inhibitors, which have been shown effective and generally well tolerated in different clinical settings. The majority of patients treated with EGFR inhibitors (EGFRIs) develop specific dose-dependent skin toxicity. This side effect may lead to physical and psychosocial discomfort which can result in dose reduction or treatment interruption. The relationship between rash and clinical outcome has stimulated interest in this particular toxicity as a possible surrogate marker of efficacy in patients treated with targeted agents against EGFR. This review aims to summarize and update the current knowledge of the clinical presentation, predictive and prognostic value, and the management of EGFRI-related skin toxicity.     

The epidermal growth factor receptor signaling network in head and neck carcinogenesis and implications for targeted therapy

Improved understanding of the molecular signaling pathways that mediate cellular transformation has led to the development of novel strategies for the treatment of cancer. The epidermal growth factor receptor (EGFR), a transmembrane protein with intrinsic tyrosine kinase activity, transduces important signals from the surface of epithelial cells to the intracellular domain. Aberrant signaling through EGFR plays a key role in the carcinogenesis of squamous cell carcinomas of the head and neck (SCCHN). SCCHN tend to express high levels of EGFR, and the degree of expression correlates with poor clinical outcome. Since EGFR is present at much higher levels in cancerous lesions than in normal epithelial tissue, the receptor has been implicated as a highly specific therapeutic target for the treatment of SCCHN. EGFR can be abrogated at the extracellular level using either monoclonal antibodies or toxin conjugates that compete with the natural ligand at the binding site of the receptor, and targeting of the EGFR intracellular domain has been achieved by specific inhibitors of tyrosine kinase activity. Antisense strategies use synthesized DNA or RNA oligonucleotides to block the translation of the mRNA sequences that code for the production of the EGFR or other proteins with a role in EGFR-mediated cell signaling. Clinical evaluation of EGFR-specific monoclonal antibodies and tyrosine kinase inhibitors has demonstrated limited toxicity in SCCHN patients, and concurrent administration with standard cytotoxic therapies has produced additive or synergistic antitumor effects.     

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.     

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.     

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.     

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.     

头颈部鳞癌分子靶向治疗进展

当前分子靶向治疗头颈部鳞状细胞癌(SCCHN)的进展非常快.由于表皮生长因子受体(EGFR)信号传导和血管发生在SCCHN的生长中起关键作用,因此EGFR及其下游效应器与血管发生过程相关的分子及其受体就成为目前SCCHN分子靶向治疗的主要靶点.     

Novel therapeutic targets in squamous cell carcinoma of the head and neck

The treatment of squamous cell carcinoma of the head and neck (SCCHN) has recently witnessed the introduction of molecularly targeted agents based on disease biology, target discovery, and validation. One class of agents, the epidermal growth factor receptor (EGFR) inhibitors, is currently in phase III trials. There are multiple processes, however, that appear to be suitable for targeted therapy beyond EGFR. These include signal transduction, cell cycle control, prostaglandin synthesis, protein degradation, hypoxia, and angiogenesis. These systems and specific protein targets will be reviewed in detail with emphasis on promising preclinical and early clinical evidence of activity.     

局部晚期头颈部鳞癌的靶向治疗进展

多学科联合治疗是局部晚期头颈部鳞癌的最佳治疗模式,而分子靶向药物也在近年应用到这一领域。由于头颈部鳞癌具有普遍的表皮生长因子受体(epithelial growth factor receptor,EGFR)的高表达,目前的靶向治疗主要针对这一靶点。西妥昔单抗作为一个人鼠嵌合的单克隆抗体,是目前唯一批准用于头颈部鳞癌的分子靶向药物。与单纯放疗相比,放疗联合西妥昔单抗能够显著改善局部晚期头颈部鳞癌患者的无进展生存和总生存,但与传统同期放化疗的比较无论在疗效还是不良反应方面尚不充分。随着诱导化疗在局部晚期头颈部鳞癌的研究进展,放疗联合西妥昔单抗为后续的治疗模式提供了新的研究思路。虽然RTOG 0522研究初步证明了在同期放化疗基础上再联合西妥昔单抗无法进一步提高疗效,但对于西妥昔单抗的化疗药物配伍的问题仍然值得探讨。而对于其他抗EGFR抑制剂而言,如何在现有证据基础上设计有针对性的临床研究是能否取得治疗更新的关键。     

STAT 3 activation in head and neck squamous cell carcinomas is controlled by the EGFR

Proliferation of squamous cell carcinoma of the head and neck (SCCHN) depends on epidermal growth factor receptor (EGFR) expression. As STAT 3 activation as well contributes to the cell growth in SCCHN, the interaction of STAT 3 and the EGFR is of great interest when considering treatment options through inhibition of STAT 3. We, therefore, evaluated the influence of blocking or activating the EGFR in human SCCHN cell lines and in vivo tumors on STAT 3 activation. We compared the effects on STAT 3 activation with the regulation of MAP Kinase under these conditions. We found that STAT 3 can be strongly inhibited via EGFR blocking in vitro as well as in vivo. However, the influence of EGFR regulation on the MAP Kinase pathway seemed to be very slight. These findings provide evidence that STAT 3 signal activity in head and neck carcinomas, which is partially responsible for proliferative activity, can be controlled via the EGFR.     

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.     

Protein kinase C zeta mediates epidermal growth factor-induced growth of head and neck tumor cells by regulating mitogen-activated protein kinase

Protein kinase C (PKC) zeta has been implicated as a mediator of epidermal growth factor (EGF) receptor (EGFR) signaling in certain cell types. Because EGFR is ubiquitously expressed in squamous cell carcinomas of the head and neck (SCCHN) and plays a key role in tumor progression, we determined whether PKCzeta is required for tumor cell proliferation and viability. Examination of total and phosphorylated PKCzeta expression in normal oral mucosa, dysplasia, and carcinoma as well as SCCHN tumor cell lines revealed a significant increase in activated PKCzeta expression from normal to malignant tissue. PKCzeta activity is required for EGF-induced extracellular signal-regulated kinase (ERK) activation in both normal human adult epidermal keratinocytes and five of seven SCCHN cell lines. SCCHN cells express constitutively activated EGFR family receptors, and inhibition of either EGFR or mitogen-activated protein kinase (MAPK) activity suppressed DNA synthesis. Consistent with this observation, inhibition of PKCzeta using either kinase-dead PKCzeta mutant or peptide inhibitor suppressed autocrine and EGF-induced DNA synthesis. Finally, PKCzeta inhibition enhanced the effects of both MAPK/ERK kinase (U0126) and broad spectrum PKC inhibitor (chelerythrine chloride) and decreased cell proliferation in SCCHN cell lines. The results indicate that (a) PKCzeta is associated with SCCHN progression, (b) PKCzeta mediates EGF-stimulated MAPK activation in keratinocytes and SCCHN cell lines, (c) PKCzeta mediates EGFR and MAPK-dependent proliferation in SCCHN cell lines; and (d) PKCzeta inhibitors function additively with other inhibitors that target similar or complementary signaling pathways.