Multidisciplinary Symposium on Head and Neck Cancer. 2 December 2005, Philadelphia, PA, USA

The Multidisciplinary Symposium on Head and Neck Cancer focused on the emerging data that underlie optimal treatment for head and neck cancers, with a particular focus on squamous cell carcinoma of the head and neck. In-depth discussions showcased the published Phase II and Phase III data on the treatment of locally advanced disease with both induction chemotherapy and concurrent chemoradiotherapy. Molecular targets of interest and relevance in this tumour type were identified, as were the agents which target these putative proteins or pathways of carcinogenesis. Preliminary results from trials incorporating molecularly-targeted agents have shown a promising role for these compounds in the management of both locally advanced and recurrent/metastatic squamous cell carcinoma of the head and neck. The Symposium brought a clear message. The management of squamous cell carcinoma of the head and neck has evolved considerably, and with the advent of newer chemotherapeutic agents and molecularly targeted therapies, this field will continue to expand over time.     

Induction chemotherapy in head and neck cancer: a new paradigm

Five hundred and fifty thousand new head and neck cancer cases are diagnosed each year worldwide. They are mostly locally advanced squamous cell carcinoma with a poor prognosis in terms of locoregional and distant failure. A major challenge for patients with locally advanced squamous cell carcinoma is to achieve a high cure rate while preserving functions. Treatment strategies are designed according to the disease stage, primary site, operable status, patient age, and performance status. Surgery, radiation therapy, chemotherapy, and more recently molecular-targeted therapies are part of these strategies, but their sequence remains to be defined. Over the last 30 years, induction chemotherapy has attained an important position in the management of patients with locally advanced squamous cell carcinoma, particularly since the introduction of taxanes. The decision to deliver induction chemotherapy (and its intensification) must be considered in the light of other treatments aiming at better locoregional control (normofractioned radiotherapy, accelerated or hyperfractionated radiotherapy, addition of concurrent chemotherapy, or of targeted therapy) with or without adjuvant treatment. This review summarizes the rationale, these data, and perspectives on induction chemotherapy-based strategies.     

Emerging drugs for head and neck cancer

Head and neck squamous cell carcinoma is a devastating disease with poor outcomes in advanced stages. For patients with locally advanced disease, a multi-modality approach with chemotherapy and radiotherapy has been used. Despite advances in diagnosis and treatment, including improvements in radiation therapy, surgical techniques, chemotherapy and prevention strategies, survival rates for patients with recurrent head and neck cancer are poor. Several cytotoxic drugs with significant activities as single agents and/or combination regimens have shown high response rates, but over the past several years, significant improvement in survival has not been achieved. New drugs, including those that target the epidermal growth factor receptor, the p53 gene, RAS protein post-translational modification, the proteosome, vascular endothelial growth factor, cyclooxygenase-2 and other molecular pathways, are promising agents in the management of head and neck cancer. Their potential is being tested in various settings, including chemoprevention, recurrent and metastatic disease and combination with radiation therapy and/or cytotoxic agents.     

Southwest Oncology Group study of Mitoxantrone for treatment of patients with advanced squamous cell carcinoma of the head and neck

Summary Twenty-two patients are evaluable for response in a Phase II trial of Mitoxantrone for advanced squamous cell carcinoma of the head and neck. One patient had a partial response, one an improvement and twenty had progressive disease. The major toxicities were leukopenia and thrombocytopenia. There was no significant antitumor activity of Mitoxantrone in this group of patients with head and neck cancer, most of whom were previously treated with radiation and chemotherapy.     

Malignancies of the head and neck: the role for molecular targeted agents

Although cancers arising in the head and neck region are a diverse group of malignancies, a unifying thread remains a poor overall survival for patients with advanced, recurrent or metastatic disease. Treatment strategies need to evolve and improve upon established therapeutic practices. As the process of cancer evolution is understood to be derived from aberrations in genetic and epigenetic processes, molecularly targeted agents offer attractive therapeutic options by restoring normal control of oncogenic processes. The direct role for the treatment of squamous cell carcinoma of the head and neck, nasopharynx and salivary gland carcinomas with these novel, molecularly targeted agents are reviewed and their potential to improve on the existing standard of care is further explored.     

Pharmacotherapy of head and neck squamous cell carcinoma

Background: The clinical management of locally advanced head and neck squamous cell carcinoma (HNSCC) is a challenging problem and requires a multidisciplinary approach. Historically, locally advanced HNSCC has been primarily managed with surgery and radiation (RT). The integration of pharmacotherapy has rapidly expanded over the years into the multimodality treatment paradigm of locally advanced HNSCC. Objective: The studies leading to the adoption of the current standard of care for locally advanced HNSCC are discussed. In addition, the limitations of these various treatment approaches are presented. Methods: An extensive literature search was conducted using the PubMed database for studies published before January 2009. The keywords used for this search were: head and neck neoplasms, chemoradiation, adjuvant chemotherapy, induction chemotherapy, EGFR inhibitor, cisplatin, carboplatin, paclitaxel, docetaxel, 5-fluorouracil, and cetuximab. Publications of randomized clinical trials and other supporting references leading to the current standard of care were particularly selected and discussed in this review. Conclusions: Various single-agent and multi-agent chemotherapeutic regimens have been examined in the context of randomized clinical trials in locally advanced HNSCC for definitive, induction and adjuvant settings. Results from these clinical trials support the use of cisplatin-based chemoradiation as the standard of care for the definitive and adjuvant settings. Recent evidence indicates that cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, is highly active as a single agent and in combination with standard chemotherapy and/or RT. Future studies should focus to determine the optimal pharmacotherapeutic regimens for use in locally advanced HNSCC.     

Treatment of head and neck cancer in the elderly

Introduction: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and the majority of patients present with advanced stage disease. Chemotherapy is an important component of head and neck cancer treatment regimens and has shown beneficial effects in locally advanced and recurrent/metastatic stages of disease. Approximately 25% of HNSCC patients are aged 70 and older, often associated with co-morbid medical conditions. Most clinical trials exclude patients of advanced chronological age such that valid information about the efficacy and safety of drugs and treatment regimens in elderly patients is not available.

Areas covered: Surgery, radiotherapy and particularly chemotherapy with the six FDA-approved chemotherapeutic agents for head and neck cancer treatment are discussed with a focus on age, performance status, comorbidities. New targeted therapies and the field of immune checkpoint inhibitors are evaluated in the context of elderly populations.

Expert opinion: Surgery, radiotherapy and administration of cytotoxic chemotherapeutic agents are largely safe and effective in elderly patients. Targeted therapies are mostly well tolerated. Clinical studies should be designed to include elderly patients (>70 years). Immune checkpoint inhibitor therapies may exert age-related effects, since substantial functional changes in T cell responses increase during the aging process.     

Clinical trials with fluorinated pyrimidines in patients with head and neck cancer

Summary While it is estimated to be one of the most prevalent cancers in the world, cancer of the head and neck is an uncommon malignant tumor in the United States and accounts for only 5% of all malignancies [1]. Head and neck cancer is a term that encompasses heterogeneous groups of patients. The most common histologic type is the squamous cell carcinoma. Cancer of the oral cavity is the most common site among the head and neck tumors. The majority of patients (70–80%) present with locally advanced (Stage III and IV) cancer. The standard treatments of surgery and/or radiotherapy have a high cure rate for patients with early disease (Stages I or II), but not for patients with locally advanced tumors. Local recurrence and persistent disease occur in more than 60% of patients present with advanced cancer, and approximately 10%–20% of all patients develop distant metastases [2–9].Chemotherapy is usually used for palliation in patients with recurrent and metastatic head and neck cancer at which time these patients have failed the definitive therapy of surgery and/or radiotherapy and the chances for salvage is almost nil. With the identification of more active cytotoxic agent(s) and combinations, chemotherapy is being investigated as part of multi-modality treatment in patients with previously untreated and locally advanced head and neck cancer [2,10].     

Head and neck squamous cell carcinoma: new translational therapies

Head and neck squamous cell carcinoma includes cancers of the mouth, throat, larynx, and lymph nodes of the neck. Although early disease is amenable to single-modality treatment with surgery or radiation, patients with advanced disease have a dramatically worse prognosis, despite potentially morbid/toxic treatment regimens involving surgery, radiation, chemotherapy, or all 3 modalities. The present review seeks to provide an overview of current understanding and treatment of head and neck squamous cell carcinoma for the nonspecialist clinician or basic/translational researcher, followed by an overview of major translational approaches to the treatment of head and neck squamous cell carcinoma. Translational research topics addressed include targeted molecular therapy, immunotherapy, minimally invasive robotic surgery, and ablation of dormant/residual tumor cells. Despite the many potentially promising avenues of head and neck squamous cell carcinoma research, only 2 new treatment approaches (antiepidermal growth factor receptor therapy and robotic surgery) have been approved by the US Food and Drug Administration in the past 30 years. Focused research programs involving integrated teams of clinicians, basic scientists, and translational clinician-researchers have the potential to accelerate discovery and change treatment paradigms for patients with head and neck cancer.     

Emerging molecular targeted therapies in the treatment of head and neck cancer

Current development of molecular targeted therapies in oncology is particularly active. The aim of this study is to review recent advances in the field of molecular targeted therapies for head and neck squamous cell carcinoma (HNSCC). As EGFR signaling pathway and angiogenesis play a key role in the growth of HNSCC, EGFR with its downstream effectors and molecular factors implicated in the angiogenesis process, such as VEGF and its receptors, represent the main targets of the new therapeutic agents now in development. Today, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of HNSCC in patients with locally advanced tumors, in association with radiotherapy, and in patients with recurrent or metastatic diseases. Future progress is expected with the integration of cetuximab into induction chemotherapeutic regimens or in association with concurrent chemoradiotherapy for locally advanced tumors and with the development and evaluation of other molecular targeted therapies such as antiangiogenic drugs. As these innovative molecules start to be used in clinical practice, the identification of predictive markers for efficacy and toxicity becomes a crucial issue.     

多西他赛、顺铂化疗并同步放疗联合综合护理在头颈部鳞癌中的应用效果

目的探讨多西他赛、顺铂化疗并同步放疗联合综合护理在头颈部鳞癌中的应用效果。方法将62例局部晚期头颈部鳞癌患者随机分为对照组（n=31）和观察组（n=31）,两组患者均采用3-DCRT放疗,总剂量为DT60～70Gy／6-7周,对照组放疗结束后静脉滴注多西他赛60mg／m2,d1,顺铂25mg／m2,d1-3,1周期／3周,共2个周期。观察组在3-DCRT放疗的同时静脉滴注多西他赛20mg／m2,d1,顺铂25mg／m2,d1,1次／周,共治疗8周。对照组给予常规护理,观察组给予综合护理干预。结果观察组和对照组的总有效率分别为70．97％和41．94％,差异有统计学意义（P〈0．05）;观察组在胃肠道反应、口腔黏膜反应及皮肤反应等方面的毒副反应较对照组明显减轻（P〈0．05）。结论多西他赛联合顺铂化疗并同步放疗治疗局部晚期头颈部鳞癌的效果较好,综合护理干预措施能减轻胃肠道反应、口腔黏膜反应和皮肤反应。     

Clinical applications of electrochemotherapy

Electrochemotherapy is a novel treatment which consists of a combination of a chemotherapeutic agent and pulsed electric fields. This relatively new treatment modality relies on the physical effects of locally applied electric fields to temporarily destabilize cell membranes in the presence of a drug to allow increased uptake of the agent into the cytosol. Electrochemotherapy has been used effectively in preclinical and clinical studies. The therapy was shown to be effective regardless of histologic type of tumor including head and neck squamous cell carcinoma, melanoma, basal cell carcinoma, adenocarcinoma and Kaposi's sarcoma. Objective response rates ranging from 72 percent to 100 percent have been reported from these trials. These responses were obtained with minimal adverse side effects. A review of the clinical data for this novel drug delivery method is presented.     

Electrochemotherapy: an emerging drug delivery method for the treatment of cancer

The combined treatment consisting of a chemotherapeutic agent and pulsed electric fields has been termed electrochemotherapy. This relatively new treatment modality relies on the physical effects of locally applied electric fields to destabilize cell membranes in the presence of a drug. Membrane destabilization, electroporation, allows increased movement of molecules into the cytosol. Thus, the pulses are used to locally deliver drugs to the interior of cells. This type of treatment has principally been used to deliver bleomycin to tumor cells in vitro and in vivo. Marked antitumor effects have been reported in preclinical studies. In addition, electrochemotherapy clinical trials have been conducted for the treatment of head and neck squamous cell carcinoma, melanoma, and basal cell carcinoma. Objective response rates ranging from 72 to 100% have been reported from these trials. A review of the preclinical and clinical data for this novel drug delivery method is presented.     

Evaluation of homoharringtonine efficacy in the treatment of squamous cell carcinoma of the head and neck: A phase II Illinois Cancer Council study

Summary Eighteen patients entered this study of the efficacy of homoharringtonine (HHT) treatment in advanced squamous cell carcinoma of the head and neck (SCCHN). Seventeen eligible patients received at least one day of the first 5-day cycle of HHT (4.0 mg/m²/day) by continuous IV infusion. Cycles were scheduled to repeat every 28 days. The major severe toxicities encountered were hypotension and myelosuppression. There was one drug-related death. Fourteen patients were evaluable for response, and no patient exhibited an objective response to treatment with HHT.Abbreviations HHT homoharringtonine - SCCHN squamous cell carcinoma of the head and neck - BP blood pressure - HCT hematocrit - CBC complete blood count - WBC white blood cell count     

New advances in targeted therapies for squamous cell carcinoma of the head and neck

Several molecular pathways are deregulated and activated in squamous cell carcinoma of the head and neck making this disease attractive for targeted molecular therapies. Cetuximab, a monoclonal antibody that binds to the epidermal growth factor receptor, improves the overall survival when combined with radiation therapy or chemotherapy. Novels agents targeting different molecular pathways in squamous cell carcinoma of the head and neck are currently under development. Among them, dual (epidermal growth factor receptor/human epidermal growth factor receptor-2) or pan-human epidermal growth factor receptor inhibitors and drugs that target the insulin growth factor-1 receptor, the MET receptor, or the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway have shown either interesting preclinical activity or promising preliminary clinical efficacy. Angiogenesis inhibitors should be used with caution in squamous cell carcinoma of the head and neck due to the risk of tumor bleeding. However, only a minority of patients seems to benefit from these new approaches. Understanding the primary and acquired resistance mechanisms to predict the treatment efficacy is of crucial importance to allow a better patient selection.     

阿帕替尼联合替吉奥诱导治疗局部晚期舌鳞癌的近期疗效

目的评价阿帕替尼联合替吉奥胶囊对局部晚期舌鳞癌患者术前诱导治疗的有效性和安全性。方法回顾性分析2017年3月至2018年12月于我院口腔颌面头颈肿瘤科就诊、口服阿帕替尼联合替吉奥胶囊治疗的9例局部晚期、初治舌鳞癌患者,评价其接受诱导治疗的局部疗效。患者接受诱导治疗后再行手术治疗,术后病理表现有高危因素者行术后放疗、定期随访,计算随访时间段内总生存率。结果9例患者接受诱导治疗局部疗效为:3例患者完全缓解,4例患者部分缓解,2例患者疾病稳定,诱导用药不良反应可控。诱导治疗后所有患者均行手术治疗,其中3例患者接受术后放疗。经7.9~26.1个月随访(中位随访16.1个月),2例复发,6例病情稳定,1例死亡。结论阿帕替尼联合替吉奥作为局部晚期舌鳞癌的诱导治疗选择,近期疗效满意,不良反应尚可接受。     

The radiosensitizing effect of β-Thujaplicin,a tropolone derivative inducing S-phase cell cycle arrest,in head and neck squamous cell carcinoma-derived cell lines

Investigational New Drugs - Resistance to radiotherapy is a common cause of treatment failure in advanced head and neck squamous cell carcinoma (HNSCC). ß-Thujaplicin, a natural tropolone...     

Phase II trial of 13-cis-retinoic acid plus interferon-α in recurrent head and neck cancer

13-cis-retinoic acid (isotretinoin) and interferon- have limited activity as single agents in advanced cancer. Preclinical data indicate that these agents have different mechanisms of action and, in combination have greater activity (that is, the ability to modulate growth and differentiation) in a number of malignant cell types than either agent alone. In clinical trials, the new biological regimen of 13-cis-retinoic acid and interferon- was shown to have major activity in advanced squamous cell carcinoma of the skin and cervix. We conducted a phase II trial of this regimen in recurrent squamous cell carcinoma of the head and neck. Of the 21 evaluable patients, none had a complete response, and only one had a partial response (5%). Two patients had minor responses, four had stable disease, and 14 experienced disease progression. Five patients developed grade 3 toxic effects, including skin toxicity, fatigue, headache, and anorexia/weight loss. The median survival duration was 25.5 weeks (range, 4–95). The combination of 13-cis- retinoic acid and interferon- at this dose and schedule is ineffective for the treatment of recurrent squamous cell carcinoma of the head and neck.     

Afatinib in squamous cell carcinoma of the head and neck

Introduction: Recently new data on the efficacy of afatinib in head and neck squamous cell carcinoma (HNSCC) have been published.

Areas covered: We searched the literature for published and ongoing studies with afatinib in HNSCC.

Phase I data and results of phase II and III studies of afatinib in HNSCC are discussed. The maximum tolerated dose (MTD) of afatinib monotherapy with continuous administration was determined at 40 or 50 mg/day, rash and diarrhea being the principal dose-limiting toxicities. The MTD was lower when combined with chemotherapy. Studies with afatinib have been conducted or are ongoing both in the recurrent or metastatic (R/M) and in the locoregionally advanced (LA) HNSCC disease setting.

Expert opinion: Comparable disease control and tumor shrinkage rates were observed with cetuximab and afatinib in HNSCC progressing after platinum-containing chemotherapy. In patients with R/M- Squamous cell carcinoma of the head and neck (SCCHN) who had progressed on/after first-line platinum-based therapy, afatinib induced significantly higher disease control rate, longer progression-free survival and improved patient-reported outcome compared to methotrexate. Randomized phase III trials studying the role of adjuvant afatinib after definitive or postoperative chemoradiation in LA-HNSCC are ongoing.