Oral chemotherapy in head and neck cancer

Chemotherapy plays an important role in the palliative treatment of head and neck cancer and in the neoadjuvant setting for larynx preservation. Together with concomitant radiotherapy, chemotherapy is also important for the curative and palliative therapy of unresectable head and neck cancer. Although issues relating to anatomical and pharmacological constraints exist, new orally administered drugs, as well as oral substitutes for the currently utilised intravenous drugs, would be extremely desirable in each of these situations. Of the oral fluorinated pyrimidines, tegafur/uracil (UFT) alone produced a complete response rate of 19%, and combination therapy of tegafur/uracil or tegafur with cisplatin or carboplatin has produced response rates comparable to those seen with intravenous fluorouracil (5-FU) plus cisplatin or carboplatin. An initial dose-finding study of 5-FU plus eniluracil indicates that further studies are warranted. The ribonuclease reductase inhibitor hydroxycarbamide (hydroxyurea) has been extensively studied in combination with 5-FU and radiotherapy (the FHX regimen) in patients with head and neck cancer, with high rates of local control. Improvement in locoregional and distant control rates may occur when FHX is combined with additional systemically active agents (cisplatin then paclitaxel) and hyperfractionated radiotherapy is used. Good candidate drugs for head and neck cancer include BMS-182751, an oral platinum complex, and capecitabine and S-1, other oral fluoropyrimidines. In addition, methotrexate and cyclophosphamide both have some activity in head and neck cancer and deserve further investigation.     

Targeting angiogenesis in head and neck cancer

In the early 1970s, the hypothesis that tumor growth is dependent on angiogenesis was first established [1]. Since then, the role played by blood vessels in tumor growth and progression has been extensively studied and debated. Preclinical evidence strongly suggests that VEGF plays a role in promoting the growth and progression of disease in various tumor types including squamous cell carcinoma of the head and neck (SCCHN), of which close to 38,500 new cases are diagnosed each year. In SCCHN, the role of anti-angiogenic therapy has yet to be defined. Traditional therapy of SCCHN has involved a multimodality approach with radiotherapy, surgery as well as chemotherapy. More recently, novel therapeutic agents have been subject to preclinical and clinical development, among which anti-angiogenic therapy has gained much recent interest. In this critical review, we give an overview of angiogenesis and its potential therapeutic targets, and we focus on its preclinical and clinical applications in SCCHN.     

Pharmacotherapy of head and neck cancer

Introduction: There are over 55,000 new cases of head and neck cancer diagnosed annually in the United States. Historically surgical resection was the standard of care, but due to vital structures in the head and neck region this led to severe morbidity. The integration of pharmacotherapy has rapidly expanded over the years into a multimodality treatment paradigm for locally advanced head and neck cancer, allowing organ-sparing treatment approaches. Here we discuss the various approaches and settings in which chemotherapy can be incorporated into the management of head and neck squamous cell carcinoma (HNSCC).

Areas covered: Chemotherapy in HNSCC can be administered in several different treatment circumstances: in the metastatic setting for palliation of symptoms and prolongation of survival, before definitive local treatment (induction), as part of definitive treatment simultaneously with radiation (concurrent) or after definitive local therapy (adjuvant).

Expert opinion: The incorporation of chemotherapy into the management of patients with head and neck cancer has allowed organ preservation approaches and improved survival. Because of the toxicities of chemotherapy, it is imperative that chemotherapy is only administered to the appropriate patient population who are more likely to benefit. Cisplatin 100 mg/m² given in combination with radiation in the non-metastatic setting is the most widely tested regimen and remains the reference regimen. Cetuximab is also an alternative, but there is no data to support the use of cetuximab in a laryngeal preservation approach or in the postoperative setting.     

EGFR-targeting monoclonal antibodies in head and neck cancer

The epidermal growth factor (EGFR) and its receptor were discovered nearly 40 years ago. Over the past decade interruption of this pathway has been exploited in the treatment of various solid tumors. Antibodies that interfere with ligand binding to and dimerization of the EGFR (and small molecules that inhibit the EGFR tyrosine kinase) are anti-proliferative, profoundly radiosensitizing, and synergistic with DNA-damaging cytotoxic agents. Proposed mechanisms of radio- and chemosensitization include enhanced apoptosis, interference with DNA repair and angiogenesis, receptor depletion from the cell surface and antibody-dependent cell-mediated cytotoxicity. This article provides a reader with a comprehensive review of EGFR-targeting antibodies under development for the treatment of head and neck squamous cell cancer (HNSCC) and also summarizes relevant clinical data in this disease with small molecule EGFR inhibitors. One of the monoclonal antibodies, cetuximab, recently received full FDA approval for the treatment of patients with locally advanced (with radiation) or metastatic HNSCC (as a single agent). Regulatory approval followed reporting of a large international study in which the addition of cetuximab to definitive radiation therapy in HNSCC resulted in statistically significant improvements in locoregional control and overall survival. Results of the pivotal trial, other clinical data supporting the regulatory approval, and a preview of the next generation of clinical trials are presented. Considerable work remains to be done, particularly to enhance our understanding of factors that may predict for favorable response to EGFR inhibitor therapy and to evaluate the impact of integrating anti-EGFR therapies into complex chemoradiation programs delivered with curative intent.     

Novel targeted therapies in head and neck cancer

Introduction: Molecularly targeted therapy, with the potential for increased selectivity and fewer adverse effects, hold promise in the treatment of HNSCC.

Areas covered: Targeted agents for HNSCC expected to improve the effectiveness of current therapy including HER family, Src-family kinase, cell cycle, MET, AKT, HDAC, PARP, COX inhibitors and antiangiogenesis.

Expert opinion: Epidermal growth factor receptor inhibitors are established in HNSCC and the need now is to find biomarkers for sensitivity to better select patients. Moreover, other pathway inhibitors hold significant promise and are being tested in clinical trials. Angiogenesis inhibition is likely to yield only modest efficacy alone but may augment existing standards. Lastly, one clinical arena where targeted therapies may find secure purchase is in the adjuvant or prevention setting where minimal or preneoplastic disease can be affected by inhibition of a single or few targets.     

Nutritional status in head and neck cancer patients

OBJECTIVE: Patients suffering from cancer of head and neck are at risk of nutritional depletion. The aim of our study was to investigate the role of type, location and stage of tumors in nutritional status. PATIENTS AND METHODS: A population of 230 consecutive patients with head and neck cancer was enrolled. A nutritional evaluation was realized. RESULTS: The distribution of tumour sites was: oral cavity (77 patients), pharynx (30 patients) and larynx (123 patients). Subjective Global Assessment (SGA) test showed significant differences. Midly malnourished frequency is higher in larynx site than others. Severely malnourished is higher in larynx and oral cavity than pharynx. In pharynx, larynx and oral cavity tumours is more frequent to be well nourished than severely malnourished. In pharynx and larynx tumours is more frequent to be mildly malnourished than severely malnourished. In stages II, III and IV are more frequent to be well nourished than severely malnourished and in stages II and III is more frequent to be mildly malnourished than severely malnourished. CONCLUSIONS: SGA test shows a good nutritional status in patients with head and neck tumours. However, SGA test shows statistical differences in some categories of tumours stages or sites.     

Novel targeted therapies in head and neck cancer

INTRODUCTION: Molecularly targeted therapy, with the potential for increased selectivity and fewer adverse effects, hold promise in the treatment of HNSCC. AREAS COVERED: Targeted agents for HNSCC expected to improve the effectiveness of current therapy including HER family, Src-family kinase, cell cycle, MET, AKT, HDAC, PARP, COX inhibitors and antiangiogenesis. EXPERT OPINION: Epidermal growth factor receptor inhibitors are established in HNSCC and the need now is to find biomarkers for sensitivity to better select patients. Moreover, other pathway inhibitors hold significant promise and are being tested in clinical trials. Angiogenesis inhibition is likely to yield only modest efficacy alone but may augment existing standards. Lastly, one clinical arena where targeted therapies may find secure purchase is in the adjuvant or prevention setting where minimal or preneoplastic disease can be affected by inhibition of a single or few targets.     

Adenoviral gene therapy in head and neck cancer

Despite advances in surgical techniques, improvement in radiation therapy and the addition of new biological agents such as cetuximab to traditional chemotherapy, the median survival of patients with head and neck cancer has changed little over the past few decades. However, recent advances in the fundamental understanding of head and neck cancer biology suggest that targeting molecular pathways underlying carcinogenesis may provide alternative or additional approaches to the treatment of head and neck cancer. Viruses, particularly adenoviruses, have been critical in the application and development of these molecular approaches. Adenoviruses have been engineered to function as vectors for delivering therapeutic genes for gene therapy. The purpose of this review is to provide a prospective on the use of adenoviruses in head and neck cancer therapy by examining clinical trials of adenovirus-mediated p53 gene therapy and by reviewing the application of a promising oncolytic adenovirus, ONYX-015, in head and neck cancer.     

EGFR-targeting monoclonal antibodies in head and neck cancer

The epidermal growth factor (EGF) and its receptor were discovered nearly 40 years ago. Over the past decade interruption of this pathway has been exploited in the treatment of various solid tumors. Antibodies that interfere with ligand binding to and dimerization of the EGFR (and small molecules that inhibit the EGFR tyrosine kinase) are anti-proliferative, radiosensitizing, and synergistic with DNA-damaging cytotoxic agents. Proposed mechanisms of radio- and chemosensitization include enhanced apoptosis, interference with DNA repair and angiogenesis, receptor depletion from the cell surface and antibody-dependent cell-mediated cytotoxicity. This article provides the reader with a comprehensive review of EGFR-targeting antibodies under development for the treatment of head and neck squamous cell cancer (HNSCC) and also summarizes relevant clinical data in this disease with small molecule EGFR inhibitors. One of the monoclonal antibodies, cetuximab, recently received full FDA approval for the treatment of patients with locoregionally advanced (with radiation) or metastatic HNSCC (as a single agent). Regulatory approval followed reporting of a large international study in which the addition of cetuximab to definitive radiation therapy in HNSCC resulted in statistically significant improvements in locoregional control and overall survival. Results of the pivotal trial, other clinical data supporting the regulatory approval, and a preview of the next generation of clinical trials are presented. Considerable work remains to be done, particularly to enhance our understanding of factors that may predict for favorable response to EGFR inhibitor therapy and to evaluate the impact of integrating anti-EGFR therapies into complex chemoradiation programs delivered with curative intent.     

Investigational drugs for head and neck cancer

Introduction: In the treatment of advanced/metastatic head and neck cancer (HNC), resistance to chemotherapy and to anti-EGFR agents remains a major issue, and new molecular drugs are eagerly awaited. Over the last decade, knowledge of the genetic landscape of HNC has rapidly grown. However, no tailored therapeutic intervention targeting HNC molecular abnormalities is currently available outside from clinical trials.

Areas covered: In this review, the authors analyze new drugs in the HNC setting which have been investigated in recently published trials or are currently being investigated. The article excludes strategies directed towards the EGFR pathway and antivascular agents.

Expert opinion: Agents acting on the PI3K axis have a strong biological rationale and show the preliminary signs of activity, in particular when combined with other agents. There is limited clinical data of the other discussed pathways; the CMET/HGF pathway as a possible modulator of anti-EGFR drug sensitivity and agents directed towards MEK, WEE-1, NOTCH represent new interesting approaches to HNC. It is of the utmost importance to try and incorporate the molecular dissection of the tumor profiles in clinical trials with such agents. Moreover, the mutational status of other cross-talking pathways should be assessed, since potential resistance mechanisms can be recognized and possibly overcome by a careful selection of patients and combination regimens. Immunotherapy represents a growing field in HNC and its wider application will impact on future therapeutic strategies, including the association with chemotherapy, targeted agents and radiation.     

The chemotherapy of head and neck cancer

Studies of combination therapy [with agents such as cisplatin, 5-fluorouracil (5-FU) and methotrexate] have shown some improvements in response rate; however, no obvious survival advantage over monotherapy in the treatment of patients with metastatic or advanced locoregional cancer of the head and neck have been observed. In the neoadjuvant setting, chemotherapy is helpful in preserving the larynx and hypopharynx but has no proven impact (positive or negative) on survival. New treatment options are needed to improve survival in head and neck cancer. Among the new options for chemotherapy in metastatic/recurrent disease is docetaxel. With monotherapy, response rates of 23-42% are seen, and, when used in combination with cisplatin and 5-FU, response rates of 52-100% have been reported in phase I/II trials. A phase III trial of the addition of docetaxel to standard neoadjuvant therapy with cisplatin and 5-FU is now underway.     

Emerging drugs for head and neck cancer

Head and neck cancer is a challenging disease. The treatment is quite complex and significant toxicity is seen with the combination of chemotherapy, radiation therapy and surgery. The present standard of care is chemoradiotherapy for most sites in the head and neck area for patients with locally advanced, unresectable disease and in patients treated for organ preservation. The recent approval of cetuximab, an EGF receptor inhibitor, for head and neck cancer in combination with radiotherapy represent an opportunity to improve the outcome for these patients, and the inclusion of this antibody within the chemoradiotherapy approaches will be studied in Phase III trials. In addition, a significant shift is occurring with the inclusion of more aggressive chemotherapy upfront, prior to chemoradiotherapy. This approach, known as sequential chemoradiotherapy, is the basis of many recently completed Phase III trials. Docetaxel, cisplatin and 5-fluorouracil appears to be the most effective induction chemotherapy regimen and is the new induction ‘standard’ that is being used by many cancer centres and intergroups going forward. It is also a new platform that will be used to add new targeted agents to induction chemotherapy.     

Emerging drugs for head and neck cancer

Head and neck cancer is a challenging disease. The treatment is quite complex and significant toxicity is seen with the combination of chemotherapy, radiation therapy and surgery. The present standard of care is chemoradiotherapy for most sites in the head and neck area for patients with locally advanced, unresectable disease and in patients treated for organ preservation. The recent approval of cetuximab, an EGF receptor inhibitor, for head and neck cancer in combination with radiotherapy represent an opportunity to improve the outcome for these patients, and the inclusion of this antibody within the chemoradiotherapy approaches will be studied in Phase III trials. In addition, a significant shift is occurring with the inclusion of more aggressive chemotherapy upfront, prior to chemoradiotherapy. This approach, known as sequential chemoradiotherapy, is the basis of many recently completed Phase III trials. Docetaxel, cisplatin and 5-fluorouracil appears to be the most effective induction chemotherapy regimen and is the new induction 'standard' that is being used by many cancer centres and intergroups going forward. It is also a new platform that will be used to add new targeted agents to induction chemotherapy.     

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.     

Capecitabine for treating head and neck cancer

Introduction: With an increasing incidence, over half a million cases of head and neck cancer (HNC) are diagnosed annually worldwide. Various chemotherapeutic agents are utilized to achieve adequate locoregional control. Cisplatin, fluorouracil (FU), and taxanes are often used to treat HNC but these regimens have shown high toxicity and poor patient compliance. Capecitabine is an orally administered prodrug that is preferentially converted to FU in tumor cells in comparison to normal cells.

Area covered: In this review, the authors evaluate the role of capecitabine in radical and palliative settings either alone or in combination with other chemotherapeutic drugs in the management of HNC. In addition, metabolic conversion, pharmacokinetics, pharmacodynamics, and toxicity profile of capecitabine are discussed.

Expert opinion: Various phase II trials conducted on capecitabine in the management of recurrent HNC have shown comparable results and tolerable toxic effects especially in pre-treated fragile patients. Capecitabine, used in induction or concurrent settings in the radical management of locoregionally advanced HNC, have also shown promising results. Randomized trials are needed to validate the role of capecitabine in the management of HNC.     

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.     

Promising newer molecular-targeted therapies in head and neck cancer

Head and neck cancer (HNC) is the fifth most common cancer in the world. In the US alone, HNC accounts for 3-5% of all malignancies annually. Squamous cell carcinoma arising from the mucosa of the upper aerodigestive tract is the most common type of HNC and accounts for 90% of HNC diagnoses. Despite continued advances in the therapeutic options, the disease-free survival, functional outcome, toxicity of therapy and overall survival have remained less than optimal for patients with locally advanced, recurrent or metastatic disease. Therefore, new approaches for the treatment of patients with HNC, particularly patients with advanced stage, are clearly needed. Among the new therapies, molecular-targeted and biological therapies have gained special attention. While clinical trial data support the use of epidermal growth factor receptor (EGFR) inhibition in metastatic and locally advanced HNC, numerous trials are seeking to establish a clear role for new therapies targeting EGFR, the receptor for the type I insulin-like growth factor, as well as anti-angiogenesis agents.     

二甲双胍抗头颈部肿瘤的研究进展

二甲双胍是治疗2型糖尿病的首选药物,近年来研究发现二甲双胍除了降糖作用外,还可以抗炎、抗衰老、抗肿瘤等作用。通过查阅大量文献就二甲双胍抗头颈部肿瘤的研究进展进行综述,并介绍了二甲双胍通过激活腺苷酸活化蛋白激酶（AMPK）信号通路、上调相关微小RNA（miRNAs）、抑制信号转导与转录激活因子3（STAT3）信号通路等作用机制抗头颈部肿瘤。     

Novel strategies in therapy of head and neck cancer

In addition to the currently available conventional therapeutic modalities i.e. chemotherapy, radiotherapy and surgery, there is a desperate need for more effective and less toxic therapies for head and neck malignancies. Chemotherapy alone shows high toxicity and a low survival rate. In some cases, malignant cells develop resistance to a particular drug and to combat this, a variety of approaches like intra-arterial therapy, induction chemotherapy, immunotherapy, photodynamic therapy as well as targeted molecular therapy have recently been employed. Techniques like intra-arterial and induction chemotherapy have showed some improvement in survival rate. Immununotherapy is in the experimental stages while photodynamic therapy is being clinically applied, but because of its side effects it is not very popular. Utilizing specific molecular targets with their inhibitors (like inhibitors of EGFR and VEGF); either alone or in combination with conventional therapy, may improve the survival rate of these patients. Blocking the signaling pathway (P13k/Akt/mTOR), with or without chemotherapy, may also overcome the problem of drug resistance. These modalities hold the promise of being more selective - harming fewer normal cells, reducing side effects and improving the quality of life. The various options and novel strategies currently available to the treating physician are critically examined in this review.