Biological agents in head and neck cancer

Survival of head and neck cancer (HNC) patients has not dramatically improved over the last 30 years, despite the advances in surgical techniques, chemotherapeutic agents and radiotherapy treatment planning and definition. Different studies in molecular biology of HNC have been carried out, providing useful results for clinical application. HNC usually includes malignant tumors arising from mucosa of the upper aerodigestive tract, from nasopharynx to larynx/trachea, while salivary gland and thyroid cancers are less frequently listed in this classification. In this review, we chose to provide a comprehensive review of the role of biological agents in head and neck subsites. Molecular characteristics and treatment-relevant signaling pathways will be briefly discussed along with the results of the more recent clinical studies that include biological agents.     

Association of DNA repair genes polymorphisms and mutations with increased risk of head and neck cancer: a review

DNA repair mechanisms allow maintain genomic stability and proper functioning within the cells. Any aberrations may cause an increased risk of many diseases such as cancer. The most crucial risk factors for head and neck squamous cell carcinoma are behavioral factors, predominantly chronic exposure to tobacco, alcohol addiction, and infection with human papillomavirus or Epstein–Barr virus. These agents can induce DNA damage; therefore, cells must activate appropriate mechanisms in order to function correctly. Cancer cells are marked with genomic instability, which is associated with a greater tendency for the accumulation of a DNA damage and increased chemo- and radioresistance. Multiple studies have assessed the correlation of increased head and neck cancer (HNC) risk with polymorphism in the DNA repair genes. However, they suggest that interaction of DNA repair genes mutations with susceptibility to HNC depends on a patient’s race and risk factors, especially tobacco smoking. Further identification of these sequence variations must be performed. In this review, we discuss the current knowledge about the DNA repair genes mutations and polymorphisms associated with the high risk of head and neck treatment.     

Xenografts derived from patients with head and neck cancer recapitulate patient tumour properties

Rodent models mimic the heterogeneity of head and neck cancer (HNC) malignancies and are used to investigate HNC-associated biomarkers and evaluate drug responses. To assess the utility of patient-derived xenografts (PDXs) as an HNC model, 18 tumour samples were obtained from surgical specimens of patients with HNC and implanted into non-obese diabetic severe combined immunodeficient mice. The histological features of PDXs and corresponding patient samples were compared. Furthermore, the present study investigated how PDX responses to anticancer drugs mimic patient clinical responses, as well as the expression of adenosine triphosphate-binding cassette transporters through chemotherapy in an HNC-PDX model. A total of five PDXs from patients with HNC exhibiting high correspondence with histopathological features of the original patient samples were established (establishment rate, 28%). The responses of three PDXs to cisplatin were associated with clinical responses of the patients. ABC transporter expression was augmented in one PDX model after anticancer drug treatment, but not in PBS-treated passaged PDXs. PDX models exhibited similar biological and chemosensitive characteristics to those of the primary tumours. PDXs could be a useful preclinical tool to test novel therapeutic agents and identify novel targets and biomarkers in HNC.     

Head and Neck Cancer in Saudi Arabia a Systematic Review A Systematic Review and Updates

Background Head and neck cancer (HNC) is the ninth most common cancer worldwide, and has a poor 5-year survival rate averaging 50%, which has not changed for decades. A high prevalence of HNC has been reported in the southwestern region of Saudi Arabia, as compared to other areas of the country. However, data in regards to HNC are scattered and not well documented. Thus, the aim of this systematic review was to gather all available and updated important information regarding HNC in Saudi Arabia, and highlight the gaps of knowledge in our country with regard to this disease. In addition, suggestions of solutions to overcome the current status and improve our future standard of care to fight HNC are also highlighted. Materials and Methods The electronic databases PubMed and Google Scholar using English-language literature were used for this systematic review, using specific inclusion and exclusion criteria and keywords. The search was performed in April 2016 and updated in June 2016. Results Our search revealed twenty-one studies that fulfilled our inclusion and exclusion criteria and that were conducted in Saudi Arabia. These studies investigated different aspects of HNC, including prevalence, risk factors, biomarkers, and assessed knowledge and awareness of both public and practitioners with regard to HNC. Conclusions This review uncovered a big gap in our epidemiological data in cancer information in general, and head and neck cancer in particular. In addition, a lack of knowledge and awareness of both the public and health care practitioners hinders the early diagnosis of disease and negatively impact the prognosis, treatment and outcome. The Ministry of Health in Saudi Arabia should develop a more systematic way and adapt policies to gather cancer information in general, and head and neck cancer in particular, from all governmental and private sectors from all over the kingdom, and develop educational programs to raise the knowledge and awareness of HNC in the country.     

18F-fluoro-2-deoxy-D-glucose positron emission tomographic imaging: recent developments in head and neck cancer

PURPOSE OF REVIEW: Positron emission tomography using 18F-fluoro-2-deoxy-D-glucose (18FDG-PET) is well established in clinical routine as a metabolism-based whole-body imaging tool for cancer diagnosis and follow-up. Several reports have appeared indicating the potential and limitations of this technique in head and neck cancer (HNC). This review limits its scope to the recent advances using 18FDG-PET in the clinical management of HNC. RECENT FINDINGS: The combination of 18FDG-PET and sentinel node biopsy has been explored for the surgical treatment planning of oral and oropharyngeal cancer. Recent reports indicate that multimodality imaging combining PET with high-end CT scanning increases the diagnostic accuracy. 18FDG-PET has a potential for use in radiation treatment planning and for the prediction of response and early evaluation of treatment efficacy. SUMMARY: Increasingly 18FDG-PET is used as a clinical imaging modality in the different stages of the management of HNC. In particular, its clinical value in initial staging of neck lymph nodes and in the evaluation of recurrent or residual disease is well established. In these settings 18FDG-PET has been shown to be more accurate than conventional imaging. Recent studies indicate that 18FDG-PET could be of additional value in staging the N0 neck, in radiation treatment planning, and in prediction of treatment efficacy.     

A systematic review of head and neck cancer quality of life assessment instruments

Although quality of life (QOL) is an important treatment outcome in head and neck cancer (HNC), cross-study comparisons have been hampered by the heterogeneity of measures used and the fact that reviews of HNC QOL instruments have not been comprehensive to date. We performed a systematic review of the published literature on HNC QOL instruments from 1990 to 2010, categorized, and reviewed the properties of the instruments using international guidelines as reference. Of the 2766 articles retrieved, 710 met the inclusion criteria and used 57 different head and neck-specific instruments to assess QOL. A review of the properties of these utilized measures and identification of areas in need of further research is presented. Given the volume and heterogeneity of QOL measures, there is no gold standard questionnaire. Therefore, when selecting instruments, researchers should consider not only psychometric properties but also research objectives, study design, and the pitfalls and benefits of combining different measures. Although great strides have been made in the assessment of QOL in HNC and researchers now have a plethora of quality instruments to choose from, more work is needed to improve the clinical utility of these measures in order to link QOL research to clinical practice. This review provides a platform for head and neck-specific instrument comparisons, with suggestions of important factors to consider in the systematic selection of QOL instruments, and is a first step towards translation of QOL assessment into the clinical scene.     

Treatment of Older Patients With Head and Neck Cancer: A Review

The incidence of head and neck cancer (HNC) in the elderly is increasing. The treatment of HNC often includes multimodality therapy that can be quite morbid. Older patients (herein, defined as ≥65 years) with HNC often have significant comorbidity and impaired functional status that may hinder their ability to receive and tolerate combined modality therapy. They have often been excluded from clinical trials that have defined standards of care. Therefore, tailoring cancer therapy for older patients with HNC can be quite challenging. In this paper, we performed a comprehensive literature review to better understand and discuss issues related to therapeutic recommendations that are particular to patients 65 years and older. Evidence suggests that older patients have similar survival outcomes compared with their younger peers; however, they may experience worse toxicity, especially with treatment intensification. Similarly, older patients may require more supportive care throughout the treatment process. Future studies incorporating geriatric tools for predictive and interventional purposes will potentially allow for improved patient selection and tolerance to intensive treatment.     

Preferences and Utilities of Health Outcomes and Treatments Associated with Head and Neck Cancer

As a result of increased patient knowledge and autonomy, patient input into treatment decisions is becoming more acceptable and common. The outcomes of treatments for cancers of the oral cavity, pharynx, and larynx, collectively known as head and neck cancer (HNC), vary. Knowing how patients value the outcomes of alternative treatments for HNC may be useful to physicians and healthcare providers in planning treatment interventions and economic (e.g. cost-utility) analyses. Therefore, we conducted a systematic literature review on HNC treatment preferences and utilities. Fifty-six studies were analyzed. Eight of these studies provided quantitative data on utilities elicited by rating scale, time trade-off, or standard gamble methods. Patients reported lower preferences and utilities than physicians and non-patients for outcomes associated with surgery, including radical neck dissection. These findings and the methods used to obtain them are useful to clinicians caring for patients with HNC and in the development of models evaluating interventions to improve HNC outcomes.     

Clinical and scientific impact of human papillomavirus on head and neck cancer

Head and neck cancer (HNC) arises from the skull base to the clavicles and is the fifth most common cancer in the world by incidence. Historically, in the developed world HNC was associated with tobacco use and alcohol consumption, and the combination of the two produced a synergistic increase in risk. However, beginning in 1983, investigators have found a significant and growing proportion of HNC patients with human papillomavirus-positive (HPV) tumors who neither drank nor used tobacco. Since that time, there has been increased interest in the molecular biology of HPV-positive HNC. Multiple studies now show that HPV has shifted the epidemiological landscape and prognosis of head and neck squamous cell carcinoma (HNSCC). These studies provide strong evidence for improved survival outcomes in patients with HPV-positive HNSCC compared to those with HPV-negative HNSCC. In many reports, HPV status is the strongest predictor of locoregional control, disease specific survival and overall survival. In response to these findings, there has been significant interest in the best management of HPV-positive disease. Discussions within major cooperative groups consider new trials designed to maintain the current strong survival outcomes while reducing the long-term treatment-related toxicities. This review will highlight the epidemiological, clinical and molecular discoveries surrounding HPV-related HNSCC over the recent decades and we conclude by suggesting how these findings may guide future treatment approaches.     

GPx3 promoter hypermethylation is a frequent event in human cancer and is associated with tumorigenesis and chemotherapy response

Glutathione peroxidase 3 (GPx3), a plasma antioxidant enzyme, maintains genomic integrity by inactivating reactive oxygen species (ROS), known DNA-damaging agents and mediators of cancer chemotherapy response. In this study, we demonstrate that loss of GPx3 expression by promoter hypermethylation is frequently observed in a wide spectrum of human malignancies. Furthermore, GPx3 methylation correlates with head and neck cancer (HNC) chemoresistance and may serve as a potential prognostic indicator for HNC patients treated with cisplatin-based chemotherapy. Our findings support the hypothesis that defects in the antioxidant system may contribute to tumorigenesis of a wide spectrum of human malignancies. GPx3 methylation may have implications in chemotherapy response and clinical outcome of HNC patients.     

Targeted therapies and radiation for the treatment of head and neck cancer: are we making progress?

Targeting specific biological pathways in tumor development has been heralded as a promising approach to the treatment of cancer. Familiar to most investigators are the studies done with epidermal growth factor receptor (EGFR) antagonists, but newer agents currently under development also target angiogenic or cell cycle pathways. EGFR activation stimulates many important signaling pathways associated with cancer development and progression, and importantly, resistance to radiation. Because EGFR overexpression portends for a worse outcome in patients with advanced head and neck cancer (HNC), selective targeting of this signaling pathway has gained attention. The agents selected for initial studies include monoclonal antibodies and tyrosine kinase inhibitors against EGFR. Encouraging laboratory findings in different xenografts resulted in rapid translation into the clinic. Results from initial clinical trials show rather surprisingly that only a minority of patients benefited from EGFR inhibition as monotherapy or in combination with chemotherapy. Current challenges for investigators are to determine (1). who will benefit from targeted agents and which agents are most appropriate to combine with radiation and/or chemotherapy, (2). how to sequence these agents with radiation and/or cytotoxic compounds, (3). reliable markers for patient selection and verification of effective blockade of signaling in vivo, and (4). mechanisms behind intrinsic or acquired resistance to targeted agents to facilitate rational development of multiple targeted therapy. Well-integrated laboratory-clinical research programs are needed to address these issues.     

Role of electrochemotherapy in the treatment of metastatic melanoma and other metastatic and primary skin tumors

Electroporation is a novel therapeutic modality that uses pulsed electrical currents to enhance the uptake of drugs, vaccines and genes into cells, and has been used for over 20 years. Electroporation therapy using cytotoxic drugs is called electrochemotherapy. Electrochemotherapy has been studied in vitro, in vivo and in clinical trials. It is potentially useful for treating patients with metastatic tumors, such as melanoma, and even select primary tumors, such as head and neck squamous cell carcinomas and basal cell carcinoma. Various chemotherapeutic agents have been tested with electroporation therapy, but bleomycin and cisplatin are the two most widely used. The biological basis of electroporation therapy is outlined in this review and basic science studies and the limited clinical studies that have involved electrochemotherapy are reviewed. Particular focus is placed on trials involving melanoma, head and neck cancers and other primary and metastatic skin cancers.     

Emerging Disparities in Prevention and Survival Outcomes for Patients with Head and Neck Cancer and Recommendations for Health Equity

Current Oncology Reports - The aim of this review is to describe less known and emerging disparities found in the prevention and survival outcomes for patients with head and neck cancer (HNC) that...     

Genetic polymorphisms and head and neck cancer risk (Review)

The aim of this report is to review and evaluate, in a comprehensive manner, the published data regarding the contribution of genetic polymorphisms to risk of head and neck cancer (HNC). All relevant studies available in MEDLINE and published before July 2007 were identified. Studies carried out in humans that compared HNC patients with at least 1 standard control group were considered for analysis. Two hundred and eighteen publications and 3 published meta-analyses were identified. Seventy-five (34%) studies were conducted in Asian, 72 (33%) in American, and 68 (31%) in European countries. The most widely studied gene was GSTM1 (58 studies), followed by GSTT1 (42 studies), GSTP1 (codon 105, 22 studies) and p53 (codon 72, 20 studies). GSTM1, GSTT1, GSTP1, XRCC1 codons 194 and 399, and CYP1A1 codon 462 were examined by meta-analyses, and significant relations were found between the GSTM1-null genotype and an increased risk for HNC. In addition, increased risk for HNC was associated consistently with the ALDH2*1/*2, p53 codon 72 Pro/Pro and EPHX1 codon 113 Tyr/His and His/His genotypes. Cohort studies that simultaneously consider multiple genetic and environmental factors possibly involved in carcinogenesis of the head and neck are needed to ascertain not only the relative contribution of these factors to tumor development but also the contributions of their putative interactions.     

Molecular therapy of head and neck cancer

Aberrant expression of growth factor receptor systems and dysregulation of the downstream cell signalling molecules have been reported in a wide range of epithelial tumours including head and neck cancer. In some cases, such alterations have been associated with a poor prognosis. In the past 25 years, several antigen specific monoclonal antibodies (mAbs, mouse, chimeric, humanized and human versions), and small molecule kinase inhibitors have been developed that are at different stages of preclinical and clinical developments. Some of these agents (e.g. Herceptin, Iressa, cetuximab, avastin) have already been approved for the treatment of epithelial tumours and may also have potential in the treatment of head and neck cancer patients. This review discusses, the development and potential of these antigen specific agents, in particular the human epidermal growth factor receptor (EGFR) inhibitors, either as a single agent or in combination with other EGFR inhibitors, biological agents (e.g. inhibitors of cycloogenase-2, angiogenesis, insulin like growth factor-I receptor and others), and conventional forms of therapy in the prevention and treatment of head and neck cancer. From preclinical and clinical studies with some of these compounds, it is evident that further detailed studies of biopsies from cancer patients are needed in order to identify markers that can be used not only in the selection of the specific population of cancer patients who would benefit from such antigen specific therapeutic strategies, but also those factors which are responsible for the poor response and the development of a phenotype resistance to such inhibitors. The results of such studies could in turn facilitate the widespread use of such agents in the treatment of a wide range of human cancers including head and neck cancer.     

Non-steroidal anti-inflammatory drug and aspirin use and the risk of head and neck cancer: a systematic review

Background  

Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with a reduced risk of several cancers. This is thought to be through the inhibitory action on the cyclooxygenase (COX) enzyme, COX-2. Evidence for NSAIDs preventing head and neck cancer (HNC) is conflicting. We conducted a systematic literature review to investigate the association between NSAID/aspirin use and risk of head and neck cancer (HNC).     

Neurocognitive Function After (Chemo)-Radiotherapy for Head and Neck Cancer

Radical radiotherapy has a pivotal role in the treatment of head and neck cancer (HNC) and cures a significant proportion of patients while simultaneously sparing critical normal organs. Some patients treated with radical radiotherapy for HNC receive significant radiation doses to large volumes of brain tissue. In fact, intensity-modulated radiotherapy techniques for HNC have been associated with a net increase in irradiated brain volumes. The increasing use of chemoradiotherapy for HNC has additionally exposed this patient population to potential neurotoxicity due to cytotoxic drugs. Patients with HNC may be particularly at risk for adverse late brain effects after (chemo)-radiotherapy, such as impaired neurocognitive function (NCF), as risk factors for the development of HNC, such as smoking, excess alcohol consumption and poor diet, are also associated with impaired NCF. The relatively good survival rates with modern treatment for HNC, and exposure to multiple potentially neurotoxic factors, means that it is important to understand the impact of (chemo)-radiotherapy for HNC on NCF, and to consider what measures can be taken to minimise treatment-related neurotoxicity. Here, we review evidence relating to the late neurotoxicity of radical (chemo)-radiotherapy for HNC, with a focus on studies of NCF in this patient population.     

头颈部肿瘤大分割放疗的研究进展及在新冠疫情中的临床价值

放疗是头颈部肿瘤综合治疗的重要部分,也是根治性手段之一。2019年新型冠状病毒肺炎疫情暴发持续至今,对肿瘤患者的治疗造成很大影响。由于常规分割放疗(2 Gy/次)往往需要6周以上连续照射,给疫情防控带来巨大挑战。大分割放疗增加单次剂量,从而减少照射次数,缩短治疗时间,可能较常规分割更适用于疫情期间的治疗。早期研究对大分割方案在头颈部肿瘤姑息治疗中的应用已有诸多探索,其安全性和有效性已得到部分确认。近期,以根治性为目的的大分割放疗及联合化疗、免疫治疗的综合治疗方案也有初步的尝试。根据疫情防控需要,国外多个专家共识也对头颈部肿瘤大分割方案进行了推荐。本文就上述进展做一综述,并讨论疫情期间实施大分割放疗的临床价值。     

EGF receptor in head and neck cancer]

EGFR is overexpressed and is associated with a poor prognosis in head and neck cancer. Among the biological and cellular effects resulting from EGFR targeting in head and neck cancer there is the capacity to restore apoptotic capacities. Other experimental results put into evidence that DNA-repair activity was reduced by the application of EGFR targeting agents. This context was in favor of a research oriented towards combination between anti-EGFR drugs and cytotoxic agents, particularly irradiation. Supra-additive cytotoxic effects have been observed at the experimental level when combining anti-EGFR drugs with irradiation in head and neck cancer. These experimental data were recently confirmed at the clinical level in locally advanced head and neck cancer.