File Name: chemotherapy in head and neck cancer .zip
Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus HPV , primarily HPV Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion.
Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy CRT for oral cavity cancers and primary CRT for pharynx and larynx cancers. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention.
Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies. Head and neck squamous cell carcinomas HNSCCs develop from the mucosal epithelium in the oral cavity, pharynx and larynx and are the most common malignancies that arise in the head and neck Fig. Increasingly, tumours that arise in the oropharynx are linked to prior infection with oncogenic strains of human papillomavirus HPV , primarily HPV, and, to a lesser extent, HPV and other strains 1 , 2 , 3.
No screening strategy has proved to be effective, and careful physical examination remains the primary approach for early detection. Although a proportion of oral pre-malignant lesions OPLs , which present as leukoplakia white patches or erythroplakia red patches , progress to invasive cancer, the majority of patients present with advanced-stage HNSCC without a clinical history of a pre-malignancy. HNSCC of the oral cavity is generally treated with surgical resection, followed by adjuvant radiation or chemotherapy plus radiation known as chemoradiation or chemoradiotherapy CRT depending on the disease stage.
CRT has been the primary approach to treat cancers that arise in the pharynx or larynx. With the exception of early-stage oral cavity cancers which are treated with surgery alone or larynx cancers which are amenable to surgery or radiation alone , treatment of the majority of patients with HNSCC requires multimodality approaches and thus multidisciplinary care. The epidermal growth factor receptor EGFR; also known as HER1 monoclonal antibody cetuximab is approved by the FDA as a radiation sensitizer, alone or in combination with chemotherapy, for the treatment of patients with recurrent or metastatic disease 4.
Although inferior to cisplatin as a radiosensitizer in HPV-associated disease 5 , 6 , cetuximab is often used in cisplatin-ineligible patients. The immune checkpoint inhibitors pembrolizumab and nivolumab are approved by the FDA for treatment of cisplatin-refractory recurrent or metastatic HNSCC and pembrolizumab is approved as first-line therapy in patients who present with unresectable or metastatic disease 7 , 8 , 9.
Detailed molecular characterization as well as immune profiling of HNSCC suggests that incorporation of prognostic and predictive biomarkers into clinical management may overcome obstacles to targeted therapies and enable prolonged survival. In this Primer, we provide an overview of the types of HNSCC and their epidemiology, as well as the pathogenesis of each type and how this influences the management approach.
Head and neck squamous cell carcinoma HNSCC arises from the mucosal epithelium of the oral cavity lips, buccal mucosa, hard palate, anterior tongue, floor of mouth and retromolar trigone , nasopharynx, oropharynx palatine tonsils, lingual tonsils, base of tongue, soft palate, uvula and posterior pharyngeal wall , hypopharynx the bottom part of the throat, extending from the hyoid bone to the cricoid cartilage and larynx. Human papillomavirus-associated HNSCCs arise primarily from the palatine and lingual tonsils of the oropharynx, whereas tobacco-associated HNSCCs arise primarily in the oral cavity, hypopharynx and larynx.
HNSCC is the sixth most common cancer worldwide, with , new cases and , deaths in refs 10 , 11 , 12 Fig. In addition to deaths directly caused by HNSCC, survivors of this cancer have the second highest rate of suicide Psychological distress and compromised quality of life QOL are likely key underlying factors for suicide The estimated age-standardized rates ASRs of head and neck squamous cell carcinoma HNSCC incidence worldwide are shown for men and women combined 10 , 11 , These risk factors include tobacco consumption, alcohol consumption, exposure to environmental pollutants and infection with viral agents, namely, HPV and EBV.
Tobacco and alcohol consumption are the high-risk factors that occur most widely geographically. The use of areca nut or betel quid products is linked to particularly high rates of oral cavity cancer in India first and fourth most common cancer in Indian men and women, respectively , Taiwan and some provinces in mainland China In general, the high male to female ratios for HPV-negative HNSCC incidence reflect the sex-specific patterns of modifiable risk behaviours, including the use of the aforementioned tobacco, smokeless tobacco, areca nut, betel quid and alcohol 21 , The effect of electronic cigarettes on HNSCC risk remains unknown and will only be evident in the coming decades.
Other risk factors include ageing, poor oral hygiene and diets lacking in vegetables 27 , Individuals with Fanconi anaemia, a rare, inherited genetic disease characterized by impaired DNA repair owing to mutations in any of the 22 FANC genes , have a —fold increased risk of developing HNSCC, primarily cancers of the oral cavity Although the mechanisms responsible for the unique proclivity of patients with Fanconi anaemia to develop HNSCC remain unknown, alterations in Fanconi anaemia pathway genes are likely to have a role.
HNSCC originates from mucosal epithelial cells that line the oral cavity, pharynx, larynx and sinonasal tract. Histologically, progression to invasive HNSCC follows an ordered series of steps beginning with epithelial cell hyperplasia, followed by dysplasia mild, moderate and severe , carcinoma in situ and, ultimately, invasive carcinoma Fig.
However, of note, most patients diagnosed with HNSCC do not have a history of an antecedent pre-malignant lesion. Given the heterogeneous nature of HNSCC, the cell of origin depends on anatomical location and aetiological agent carcinogen versus virus. However, in each case, normal adult stem or progenitor cells are likely candidates for the cell of origin, giving rise, following oncogenic transformation, to cancer stem cells CSCs with properties of self-renewal and pluripotency.
The mucosal epithelium lining the oral cavity, pharynx, larynx and sinonasal tract is the site of origin for head and neck squamous cell carcinoma HNSCC. In a model of ordered histological progression of HNSCC 68 , mucosal epithelial cell hyperplasia is followed by dysplasia, and carcinoma in situ precedes the development of invasive carcinoma. Specific genetic events have been found to be enriched at each stage of progression and are indicated.
LOH, loss of heterozygosity. Histopathology images of hyperplasia, dysplasia, carcinoma in situ and invasive carcinoma are reprinted from ref. Histopathology image of normal mucosa courtesy of R. Jordan, University of California San Francisco. CD44 is a cell surface receptor for hyaluronic acid and matrix metalloproteinases MMPs and is involved in intercellular interactions and cell migration. ALDH1 is an intracellular enzyme that converts retinol into retinoic acid, plays a part in cellular detoxification and is a marker for both normal stem cells and CSCs.
Frequently lethal, SPTs may share some molecular abnormalities with the initial primary tumour or may exhibit marked differences. In tobacco-associated HNSCC, the size of the damaged anatomical field may increase with patient age 51 , Considering the concept of field cancerization, the development of SPTs may reflect distinct CSCs arising from independent oncogenic transformations. Tobacco consists of more than 5, different chemicals, of which dozens have been shown to have carcinogenic activity.
The chemicals thought to be most responsible for the cancer-causing effects of tobacco are polycyclic aromatic hydrocarbons PAHs , including benzo a pyrene, and nitrosamines, including 4- methylnitrosamine 3-pyridyl butanone and N -nitrosonornicotine 53 , In smokeless tobacco, nitrosamines are the dominant carcinogen, whereas the carcinogens in areca nut and betel quid are poorly defined Tobacco-derived carcinogens, including PAHs and nitrosamines, undergo metabolic activation, with detoxification enzymes and pathways promoting excretion Fig.
However, many of the reactive metabolites of these carcinogens can also form covalent DNA adducts, which, if not properly repaired, lead to mutations and other genetic abnormalities. The propensity for tobacco carcinogens to promote genetic changes and neoplastic transformation probably depends on the balance between metabolic activation versus detoxification and DNA repair Fig. The use of tobacco products is also associated with inflammation in the exposed tissues.
Coincident with inflammation is the local production of cytokines, chemokines and growth factors that can have an important role in promoting proliferation, angiogenesis and, ultimately, carcinogenesis. Consumption of tobacco products or betel quid the leaf of Piper betle and areca nut Areca catechu , exposure to environmental pollutants or excessive alcohol consumption are primary factors in the development of human papillomavirus HPV -negative head and neck squamous cell carcinoma HNSCC.
Tobacco, and tobacco smoke in particular, are rich in polycyclic aromatic hydrocarbons and nitrosamines, which are known human carcinogens and are associated with a strongly increased risk of HNSCC. Metabolic activation of carcinogens results in the formation of reactive metabolites, which, if not detoxified and excreted, can damage DNA, typically by generating bulky DNA adducts. If the DNA damage is faithfully and accurately repaired, there may be no lasting consequences. However, if the damaged DNA is not promptly repaired, or is repaired errantly by lower fidelity repair mechanisms, then permanent damage in the form of mutations, deletions and amplifications can occur.
Excessive alcohol consumption is another key risk factor for HPV-negative HNSCC and is known to synergize with tobacco use to promote carcinogenesis Alcohol might serve as a solvent for carcinogens, enhancing the exposure of epithelial cells to these substances In addition, alcohol is metabolized to acetaldehyde, which is known to form DNA adducts In HNSCC tumour specimens, the viral genome is typically found integrated at a single, albeit variant, genomic site The genome consists of seven early genes E1 — E7 and two late genes L1 and L2.
The L1 and L2 genes encode viral capsid proteins, whereas the E1 — E5 genes encode proteins that are primarily involved in replication and transcription of the viral genome. The bicistronic E6 and E7 genes are essential for oncogenic transformation of the host cell. E6 protein forms a complex with the cellular ubiquitylation protein E6-AP and the tumour suppressor p53 to promote ubiquitylation and proteasomal degradation of p53 ref.
E6 may possess other transforming activities beyond p53 degradation but these functions are less well characterized 61 , 62 , E7 protein binds strongly to the cell cycle regulator retinoblastoma-associated protein RB1 , promoting proteasomal destruction of RB1 and the release of E2F family transcription factors The liberated E2F proteins drive the cell cycle beyond the restriction point also known as the G1—S checkpoint and into S phase.
In addition to E6 and E7, E5 also has a role in oncogenic transformation by helping to drive cell cycle progression 66 , Differentiation of basal epithelial cells leads to their detachment from the basement membrane and upward migration, with progressively increasing differentiation leading to the sloughing off of terminally differentiated, non-proliferating cells. The palatine and lingual tonsils are also characterized by numerous tissue invaginations, commonly termed crypts, which are particularly enriched in stem cells at their base.
A unique, reticulated squamous epithelium lines the crypt structure and gaps or fissures in the basement membrane and basal layer also occur. Infiltrating immune cells also make contact with the viral particles. Stable integration of the viral genome into the host genome, and the concerted action of HPV E6 and E7 proteins on cellular p53 and RB levels, respectively, acts to promote cellular transformation.
The accumulation of additional genetic alterations is needed to induce full transformation, including the acquisition of invasive and metastatic phenotypes. There is a tremendous need to identify molecular biomarkers that can be used to predict progression of pre-malignant HNSCC lesions, prognosticate survival, reveal new targets for intervention and predict response to therapeutic agents.
The search for biomarkers has focused on defining the molecular abnormalities that characterize HNSCC. In this section, we highlight findings regarding genetic and epigenetic alterations, as well as dysregulation of cellular signalling pathways, which occur during HNSCC development. HNSCC is characterized by genetic instability, with frequent loss or gain of chromosomal regions The availability of a model of ordered histological progression of HNSCC has enabled assignment of some chromosomal abnormalities to specific stages of progression 57 , 68 Fig.
Loss of 9p21 occurs during progression of normal head and neck epithelial mucosa to hyperplasia. Progression from hyperplasia to dysplasia is marked by loss of 3p21 and 17p13, the site of TP The transition from dysplasia to carcinoma in situ involves loss of 11q13, 13q21 and 14q32, whereas loss of 6p, 8, 4q27 and 10q23 is observed in the progression to invasive carcinoma.
Collectively, these studies of chromosomal abnormalities reveal that multiple genetic alterations may be required for full transformation to invasive HNSCC Furthermore, whether progression of HNSCC is strictly dependent on the temporal sequence of these alterations or, instead, on their collective accumulation, remains unresolved. A detailed analysis of of these tumours, consisting of HPV-negative and 36 HPV-positive tumours, revealed a high degree of genomic instability; tumours had an average of CNAs and 62 chromosomal structural abnormalities for example, fusions Mutational profiling revealed that HNSCC-associated mutations are significantly enriched in 11 genes Thus, in contrast to many other solid tumour malignancies that are frequently driven by mutations in RAS or other oncogenes, HNSCC might be more frequently driven by loss of tumour suppressors.
Comparison of HPV-positive and HPV-negative tumours failed to detect previously reported differences in overall mutation rates
Head and neck cancer: causes, prevention and treatment. Send correspondence to. Although head and neck carcinoma ranks fifth among cancer types, patient survival rates have not changed significantly over the past years. Other factors may influence the development of head and neck carcinoma. Surgery is the main treatment option, and the addition of radiotherapy following surgery is frequent for patients in the early stages of the disease. Other therapies target specific genetic molecular components connected to tumor development.
PDF | Head and neck squamous cell cancer (HNSCC) is most commonly a tobacco-related disease, affecting nearly people worldwide.
Treating head and neck cancer patients with systemic therapy is challenging because of tumor related, patient related and treatment related factors. In this review, we aim to summarize the current standard of care in the curative and palliative setting, and to describe best practice with regard to structural requirements, procedures, and monitoring outcome. Treatment advice for individual head and neck cancer patients is best discussed within a multidisciplinary team.
Chemotherapy uses anti-cancer cytotoxic drugs to destroy cancer cells. Cytotoxic means toxic to cells. Chemotherapy can be given in combination with radiotherapy.
Primary site cancers of the oral cavity, oropharynx, and larynx. A, to B, to American Joint Committee on Cancer stage of oral cavity and oropharyngeal cancers and laryngeal cancers from to and from to
MACH-NC = Meta-Analysis of Chemotherapy in Head and Neck Cancer; PF = cisplatin + fluorouracil. 1. Pignon et al. Lancet. ; 2. Monnerat et al.
Metrics details. Definitive chemoradiotherapy dCRT is a standard treatment for patients with locally advanced head and neck cancer. There is a clinical need for a stratification of this prognostically heterogeneous group of tumors in order to optimize treatment of individual patients. Here we report the clinical results of the cohort which represent the basis for biomarker discovery and molecular genetic research within the framework of a clinical cooperation group. Patient data were collected and analyzed for outcome and treatment failures with regard to previously described and established risk factors.
However, its role is yet to be clearly defined outside of larynx preservation. Patients with high risk of distant failure might potentially benefit from sequential treatment. It is now widely accepted that TPF docetaxel, cisplatin, and fluorouracil is the standard IC regimen. Essays that have compared this approach with the standard of care, concurrent chemoradiotherapy CCRT , are mostly inconclusive.
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