Head and neck squamous cell carcinoma is the sixth most common cancer type worldwide correlated with high morbidity and mortality rates. The malignancy develops in the upper aerodigestive squamous epithelium post - exposure to carcinogens from tobacco and alcohol. Human Papillomavirus and Epstein Barr Virus have also been strongly implicated as causative agents in a subset of HNSCCC. The complex anatomy of the head and neck and vital physiological roles of the tumour-involved structures dictate that the goals of treatment are not only to improve prognosis but also to preserve organ function. Multidisciplinary management procedures including surgery, chemotherapy and radiotherapy have played vital roles in the optimal assessment and treatment of the disease. Surgery as the main treatment modality for early staged primary tumours carrying a favourable prognosis and combined modalities for late or locally advanced and metastatic tumours. New research and innovations have successfully incorporated potentially curative treatment procedures for locally advanced squamous cell carcinomas of the head and neck such as IMRT, Immunotherapy drugs, molecularly targeted agents (EGFRI and Mab Cetuximab).
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90% of all head and neck cancers are squamous cell carcinomas (Peedell 2005). According to the statistical data (Figure 1) published in 2002 by cancer research UK, shows a considerable variation in the incidence of Head and neck squamous cell carcinomas (HNSCC) around the world. HNSCC accounts for 4% of all cancers in the UK, currently ranked as the sixth most common cancer type with 650,000 estimated new cases and 350,000 deaths per year globally (Argiris et al, 2008). According to recent epidemiological studies in the Indian sub continent, the condition has been reported to constitute 30% - 40% of all other malignancies (Bhattacharya et al. 2005). Cohort studies by Robert and Jeffrey, (2005) have shown the malignancy to be more common in men than women by the ratio 3:1 indicating a higher male incidence than women (see Table 1).
Environmental factors: Chronic tobacco smoking, excessive alcohol consumption, chewing betel nut, leaf and quid, inhalation of paint fumes, plastic by-products, wood dust and continual exposure to asbestos have all shown inductive activity in the cancer genesis (Mondal et al. 2003). Machado et al. (2010) stated that, increasing evidence shows association of Human Pappilloma virus (HPV) especially type 16 and 18 to the incidence of oropharyngeal carcinoma through the expression of E6 and E7 oncoprotiens. Also a strong association of Epstein Barr Virus (EBV) to nasopharyngeal carcinoma has been shown by Goldenberg et al (2001) through in vivo studies.
Genetic factors: Substantial numbers of genetic factors have been identified to have an inductive effect to the genesis of HNSCC. Translocation in chromosome 8p24 is a very common event in the ontogenesis of HNSCC as it's involved in the amplification of MYC proto-oncogene (Nilanjana et al. 2005). According to mondal et al. (2003) allelic deletions in chromosome 11q21-24 and p13-15 have increasingly been linked to the incidence of SCC of the oral cavity, larynx and orofacial regions (Table 2.1). Nonetheless, increasing studies have emerged associating racial differences to incidences of particular HNSCC such as pharyngeal and oral cavity SCC (see Table 2.2).
Aetiological factors of HNSCC
Betel Nut, leaf quid
Paint and print
Del.11q21-24 and p13-15
Oral cavity, oropharynx, hypopharynx, larynx, cervical oesophagus
Oral cavity, oropharynx, hypopharynx, larynx, cervical oesophagus.
Oral cavity, oropharynx
Larynx, pharynx, oral cavity.
Nasal cavity/sinuses, larynx, nasopharynx.
Larynx, pharynx, oral cavity.
Larynx (resin and ruber), oral cavity, pharynx (vinyl chloride)
Larynx, oral cavity, pharynx
Larynx, oral cavity
Oral cavity, larynx, pharynx
Table 2.1: showing aetiological factors of head and neck cancer adopted from (Evans et al, 2006)
Male (Incidence Rate/ Death Rate) per 100,000
Female (Incidence Rate/ Death Rate)
15.4 / 3.9
6.1 / 1.4
15.7 / 3.7
6.1 / 1.4
16.1 / 6.3
5.8 / 1.5
10.5 / 3.1
5.3 / 1.2
American Indian/Alaska Native
9.6 / 3.5
5.2 / 1.6
8.7 / 2.5
3.6 / 0.8
Table 2.2: showing the incidence and death rate of oral and pharyngeal carcinoma in both males and females of different racial origins.
1.3 Clinical Signs and Symptoms of HNSCC
Always on Time
Marked to Standard
HNSCC present distinct signs and symptoms depending on the primary sites of origin. Generally malignant ulcerations of the surface mucosa, enlargement of adjacent lymph nodes in particular regions may be detected. In the Oral cavity, unhealing sores or ulcer may be prominent, ear pain experienced on side of the lesion and indurated ulcer may be felt during palpation, whereas for the larynx, continual hoarseness in the voice, ear pain emanating from outside the ear, difficulty breathing with stridor. Cancer of the nasal and paranasal sinuses, nasal obstruction, bloody nasal discharge are common and facial swelling accompanied with pain and diplopia (visual impairment) accompanied with unresponsiveness to antibiotics. Patients with Nasopharyngeal carcinoma, obstruction of the nostrils and nasal blood discharge are prominent, neurological problems due to cranial nerve involvement, and deafness due obstruction of the eustachain tube could occur. (Rubin, 2001). Oropharyngeal tumours present symptoms at a later stage, a feeling of discomfort in the throat when swallowing and radiating pain to the ear is exhibited, also mass in the neck may be seen but at a much later stage. Involvement of the Hypopharynx may present vague symptoms such as discomfort in swallowing which progresses to dysphagia , radiating pain to the ear, respiratory obstruction and hoarseness in the voice occurring at a later stage (Horwich 1995).
1.4 Anatomy of the head and neck
The head and neck consists of complex structural organs subjected to distinctive roles. It contains of four major intrinsic cavities, the oral cavity, nasal cavity, pharyngeal cavity and laryngeal cavity (See figure 2). The framework of these cavities is bony and cartilaginous to which muscles and connective tissues attach covered by a lining of squamous epithelial cells (Johnson and Jacobson, 2006).
Figure 1.1: Showing the anatomy of the head and neck adopted from web calf (http://www.webcalf.com) on 06/04/11
1.4.1Pharynx: Consists of two distal sphincters that help to channel food and air to the right direction .The organ is divided into three anatomical parts. The Nasopharynx, an organ located behind the nasal cavity which extends from the base of the skull to the upper part of the soft palate below. Second is the oropharynx, situated behind the oral cavity including the soft palate, posterior third of the tongue, uvula, faucial pillars and tonsils. Thirdly the hypopharynx, located behind the larynx and extends from the floor of vallecula suclus above to the level of the lower border of the cricoid cartillage where it joins the eosophagus. (Robert and Jeffrey, 2005).
Figure 1.2: showing the Normal Anatomy of pharynx adopted from... 06/04/11 http://trusted.md/feed/items/dr_rob_lamberts/2007/10/22/physical_exam_the_fair_inks
1.4.2 Larynx: Is an essential organ in speech production and also acts as a protective sphincter to keep the lower part of the respiratory tract free from any foreign bodies. The larynx extends from the epiglottis and valleculae superiorly to the lower border of the cricoid cartillage inferiorly (Johnson and Jacobson, 2006). The organ is divided into three interrelated regions, the glottis (middle of the vocal cords separating the true and false vocal cords), supraglottis (above the vocal cords containing the epiglottis) and subglottis (below the vocal cords horizontal to the true vocal folds) (Robert and Jeffrey 2005). (figure 2.2)
Figure 1.3: showing cross sectional diagram of larynx adopted from... 6/04/11
1.4.3 Oral cavity: Extends from the skin vermilion(line that separates between the lips and skin) junction of the lips to the soft and hard palates above and to the line of the papillae on the tongue below which includes, lip, two thirds of tongue, floor of mouth, hard palate , buccal mucosa and lower alveolus(figure 2.3) (Anthony & Peter 2005).
Figure 1.4: showing the anatomical structure of oral cavity adopted from... 6/04/11
1.4.4 The nasal cavity and paranasal sinuses. The nasal cavity is a large air filled space behind the nose where air passes on the way to the throat. Paranasal sinus are four paired air filled areas that surround the nasal cavity in the cheeks above and between the eyes and behind the ethmoids ( maxillary sinuses, frontal sinuses, ethmoid sinuses and spenoid sinuses) (Dubey et al. 1999) ( see Figure 2.4).
Figure 1.5: showing a cross sectional view of the nasal cavity and paranasal sinuses adopted from sinomarin (sinomarin.net/images/nose.) on 6/04/11
1.4.5 Types of HNSCC
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HNSCC are heterogeneous malignant tumours arising from diverse complex structures of the head and neck region lined with squamous epithelial cells. The tumours are categorised according to the anatomical regions of origin such as the, larynx (laryngeal carcinoma, pharynx (pharyngeal carcinoma), oral cavity (carcinoma of oral cavity), nasal cavity (carcinoma of nasal cavity) and paranasal sinuses (carcinoma of paranasal sinuses) (Black et al) where they demonstrate significant biological and clinical neoplastic behaviours (Patmorea et al.2007).
Aims and Objectives:
The aim of this project is critically analyse the Pathophysiology of head and neck squamous cell carcinoma and how the disease is managed.
Review different literature sources in order to provide a comprehensive analysis of the Pathophysiology and management of HNSCC.
Explore different treatment procedures used in management of the disease.
2.0. Pathophysiology of Head and Neck Squamous cell carcinoma
The pathogenesis of HNSCC appears to evolve through complex multistage processes involving biomolecular changes to DNA resulting in invasive carcinoma. Exposure to associated risk factors such as, carcinogenic agents in tobacco and alcohol or HPV through expression of E6 and E7 oncoproteins result in DNA mutation hence causing uncontrolled cell proliferation.
HPV: E6 oncoprotein gene targets P53 gene for degradation and therefore prevents controlled death of abnormal cells whereas E7 gene inactivates Rb (retinoblastoma) function which results in abnormal cell proliferation and disturbs the normal cell cycle regulation (Wang, 2007)
Carcinogens: Damage the DNA causing accumulation of DNA abnormalities within the cell, resulting to alteration of stem cell maturation, differentiation and disturbance in the regenerative processes, hence the appearance of malignant transformed cells (klonisch et al. 2008).
Persistent cell growth and proliferation in the affected region forms a local mass of abnormal cells. Production of degradative enzymes by abnormal cells in the presence of motility factors enables the tumour cells to metastasize to adjacent or deep tissues (Leemans et al.2010). (Evans et al. 2003). (See flow diagram 1.6)
Normal cell Persistent genetic damage Somatic mutation
Invasiveness Vascularisation Tumour formation
Figure 1.6: Showing the development of metastasizing cancer adopted from Tobias and Houchhauster (2010).
2.1. Hypopharyngeal Carcinoma:
Carcinomas of the hypopharynx are very uncommon tumours, highly lethal and demonstrate a diffuse local spread and a natural history of early distant metastasis resulting in a poor 5 year prognosis ranging between 10% - 20% (Nassar and Ibrahim, 2007). The premalignant mucosal lesions develop into hyperproliferative lesions, acquiring the ability to metastasize and invade local structures, lymphatics in order to spread to regional lymph nodes and also invade vascular channels gaining access to other organs. (Horwitz et al. 1979) (see. figure 2.5).
Figure 1.7: showing the metastatic spread of hypopharyngeal carcinomas.
2.2. Oropharyngeal Squamous cell carcinoma (OPSCC);
Oropharyngeal carcinomas are usually seen as large primary tumours or post metastasis to regional lymph nodes but rarely seen at early stages with high incidences commonly seen in patients in their fifth or seventh decades (selek et al. 2004). Human Papilloma virus type 16 and 18 have been linked to the increased incidence of OPSCC. The virus affects the transitional epithelium of the upper aerodigestive tract, integrating the viral DNA into the host DNA. Also viral RNA and oncogenic proteins such as E6 and E7 facilitate in the disruption of vital tumour suppressor genes p53 and Rb which enables the tumour cells to proliferate and metastasize to different organs of the body (see fugure 2.6) (Van Monsjou et al. 2010). However according to Pezier and Patridge, (2011) HPV related OPSCC is associated with improved survival compared to non-HPV SCC as they show high sensitivity to chemotherapy and radiotherapy.
Figure 1.8: Showing the metastatic spread of oropharyngeal carcinomas.
2.3. Laryngeal carcinoma:
Carcinogenesis induced by DNA mutation due to exposure to carcinogenic substances resulting in progressive accumulation of genetic alterations in normal epithelial cells lining the larynx , eventually leading to a selection of clonal population of transformed malignant cells in the region (Ha and Califano, 2002). The modification could take place in the extracellular matrix (ECM) which provides a frame work or site for cellular events, including proliferation, adhesion, differentiation, regulating tissue repair and metastasis. Within the ECM are two proteogylcans with contradictory roles, versican and decorin, Versican directly or indirectly regulates cell adhesion, migration and proliferation whereas decorin effectively inhibits tumour cell growth through indirect inhibition of tumour cell growth factor receptors. However, it has been proven that both proteins undergo alteration during the progression of laryngeal carcinoma contributing to a change in the structural composition of the interstitial ECM which aids in the metastatic spread of cancer by gaining access to lymphatics and systemic circulation thus presenting mild phenotypic laryngeal cancerous lesions (Skandalis et al. 2006).
2.4 Carcinoma of the Nasal cavity and paranasal sinuses
Cancer of maxillary sinus is more common than that of the nasal cavity, it grows within the bony confines of the sinuses but rarely presents any symptoms until it metastasizes to adjacent regions (Mendhall et al, 2008). According to Dubey et al, (1999) the lethality and the poor prognosis of the malignancy is directly linked to the early presented signs and symptoms which are trivialised and confused with inflammatory conditions, hence late diagnosis.
3.0 Diagnosis of Head and Neck Squamous Cell Carcinomas
HNSSC may display diverse and vague signs and symptoms hence, early detection is very crucial in the disease diagnosis and management. It limits morbidity of treatment and increases the chances of cure (Haddad et al. 2008). A multidisciplinary diagnostic approach may be considered depending on the location or severity of the condition. Procedures used in diagnosing HNSCC may be categorised into three groups; Physical examination, laboratory diagnosis and imaging diagnostic techniques.
3.1 Physical examination
3.1.1 Inspection and palpation:
Inspection and palpation are the initial steps taken in the diagnosis of head and neck cancers especially oral cavity and oropharyngeal carcinomas. Careful inspection for location of any lump and palpation of the lymph nodes in intra and extra oral examination is essential (Maurizio and Eckart 2010) (figures 1&2). It's also useful in the prediction of metastasis in the oral cavity (Martinez-Gimeno et al. 2010). However as stated by Hang and Hao, (2002) should not depend on palpation alone to determine appropriate treatment but additional diagnostic techniques should be used.
Figures 1.8 and 1.9: showing inspection and palpation of head and neck regions for clinical symptoms of HNSCC.
3.2 Laboratory diagnosis.
Is a medical procedure that involves the removal of cells or tissues to determine the presence or extent of the disease. Tissue biospy still remains to be an essential requirement in the establishing diagnosis and a means of guiding treatment. Techniques used to obtain biopsy include open excisional biopsy (OEB), Fine needle aspiration cytology (FNAC), core needle biopsy (CNB) and open surgery biopsy with OEB and FNAC as the most commonly used methods (Pfeiffer et al. 2009) . For instance, in diagnosing oropharyngeal carcinoma, prior to sampling, painkillers or anaesthetics are applied to the area of the lesion, then biopsy is obtained and sent off to laboratory for analysis.
Figure 2.0: showing a biopsy sample taken from a lesion in the oropharynx, adopted from ... date.....
3.3 Imaging Diagnostic Techniques:
3.3.1 Laryngoscopy and Nasopharyngoscopy:
Laryngoscopy could be a direct or indirect procedure using either a flexible laryngoscope incorporated with a thin fibre optic endoscope or a rigid laryngoscope embodied with a metal tube and angled lens inserted through the mouth to the site of infection (de-Bree et al. 2008). The device aids the physician to diagnose and asses lesion extension and vocal cord morbidity in patients suspected with hypopharyngeal and laryngeal carcinomas despite being the most difficult sites to examine (Marioni et al. 2005).
Nasopharyngoscopy analogously uses flexible and optical instruments with a long tube fitted with an eye piece, lenses and light source to detect any cancerous lesions such as swellings, bleeding in sites ranging from the nasal passage to the larynx including, the pharynx, nasal cavities, maxillary sinuses (Mackie et al. 2000).
Figure 2.1: Showing rigid laryngoscope inserted through the mouth adopted from .... date....
3.3.2 Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) Scan:
The detailed anatomicalpathological data obtained, CT scan and MRI have become the prime methods of choice for imaging in cases of suspected or proven head and neck cancers
Considered as one of the most preferred diagnostic imaging tools for HNSCC. It uses x-ray beams in order to provide detailed and accurate images of the tissue being examined indicating the extent and size of the tumour. It may guide the radiologist to perform further test such as biopsy, based on which suitable treatment modalities are devised (Daisne et al. 2003).
A very reliable diagnostic method which uses strong magnetic fields and radio waves to produce detailed thin sliced images of the affected region showing metastatic spread (Manavis et al. 2005). More preferred than CT scan especially in the diagnosis of oropharyngeal and oral cavity SCC but used less often than CT scan, except in incidents where additional details is required and no better non invasive methods at disposal. However as stated by hoshikawa et al. (2009) these imaging techniques have limited capabilities in assessing therapeutic effects of treatment thus difficulty to detect any recurrent tumours and improve treatment regimens.
Figures 2.2 and 2.3: Showing diagnostic uses of CT and MRI scans.
4.0 Staging of Head and Neck Squamous cell carcinomas
The aforementioned diagnostic procedures prove very crucial in tumour staging to consequently dispatch appropriate treatment regimens and asses prognosis (Takes, 2004). The presence of tumours in distinct anatomical sites of the head and neck exhibiting diverse clinical behaviours (Patel and Shah, 2006) requires a rigorous staging system.TNM is the preferred and universally accepted staging system for malignant HNSCC designed to describe the anatomical extent of primary tumours (T), nodal involvement (N) and distant metastasis (M) (Van der Schroeff and Baatenburg de Jong, 2009) (Table 2.3). However according to manikantan et al, ( 2009) despite the system's positive aspects, numerous controversial flaws have been acknowledged in the system and anticipating changes to improve it's purpose.
T - Primary tumor
Tis - Preinvasive cancer (carcinoma in situ)
T0 - No evidence of primary tumor
T1 - Tumor 2 cm or less in greatest dimension
T2 - Tumor larger than 2 cm but not larger than 4 cm
T3 - Tumor larger than 4 cm
T4 - Tumor with extension to bone, muscle, skin, antrum, neck
Tx - Minimum requirements to assess primary tumor cannot be met
N - Regional lymph nodes
N0 - No evidence of regional lymph node involvement
N1 - Evidence of involvement of a movable homolateral regional lymph node smaller than 3 cm
N2a - Evidence of involvement of a movable homolateral regional lymph nodeÂ 3-6 cm
N2b - Evidence of involvement ofÂ multipleÂ homolateral regional lymph nodes smaller than 6 cm
N2c - Evidence of involvement of contralateral or bilateral regional lymph nodesÂ smaller than 6 cm
N3 - Any lymph node larger than 6 cm
Nx - Minimum requirements to assess the regional nodes cannot be met
M - Distant metastases
M0 - No evidence of distant metastases
M1 - Evidence of distant metastases
Mx - Minimum requirements to assess the presence of distant metastases cannot be met
Stage 1 - T1/N0/M0
Stage 2 - T2/N0/M0
Stage 3 - T3/N0/M0, T3/N1/M0
Stage 4 - Any T/N1/M0, any T/N0/M0, any T/N2/M0, any T/N3/M0, any T/any N/M1
Table 2.3: showing TNM staging procedure used for HNSCC adopted from http://emedicine.medscape.com/article/1289986-overview. On 29th/03/11
5.0 Clinical Management of Head and Neck Squamous cell Carcinomas.
The diverse non- specific clinical symptoms presented by HNSCC patients at different stages endow the treating physicians with numerous challenges in managing the disease, thus multidisciplinary teams endeavour to work aside to ensure optimal management. including; medical and radiation oncologists, head and neck surgeons, pathologists, nuclear medicine physicians (Fanucchi et al. 2006). The adopted approach may entail using different treatment modalities depending on the clinical staging of the tumour. Early HNSCC's are essentially managed with single modality treatment such as surgery, chemotherapy or radiotherapy, whereas patients with the advanced locoregional malignancy may be treated with combined modalities based on expert opinion (Anthony et al. 2010) (See Flow chart)
Surgical intervention is the main treatment option commonly used for HNSCC despite the complications that may arise (Kerawala, 2010). Surgical intrusion of the affected tumour site is a significant and effective treatment option in patients with the malignancy although successful management is greatly influenced by the extent of tumour staging (size, location and histopathology). Optimal tumour management with surgery alone is mainly achieved in early stage tumours (T1-T2) in sites such as the tongue and oral cavity, whereas locally advanced stage tumours (T3-T4) require combined treatment modalities with either radiation or chemotherapy with the main goal of restoring organ function, improving quality and quantity of life (Scarpa, 2009). Adjuvant chemotherapy after surgery has shown decreased recurrence and improved survival rate evidently in cases with poor prognostic features (intext cite). According to recent studies by Takenori et al. (2011) suggesting the use of surgery for management of advanced oral SCC due to the less effectiveness of adjunctive therapy in survival benefit compared to surgery alone. Kumar et al, (2005) stated that acute radiation effects are more severe in combined therapy than in single modality treatments.
5.2 Radiation therapy:
Radiotherapy and surgery perceived as the main treatment modalities for HNSCC, Radiotherapy is relatively complex as it can be delivered with a curative intent to improve local region control after surgery or to provide symptomatic relief. It results in high tumour control and cure rates for early stage tumours and it's by default the treatment choice for patients unfit for surgery (Argis et al, 2008). Radiation therapy renders the cell DNA unable to undergo normal mitotic mechanisms causing mitotic death and shrinkage of the tumour as well as ensuring conservation to the organ concerned and it's partial function (Donato et al, 2003). Radiation therapy alone is used for locally advanced tumours that are unressectable due to a large tumour size. but addition with chemotherapy after surgery has shown decreased recurrence and improved survival rate evidently in cases with poor prognostic features(intext cite). According to studies done by Creak et al. (2005) a diverse number of patients post-radiotherapy of approximately 60-70Gy radiation dose showed tumour persistence and recurrence within weeks or months indicating poor tumour response to the therapy.
5.3 Chemotherapy: (change sentence const.)
Chemotherapy is prominently used in different treatment regimens for HNSCC patients particularly with locoregionally advanced tumours (see table 2.4). The role of chemotherapy varies depending on the stage of the disease, patients with metastatic, incurable locoregional HNSCC, chemotherapy is only palliative (relieving symptoms) whereas patients with potentially curable locoregional disease, chemotherapy is an integral component of multimodality treatment approach particularly when the tumour is unresectable or when organ preservation is one the main goals of the therapy (Syrigos et al, 2009). A line of chemotherapeutic agents used include 5-flurouracil(5-FU), methotrexate, cisplatin, bleomycin and taxanes, however the standard regimen for HNSCC is combination of cisplatin with 5-FU approved to induce a response rate of 70%- 88% for organ preservation and 40%-50% for locoregion recurrence (Bhide et al, 2000) . According to retrospective studies by Cruz et al. (2007) new combination regimens of texanes have shown to be more active than the standard treatment. Despite the intensive research for many years, chemotherapeutic agents still poses some controversies due to multitudes of side effects exhibited such as myelosuppression (methotrexate) neurotoxicity (taxanes) pulmonary fibrosis (bleomycin), nephrotoxicity (cisplatin), and nausea. Thus neccessary follow up on patients is required to confirm the presence of any end-organ dysfunction.(Juneja and Lacey, 2009).
Role of chemotherapy in management of HNSCC
Types of chemotherapy
Given prior to loco-regional treatment (radiation or surgery) to reduce tumour burden.
Used following local treatment (surgical or radiation therapy) to minimise recurrence.
Used after recurrence of refractory tumour following previous treatment
Chemotherapy administered simultaneously with radiation therapy to increase radiosensitivty
Table 2.4: showing types of chemotherapy with their roles in managing HNSCC adopted from Evans et al. 2006.
5.4 Combined chemotherapy and radiotherapy:
The complexity of treatment modalities relatively varies with advancement of the disease, hence the requirement of detailed, careful examination of the patient prior to selection of suitable combination therapy (see table 2.5) (Syrigos et al, 2009). According to Aldelstein, (2003) after significant long- term functional deficits and radiation induced long- time toxicities following combination of surgery with radiation therapy. The emergence of chemoradiotherapy as a standard care procedure for HNSCC has proven advantageous in preserving both organ structure and function thus used in cases where surgical resection is suspected to cause huge functional and cosmetic defects especially in oropharyngeal carcinomas (Nagraj et al. 2010). There's however limited evidence regarding the survival benefit of the combined treatment modality with oral cavity SCC (Day et al. 2003).
Factors to consider prior to selection of combination therapy
Presence of severe co-morbidities and age-related frailty in patient
Underlying severe psycosocial problems
Presence of rapidly growing tumours with advanced nodal involvement
Location of the primary tumour
Goals for the therapy (organs preservation, increase quality of life, reduction of metastasis)
Table 2.5: Shows vital factors to consider before selection of combination therapy, adopted from (Syrigos et al, 2009).
Locoregionally advanced HNSCC
Stage IV/B and stage III, high risk locations
(CT head and neck, CT chest, ENT exam, +/- additional studies, e.g. PET
Stage I and stage II
Careful evaluation of treatment goals and performance status
Careful evaluation of treatment goals.
Physician's preferences? No Yes
(Single modality) level I evidence.
Use in patients with poor performance status.
Substantial functional impairment with surgery
(Single modality) level I evidence.
Use in patients with adequate performance status.
No significant functional impairment with surgery
Level I evidence
Locoregionally advanced disease (chemotherapy based: level I evidence).
Radiation with concomitant cetuximab (level I evidence).
Locoregionally advanced disease single modality radiation is not considered adequate (level I evidence).
If upstaging occurs or if high risk features are present, adjuvant treatment is indicated
High risk features?
Radiation with concomitant cetuximab (level I evidence)
Chemotherapy at reduced intensity(expert opinion)
Radiation single modality (expert opinion)
Palliative measures (expert opinion)
Radiation (single modality)
Level II evidence (vs no treatment)
Expert opinion (vs chemoradiation)
Cisplatin - single agent 30% local failure rate (level I evidence)
Combination chemo (cisplatin/5-FU, TFHX, etc level II evidence.
In high risk situations, may help to reduce the risk of distal failure ?
5.5 Other management procedures:
The intricacy of different head and neck regions predisposes the patient to physical and psychological ordeals after invasive treatment. (Table 2.6) shows a multidisciplinary management team with supportive techniques which could be substituted for or supplemented with the aforementioned treatment procedures in order to minimise the damage and maximise eradication (see Table 2.6) (Evans et al. 2006).
Clinical nurse specialist
Dental hygienist / Dentist
Psychotherapist / physiotherapist
Palliative care team
Speech and language therapist
Pain and management therapist
Table 2.6: showing different supportive team members in managing HNSCC adopted from Evans et al. (2006).
Prognosis of HNSCC is immensely dependent on the staging and location of the tumour. Overall a good prospect of long term remission in early tumours (T1-T2, N0-N1) ranges between 60% - 90% 5 year survival rates however patients at stage 4(T4) carry no higher than 30% chance (Obe and Johnston, 2001). (See table 2.5)
5- Year survival rate (%)
95% / 80% / 50% (possible relapse)
80% / 70%
No more than 40%
Majority present with locally advanced disease
15% - 20%. Post - surgery 35%
Nasal cavity and paranasal sinuses
Depending on stage
70% post-radical radiotherapy
Local-regionally advanced disease
60% (possible relapse)
Table 2.7: Showing a 5-year survival rate in different HNSCC adopted from Obe and Johnston (2001).
6.1 Follow up and prevention
Patient follow up after treatment is a very essential aspect of management as it allows early detection of recurrent and second primary tumours (Joshi et al, 2009). The practitioner may decide accordingly for a routine use of post-operative radiotherapy, further surgical excision or palliative radiotherapy for less aggressive distant metastatic tumours. Preventative measures are also of paramount importance to improve prognosis (chen-shuan et al. 2010). According to Silverman, (2001) early detection and education of patients and the general public of associated disease risk factors is crucial in preventing of the disease. However according to a questionnaire study by Joshi et al, (2009) little survival benefit has been achieved from patient follow ups. Invest
7.0 New Research and Innovation:
A great deal of research has been endowed in developing better treatment procedures. Use of endoscopic laser surgery/ressection for conservatory benefits in areas such as larynx providing good voice and adequate swallowing presservation. Innovation of intensity modulation radiotherapy (IMRT) with a better therapeutic index of radiotherapy reducing the risk of xerotosmia (chronic radiation toxicity) (Fanucchi et al, 2006). However, with hearing deficit still signifcant with IMRT due to high toxic dose, tomotherapy now allows tumours to be irradiated with great accuracy, using very high doses but with minimal effect on the neighbouring cells (Nguyen et al, 2011). Immunological innovations have been proposed to deal with the immunological aspects of the disease such as immune surveillance. Immune therapy, in particular adoptive T Cell therapy, Dendritic cell therapy have shown promise as putative tumour specific therapy with clinical benefits (McKechnie et al, 2004). Incoporation of molecularly targeted agents have increasingly helped in directing appropriate treatment for locally advanced HNSCC most likely to respond to suitable treatment regimens. These include Epidermal growth factor inhibitors (EGFRI) and monoclonal antibody cetuximab (Mab Cetuximab) (Bernier, 2008)
The uncontrolled wide spread of HNSCC associated risk factors around the world particularly in developed countries has led the malignancy to pose a great threat to the population as whole despite the management land marks in place with new treatment procedures under review. Education is still of paramount importance to imbue the general public with the knowledge of the disease, understanding the associated risk factors so as to take precautionary/ preventative measures to prevent the condition.