Management Development Institute of Singapore in Tashkent Faculty of Business Marketing Management of Marketing Channels Assignment Name: Gafurov Nodirbek Batch#: B0900377 Table of Contents Executive Summary3 Introduction4 The Role of….
Squamous cell carcinoma of the head and neck region: Pathophysiology & management of the disease
Head and Neck cancer is increasingly becoming a very serious public health issue in the world, correlated with high incidence and mortality rates mainly in developing countries(Jeffries and Foulkes 2001). Deformities caused by the malignancy such as facial and neck injuries profoundly affect the individual’s social and emotional well being (Murphy et al. 2007).
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 worldwide with 650,000 estimated new cases and 350,000 deaths per year (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 Souhami and Tobias, (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).
Cancer siteIncidence rate (2007)Death rate (2008)
Table 1: Showing the latest UK incidence and mortality rate of the squamous cell carcinomas of various head and neck regions adopted from cancer research UK on 15/04/2011. http://info.cancerresearchuk.org/prod_consump/groups/cr_common/@nre/@sta/documents/generalcontent/crukmig_1000ast-2735.pdf .
Figure1: Showing incidence of HNSCC in different countries in 2002. Adopted from Cancer Research UK on 15/04/2011/. http://info.cancerresearchuk.org/cancerstats/types/oral/incidence/
1.2 Aetiological factors of HNSCC:
A relatively diverse number of aetiological agents have been linked to the incidence of HNSCC. Epidemiological studies have shown an association of both environmental and genetic factors (Evans et al, 2006).
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 oncoprotein. 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 is 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 (National cancer institute) (see Table 2.2).
Aetiological factors of HNSCC
Table 2.1: showing aetiological factors of head and neck cancer adopted from (Evans et al, 2006).
Table 2.2: showing the US incidence and death rate of oral and pharyngeal carcinoma in both males and females of different racial origins adopted from National cancer institute on 28/04/11. http://www.cancer.gov/cancertopics/types/throat
1.3 Clinical Signs and Symptoms of HNSCC
HNSCC presents 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 indurate ulcer may be felt during palpation, whereas, in the larynx, continual hoarseness in the voice, ear pain emanates from outside the ear and difficulty breathing with a stridor. Symptoms in the nasal and paranasal sinuses include nasal obstruction, bloody nasal discharge and facial swelling accompanied with pain as well as diplopia (visual impairment). Patients with Nasopharyngeal carcinoma experience prominent obstruction of the nostrils and nasal blood discharge, neurological problems due to cranial nerve involvement, and possibility of deafness due to obstruction of the eustachain tube. (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, a mass in the neck may be visible but at a much later stage. Hypopharyngeal carcinomas may present vague symptoms such as discomfort during 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 is made up of complex structural organs subjected to distinctive roles. It contains 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 adapted from web calf : http://www.webcalf.com [Accessed 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. (Souhami and Tobias, 2005).
Figure 1.2: showing the Normal Anatomy of pharynx adopted from clinic- clinic. http://www.clinic-clinic.com/images/pharynx.gif [accessed: 29/04/11] 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). It divides 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) (Souhami and Tobias, 2005). (See figure 2.2)
Figure 1.3: showing cross sectional diagram of larynx adapted from Wigston choir: http://www.wigstonchoir.org.uk/images/larynx.jpg [Accessed on 29/04/11].
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 the lips, two thirds of tongue, floor of mouth, hard palate, buccal mucosa and the lower alveolus(figure 2.3) (Neal & Hoskin, 2005).
Figure 1.4: showing the anatomical structure of oral cavity adapted from BlogSpot: http://learn-free-medical-transcription.blogspot.com/2009_02_24_archive.html [Accessed on 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 Cancer research UK http://www.cancerhelp.org.uk/type/nasal-cancer/about/the-nasal-cavity-and-paranasal-sinuses. and Health all refer http://health.allrefer.com/health/foreign-body-in-the-nose-nasal-anatomy.html [Accessed on 29/04/11] 1.4.5 Types of HNSCC:
HNSCC are heterogeneous malignant tumours arising from previously mentioned 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 the management of HNSCC.
Explore different treatment procedures used in managing the disease.
2.0. Pathophysiology of Head and Neck Squamous cell carcinoma
The pathogenesis of HNSCC appears to evolve through complex multistage processes involving alteration of molecules that regulate cellular signalling pathways in DNA damage response, cell cycle arrest and apoptosis (Figueiredo et al, 2004). Chronic exposure to risk factors such as, carcinogenic agents in tobacco and alcohol or HPV through expression of transforming oncoprotein E6 and E7 has shown to have an alterative effect in the molecules, resulting in DNA mutation hence, uncontrolled cell proliferation. (Evans and Powell, 2010)
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 in 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 proliferation in the affected region results in a local mass of abnormal cells producing degradative enzymes in the presence of motility factors enabling the tumour cells to metastasize to adjacent or deeper tissues (Leemans et al.2010) and (Evans et al. 2003). (See flow diagram 1.6)
Normal cell Persistent genetic damageSomatic mutationInvasiveness VascularisationTumour formationMetastasis
Figure 1.6: Showing the development of metastasizing cancer adapted from Tobias et al, (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, hence a poor 5 year prognosis ranging between 10% – 20% (Nassar and Ibrahim, 2007). Alterative effect of carcinogens on the p53 gene in the mucosa causes premalignant mucosal lesions to develop into hyperproliferative lesions, acquiring the ability to metastasize and invade local structures, lymphatics then spreads to regional lymph nodes and invading vascular channels gaining access to other organs. (Chien et al, 2003) (see. figure 2.5). According to studies by Hattori et al, (2000), minimal association of p53 mutation and exposure to carcinogens has been linked in the incidence of second primary hypopharyngeal carcinomas.
Figure 1.7: showing the metastatic spread of hypopharyngeal carcinomas adopted from cancer clinical trials http://www.cancertrialshelp.org/blog/wp-content/uploads/2010/10/Throat-cancer-stage-4c.jpg [Accessed on 28/04/2011].
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 Papillomavirus 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 rate compared to non-HPV SCC because they show high sensitivity to chemotherapy and radiotherapy.
Figure 1.8: Showing the metastatic spread of oropharyngeal carcinomas adopted from cancer clinical trials. http://www.cancertrialshelp.org/blog/wp-content/uploads/2010/10/Throat-cancer-stage-4c.jpg [Accessed on 28/04/2011] 2.3. Laryngeal carcinoma:
Carcinogenesis is induced by DNA mutation as a result of exposure to carcinogenic substances leading to a progressive accumulation of genetic alterations in the normal epithelial cells lining the larynx, consequently leading to a selection of clonal population of transformed malignant cells in the region (Ha and Califano, 2002). The Extracellular matrix (ECM) provides a frame work or site which contributes to series of cellular events such as 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, during the progression of laryngeal carcinoma, both proteins undergo alteration resulting in a change to the structural composition of the interstitial ECM which aids in the metastatic spread of cancer through access to the lymphatics and systemic circulation, therefore presenting phenotypic laryngeal cancerous lesions (Skandalis et al. 2006).
2.4 Carcinoma of the Nasal cavity and paranasal sinuses
Nasal cavity and paranasal sinus carcinomas manifest similar clinical signs and symptoms strongly linked with exposure to occupational chemicals such as nickel and chromium dust (Cancer research UK). Carcinoma of the paranasal sinuses particularly in the maxillary region tend to be more common than that of the nasal cavity characteristically known for rapid growth and extensive local destruction (Shindo et al, 1990). It grows within the bony confines of the sinuses but rarely presents any symptoms until it metastasizes to adjacent regions (Mendhall and Pfister, 2008). According to Dubey et al (1999), the lethality and the poor prognosis of the malignancy is directly linked to the trivialised early presented signs and symptoms often confused with inflammatory conditions, hence it’s late diagnosis. Studies by Alos et al, (2009) proved that patients who are HPV positively associated with the condition carry a better prognosis than HPV negative patients.
3.0 Diagnosis of Head and Neck Squamous Cell Carcinomas
HNSSC may display 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. Diagnostic procedures used 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 serve as the initial steps in the diagnosis of head and neck cancers especially oral cavity and oropharyngeal carcinomas for presence of any lump as a indication of lymph node involvement (Maurizio and Eckart 2010) (figures 1&2). The procedure also serves crucial in the prediction of metastasis in the affected sites (Martinez-Gimeno et al. 2010). However, as correctly stated by Hang and Hao (2002), in order assign suitable treatment, additional diagnostic techniques should be incorporated rather than palpation alone .
Figures 1.8 and 1.9: shows inspection and palpation of head and neck regions for suspected HNSCC patients adopted from a practical guide to clinical medicine. http://eglobalmed.com/core/PracticalGuideClinicalMedicine/medicine.ucsd.edu/clinicalmed/head.html. [Accessed on 29th/04/2011] 3.3 Imaging Diagnostic Techniques:
3.2.1 Laryngoscopy and Nasopharyngoscopy:
Laryngoscopy is either a direct or an 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 (see figure 2.1) (de-Bree et al. 2008). The technique 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 (Mackie et al. 2000).
Figure 2.1: Showing rigid laryngoscope inserted through the mouth adopted from Nucleus medical media http://iv.nucleusinc.com/generateexhibit.php?ID=8128&ExhibitKeywordsRaw=&TL=&A=1029 [Accessed 28/04/2011] 3.2.2 Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) Scan:
The detailed anatomical pathological data obtained using CT and MRI scans makes the imaging procedures the prime methods of choice in diagnosing suspected or proven head and neck carcinomas for subsequent clinical management (Petrou and Mukherji 2008).
One of the most preferred and frequently used diagnostic imaging tools for HNSCC. It uses x-ray beams in order to provide detailed and accurate images of the site under examination, indicating the extent and size of the tumour which may guide the radiologist in performing further test such as biopsy (Daisne et al. 2003).
A very reliable diagnostic technique 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). Generally preferred over CT scan and primarily used in diagnosing tumours confined in the oral cavity, but less often used than CT, except in cases where additional detail is required and no better non invasive methods available (Rumboldt et al 2006). However as stated by hoshikawa et al. (2009) the preceded imaging techniques have limited capabilities in assessing therapeutic effects of treatment therefore difficulty arises in detecting recurrent tumours at a early stage.
PET (Positron Emission Tomography) scan however, unlike CT and MRI has been shown to offer higher sensitivity for imaging of treated head and neck cancers (Rumboldt et al, 2006). The reason being as stated by Passero et al (2010), it assesses metabolic activity within the target lesion hence; it differentiates between normal and cancerous cells.
Figures 2.2 and 2.3: Showing diagnostic uses of CT and MRI scans adopted from magnet lab and health republic on 28/04/2011. http://www.magnet.fsu.edu/education/tutorials/magnetacademy/mri/ and http://healthrepublic.org/CtScan.html
3.3 Laboratory diagnosis.
Is a medical procedure that involves the removal of cells or tissues to determine presence or absence, size and extent of disease spread (Adoga et al, 2009).Tissue biopsy still remains to be an essential requirement in the establishing histological diagnosis and a means of guiding treatment. However, Rumboldt et al, (2006) states that, the procedure acts as a supplement to the preceded physical examination and radiological investigations. Techniques used include open excisional biopsy (OEB), Fine needle aspiration cytology (FNAC), core needle biopsy (CNB) and open surgery biopsy, although OEB and FNAC being the most commonly used methods (Pfeiffer et al. 2009) .
Figure 2.0: showing a biopsy sample taken from a lesion in the oropharynx, adopted from Medical images on 28th/04/2011. http://medicalimages.allrefer.com/large/oropharyngeal-biopsy [Accessed on 28th/04/2011] 4.0Staging of Head and Neck Squamous cell carcinomas
The aforementioned diagnostic procedures prove very crucial in tumour staging and determining factors in designating appropriate treatment regimens and assessing prognosis (Takes, 2004). The presence of tumours in distinct anatomical sites of the head and neck exhibiting diverse clinical behaviours, requires a rigorous staging system (Patel and Shah, 2006).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 node 3-6 cm
N2b – Evidence of involvement of multiple homolateral regional lymph nodes smaller than 6 cm
N2c – Evidence of involvement of contralateral or bilateral regional lymph nodes 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 adapted from e medicine http://emedicine.medscape.com/article/1289986-overview. [Accessed 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 management team with numerous challenges hence, multidisciplinary management teams including; medical and radiation oncologists, head and neck surgeons, pathologists, nuclear medicine physicians endeavour to work together to ensure optimal management of the malignancy. (Fanucchi et al, 2006). The adopted approach may entail using different treatment modalities depending on the staging of the tumour. Single modality treatment such as surgery, chemotherapy or radiotherapy is primarily used for early stage SCC 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). Surgery is a very effective treatment procedure in eradicating or reducing tumour burden inspite it’s successful management being influenced by tumour staging which guides adjuvant treatment decisions. Significant effects however could be seen in early staged tumours (T1-T2) primarily in the tongue and other sites of the oral cavity (Scarpa, 2009). Studies by Goda et al (2011) have shown exceptional and durable local control of advanced tumours with adjuvant radiotherapy following surgery. Choe et al, (2010) has also highlighted adjuvant chemotherapy after surgery to be associated with a favourable outcome for locoregionally advanced HNSCC.However, recent studies by Takenori et al. (2011) indicated adjunctive therapy less effective in survival benefit compared to surgery alone. Kumar et al, (2005) in agreement stated that, because acute radiation effects are more severe in combined therapy than in single modality treatments.
5.2 Radiation therapy:
Radiotherapy and surgery serve as the main treatment modalities for HNSCC, however the role of radiotherapy is relatively complex as it can be delivered, with a curative intent to improve local region control post surgery or for palliative use. It results in high tumour control and cure rates for early stage tumours and 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 preserving the organ involved (Donato et al, 2003). Although single modality radiotherapy can be used for locally advanced tumours, according to studies by Creak et al. (2005), a significant 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. However, combined postoperative administration of chemotherapy (cisplatin) and radiotherapy has shown decreased local and regional recurrence (Cooper et al, 2004)
Figure 2.1: Showing a view of radiotherapy machine adapted from med gadget http://medgadget.com/archives/2008/07/varians_rapidarc_radiation_delivery_system_goes_clinical.html [Accessed on 30th/04/11]
Chemotherapy is significantly used in different treatment regimens for HNSCC patients particularly with locoregionally advanced tumours (see table 2.4) (Evans et al 2006). 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 acts as an integral component of multimodality treatment approach particularly when the tumour is unresectable and 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) . However, retrospective studies by Cruz et al. (2007) have shown a higher activity of new combination regimens with texanes compared to the standard treatment. Despite the enormous benefits, considerable measures aught to be taken such as follow up on patients to confirm presence of any end organ dysfunction as a result of the toxicity yielding side effects such as myelosuppression, neurotoxicity, pulmonary fibrosis, nephrotoxicity, and nausea. (Juneja and Lacey, 2009).
Role of chemotherapy in management of HNSCC
Types of chemotherapyRole
Single modality Curative intent
Neoadjuvant Given prior to loco-regional treatment (radiation or surgery) to reduce tumour burden.
Adjuvant Used following local treatment (surgical or radiation therapy) to minimise recurrence.
Salvage Used after recurrence of refractory tumour following previous treatment
Concomitant 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 therapy (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, therefore used in cases where surgical resection is suspected to cause huge functional and cosmetic defects especially in oropharyngeal carcinomas(see flow chart) (Nagraj et al. 2010). There’s however limited evidence regarding the survival benefit of the combined treatment modality in 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 patientUnderlying severe psychosocial problemsPresence of rapidly growing tumours with advanced nodal involvementLocation of the primary tumourGoals 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, adapted from (Syrigos et al, 2009).
5.5 Non-invasive Management Procedures:
The delicacy of the involved regions after invasive treatment may subject the patient to physical and psychological complications (Paleri et al 2010). (Table 2.6) shows a multidisciplinary support management team with techniques which could be substituted or supplemented with the aforementioned management procedures in order to minimise the complications and maximise eradication (see Table 2.6) (Evans et al. 2006).
Clinical nurse specialistDietitianDental hygienist / DentistPsychotherapist / physiotherapistPalliative care teamSpeech and language therapist
Pain and management therapist
Table 2.6: showing different supportive team members in managing HNSCC adapted from Evans et al. (2006).
Prognostic measures after treatment are essentially dependent on three factors; Staging, tumour site and modality of treatment (See table 2.5). Nonetheless, a good prospect of long term remission is generally seen in early tumours (T1-T2, N0-N1) ranging between 60 – 90% 5 year survival rates whereas patients at stage 4(T4) with no higher than 30% 5 year survival chance (Obe and Johnston, 2001)
Table 2.7: Showing a 5-year survival rate in different HNSCC adapted from Obe and Johnston (2001).
6.1 Follow up and prevention
Follow after treatment coupled to prognosis is a very essential aspect of patient management as it allows early detection of recurrent and second primary tumours (Joshi et al, 2009). Preventative measures however, are of the upmost importance in improving prognosis and reducing disease occurrence (chen-shuan et al. 2010). According to Silverman, (2001) early detection and patient education as well as the general public of the malignancy, is a crucial step in disease management. However, a questionnaire studies by Joshi et al, (2009) have shown little survival benefits achieved from patient follow ups.
7.0 New Research and Innovation:
A great deal of research has been endowed in developing better treatment procedures. The use of endoscopic laser surgery/ressection for conservatory benefits in areas such as larynx has provided good voice and adequate swallowing presservation. Innovative use of intensity modulation radiotherapy (IMRT) offering 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 doses, 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 also 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). Finally, Incoporation of molecularly targeted agents have increasingly helped in directing appropriate treatment to locally advanced HNSCC therefore enhancing the effect of the treatment on the tumour. These include Epidermal growth factor inhibitors (EGFRI) and monoclonal antibody cetuximab (Mab Cetuximab) (Bernier, 2008)