State of the Art Oncology in EuropeFont: aaa

Oral cavity cancer – 2015


1. General information

1.1 Epidemiology

1.1.1 Incidence

According to the RARECAREnet project, malignant epithelial tumours of oral cavity are rare. There are on average 17,500 cases a year in Europe (EU27) (RARECAREnet). For the period 2000-2007, the European crude incidence rate of malignant epithelial tumours of oral cavity was 3.5 per 100,000 per year. Age-adjusted incidence for oral cavity cancers was higher in men (5.0 per 100,000/year) than in women (1.2 per 100,000/year).
Incidence was highest (6.3 per 100,000) in the oldest age group of patients (65 years old and older); in the age group 25-64 incidence rate was 4.2 per 100,000. Very few cases were observed in children, adolescents and young adults (<25 years of age), whose incidence rate was 0.2 per million per year (RARECAREnet).
There were geographical differences in the occurrence of the disease: incidence rate (per 100,000/year) was lowest in UK and Ireland (3.4) and highest in Central and Southern European Countries (4.2 and 4.7, respectively). The annual age-adjusted incidence rates ranged between 3.4 and 4.7 across European regions (RARECAREnet).
According to GLOBOCAN, which estimates the worldwide incidence, cancer of oral cavity, together with lip cancer, is very high in populations from South-Central Asia (10 per 100,000/year) and Melanesia (23/100,000/year) in males (Ferlay 2015). Europe is among the regions with the highest incidence, along with Northern America, Australia and New Zealand.

1.1.2 Survival

Survival from malignant epithelial tumour of oral cavity diagnosed in Europe during 2000 and 2007 was 71% at one year, 48% at three years, and 41% at five years. There has been a moderate improvement in European survival figures since the end of 1990s, especially for 3-year survival which increased from 45% to 52%.
One- and 5-year survival improved from 68% to 72% and 37% to 43%, respectively (RARECAREnet). Five-year survival was better in women (51%) than in men (38%). Patients older than 65 years had 5-year survival of 34%, compared to 44% of the youngest age group (25-64 years). In Europe (EU27), about 96,200 people are living with a diagnosis of epithelial tumour of oral cavity (Gatta 2011).

1.2 Aetiology and risk factors

1.2.1 Tobacco

Tobacco use is the most well recognised independent risk factor in the development of oral cancer. Consumption is most commonly through cigarette smoking, although smokeless tobacco products (often chewed or sniffed) also present a risk to users. Chronic exposure to the multitude of carcinogens present in tobacco products leads to genomic mutations in oral cavity mucosa. This is why tobacco use not only increases the risk of primary oral squamous cell carcinoma (OSCC), but also the development of premalignant lesions such as oral leukoplakia, with or without dysplasia. Indeed, this phenomenon of “field cancerisation” was first described by Slaughter et al over six decades ago (Slaughter 1953). Malignant transformation in oral leukoplakia without dysplasia is thought to occur in approximately 2% of lesions, but is considerably higher (around 14%) if there is dysplastic change present (Mehanna 2009; Amagasa 2006).
A dose-dependent effect is seen with tobacco consumption and oral premalignant lesions and cancer development. This dose effect can be increased by both the duration of exposure and quantity of tobacco consumption, and are both directly proportional to the risk of oral cancer development (Warnakulasuriya 2005). Smokers have a 7-10 fold increased risk of oral cancer compared to never smokers. The anatomical site for development of oral mucosal pathology varies according to the type of tobacco use. Chewing, smoking and reverse smoking (where the lit end of the cigarette is placed inside the oral cavity) increase the risk of lesions in the buccal mucosa, floor of mouth and hard palate respectively (Napier 2008).

1.2.2 Alcohol

Alcohol is an independent risk factor for oral cancer. Data for this association is often unclear from the literature because there has been no control for the confounding effects of tobacco use and poor diet. A recent meta-analysis demonstrated a clear increased risk for oral cancer development with alcohol consumption. A strong dose-effect was present with relative risk increasing from 1.13 (95% CI 1.00-1.26) for light intake (≤12.5 g/day), 1.83 (95% CI 1.62-2.07) for moderate intake (≤ 50 g/day) and 5.13 (95% CI 4.31−6.10) for heavy intake (>50 g/day). This 5-fold increased risk of oral cancer with heavy alcohol use was the most significant risk seen across the multiple anatomical sites studied (Bagnardi 2014). Certain forms of alcohol, in particular spirits and fortified wine, seem to have an increased ability to induce mucosal instability (Jaber 1999).
Combined exposure to both tobacco and alcohol increases the risk of oral cancer in a multiplicative rather than simply additive way. A case-controlled study of 1,114 patients and 1,268 population-based controls gave odds ratio (OR) for oropharyngeal cancer of 38 and >100 for males and females, respectively, that were both heavy smokers and heavy drinkers. This effect was preserved even with oral and pharyngeal tumours analysed separately (Blot 1988). This effect is thought to result from an increased permeability of oral mucosa after contact with alcohol, leading to a greater penetration of tobacco carcinogens (Squier 1991).
There are several mechanisms through which alcohol induces cancer. Ethanol is not directly carcinogenic but its metabolite, acetaldehyde, is. This metabolism of ethanol begins in the saliva of the oral cavity. Ethanol also promotes production of highly reactive oxygen spe¬cies, which are mutagenic to DNA. Furthermore, it can alter DNA methylation and has hormonal effects, including increasing oestradiol levels. It may also exacerbate already ex¬isting cancers through immunosuppression and/or angiogene¬sis, and may also decrease the effect of chemotherapeutics (Seitz 2007).
Both the World Cancer Research Fund (WCRF)/American Institute of Cancer Research (AICR) and the International Agency for Research of Cancer (IARC) Reports judge the evidence sufficient to conclude that consumption of alcoholic beverages is causally related to the development of cancer in the oral cavity, together with larynx and pharynx. The risk increases dose-dependently, with no lower threshold identified (AICR 2007; IARC 2010).

1.2.3 Viral

Strong evidence has emerged for the aetiological role of the Human papillomavirus (HPV) in the development of oropharyngeal cancer (Mehanna 2010; Ndiaye 2014). Infection with high-risk serotypes, predominantly type 16, is thought to account for the dramatic increase in incidence and changing demographics of patients with oropharyngeal cancer. A similar role in oral cancer has not been conclusively established. Reasons for this ambiguity include studies inadequately separating out oral cavity and oropharyngeal cancers (thereby potentially increasing the apparent HPV positivity rates in the cohort), the inability to determine if the detection of HPV has come from the tumour cells or surrounding normal mucosa, and the fact that presence of HPV does not prove causality as the carcinogenic driving force (Mirghani 2014). Indeed, in a recent review, it was concluded that although detection of HPV-DNA in oral cancer specimens is not uncommon, E6/E7 mRNA expression is, making the likelihood of HPV being the driving force behind the tumourigenic process unlikely (Mirghani 2014). Similar conclusions are reached by studies examining the role of HPV as a prognostic factor in the development of oral cancer from premalignant lesions (Yang 2009; Nielsen 1996; Montebugnoli 2010; Nankivell 2014).

1.2.4 Trauma

The effect of chronic trauma on oral mucosa has been postulated as a cause for the development of oral cancer. A 10-year retrospective case series analysed 881 patients referred to a single tertiary centre. Tumours in patients who smoked were typically located on the tongue, floor of mouth and retromolar trigone. However, twice as many oral cancers were found to develop in areas of the oral cavity subjected to chronic dental trauma in non-smokers without any other risk factors compared to smokers (66% vs. 33%; p <0.001) (Perry 2015). Other smaller studies have similarly suggested a link between trauma, for example through ill-fitting dentures, and oral cancer. The results of these studies should be interpreted with caution, however, as the effect of confounding factors such as smoking and HPV status has not always been adequately controlled for (Thumfart 1978; Velly 1998; Lockhart 1998). Therefore, the data is currently inadequate to confirm trauma as a definite cause for oral cancer development.

1.2.5 Candida infection

Candida spp are fungi commonly found in normal oral cavities as a commensal, but can on occasion become pathogenic and invade the mucosa to cause an inflammatory response. This occurs particularly in immunocompromised patients. Epithelial hyperplasia is often noted, and even cellular atypia, although in these cases it can be challenging to know whether this atypia represents true epithelial dysplasia, or an inflammatory reaction to the fungal infection. A correlation between the amount of yeast and the presence and degree of dysplasia has been demonstrated (McCullough 2002). One particular type of oral mucosal candidal lesion is chronic hyperplastic candidiasis (CHC). Studies suggest an increased risk of oral cancer in patients with this condition (Bastiaan 1982). A recent national cohort study described a significantly raised standardised incidence ratio for patients developing cancer of the mouth (32.0; 95%CI, 21.1-46.6) and tongue (17.1; 95%CI 6.9-35.3) in the first year after detection of candidiasis during admission to hospital (Nørgaard 2013). This risk remained with longer follow-up of up to 10 years. It is not clear if this increased risk is a direct result of the candidal infection (through various postulated mechanisms including the production of nitrosamines), or whether infection with an opportunistic fungal infection is a marker for immunocompromise (Hooper 2009). It may also represent the fact that the risk factors for cancer and candidal infection are similar.

1.2.6 Genetic

Common genomic alterations seen in oral cancer include mutations to p53, EGFR and p16 genes. The latter is often effected through HPV infection and is covered in another section, whilst the p53 mutational burden is driven largely through the carcinogenic effects of tobacco and alcohol.
The epidermal growth factor (EGF) receptor family has been extensively studied in relation to cancer biology. Strong evidence exists for their role in carcinogenesis in many solid tumours, including those arising in the breast, ovary, colon, and lung (Normanno 2008). It is now widely accepted that overexpression of EGFR occurs in a majority of head and neck cancers; despite this, there is a wide variability of reported rates of EGFR expression in HNC in the literature (36-100%) (Normanno 2008; Grandis 1993). EGF pathway activation may be upregulated in a variety of ways, including increased copy numbers of the genetic locus demonstrated in oral squamous cell carcinoma cell lines (Martin 2008). Expression of EGF receptors and copy number variations are correlated with clinical outcomes in oral cancer. In a study of locally recurrent oral cancers, EGFR positive cases had a 3-year cancer specific survival of 27.2% vs. a 3-year cancer specific survival of 64.3% in those cases negative for EGFR (p =0.001) (Agra 2008).
Different phenotypic mutations of EGFR may also occur. One common mutation, EGFRvIII, has been shown to be present in over 40% of head-and-neck squamous-cell carcinomas (HNSCC). The mutation harbours an in-frame deletion, affecting the extracellular binding domain of the receptor (Sok 2006). This alteration, reducing the normally 170 kilodalton (kDa) receptor, to a smaller 150 kDa receptor protein, not only allows it to achieve ligand-independent activation, but may also account for the resistance to monoclonal antibody therapy in those tumours heavily expressing mutant EGFR (Sok 2006; Hirsch 2003; Moscatello 1995).
Fanconi anaemia is a rare autosomal recessive disorder characterised by bone marrow failure and congential malformations as well as a significantly increased risk of developing certain cancers. A study examining 754 patients from the International Fanconi Anemia Registry, demonstrated that 19 (3%) had head and neck cancer, with 13 of these being oral cavity cancers. This incidence of head and neck cancer is significantly higher than that observed in the general population (standardised incidence ratio: 500; 95%CI 300-781; p <0.001) (Kutler 2003).

1.2.7 Diet

Evidence is emerging for the protective effect of certain diets on the development of oral cancer. A case control study over a study period of 12 years recently demonstrated convincing evidence for the protective effective of a Mediterranean diet. As levels of the Mediterranean Diet Score increased, corresponding levels of oral cancer decreased (ORs for subjects with 6 or more Mediterranean Diet Score components compared with 2 or less being 0.20; 95%CI 0.14-0.28; p <0.0001) (Filomeno 2014). Benefit from this type of diet is thought to come from the high levels of antioxidants and trace elements (Marchioni 2002). Vitamin deficiencies in vitamin A, C, and E have also been linked to higher rates of oral cancer.
The most recent report coordinated by WCRF/AICR (2007) (AICR 2007) concluded that the evidence of a protective effect of fruits and vegetables was “probable” on cancer for mouth, together with pharynx and larynx. The WCRF/AICR current dietary recommendations for cancer prevention include «eating at least five portions/servings of a variety of non-starchy vegetables and or fruits every day».

2. Pathology and biology

2.1 Hstological types

2.1.1 Squamous cell carcinoma (ICD-O code: 8070/3)

More than 90% of cancers of the oral cavity are squamous cell carcinomas (SCC). When small, these tumours may have little in the way of symptoms. A thorough history and examination is therefore necessary along with a high index of suspicion especially in patients with significant exposure to risk factors such as tobacco and alcohol. The oral cavity may exhibit patches of white or red mucosa (leukoplakia or erythroplakia, respectively, or a combination of the two) representing premalignant changes.
The prerequisite histological features of SCC are squamous differentiation, often seen as keratinisation with variable “pearl” formation, and invasive growth (Barnes 2005). Invasion occurs when there is breach of tumour through the basement membrane and into the underlying tissues. Other histological features include the invasion of surrounding blood and lymphatic vessels as well as spread along neural tissue. SCC can be further graded depending on the degree of cellular differentiation and abnormal mitotic activity into well, moderately and poorly differentiated tumours. Those exhibiting poor differentiation have a more aggressive phenotype. However, the majority of tumours show moderate differentiation, and therefore its use as a prognostic feature is limited. Of more importance is the nature of the invasive front. This can be described as either expansive/cohesive or infiltrative/non-cohesive, with the latter type having a poorer outcome (Barnes 2005; Helliwell 1998; Bryne 1995).

2.1.2 Verrucous carcinoma (ICD-O code: 8051/3)

This is a specific type of well-differentiated SCC, first described in 1948 (Ackerman 1948). Verrucous carcinoma is thought to be associated with HPV infection and smokeless tobacco use. It accounts for between 2-12% of oral cancers (Rekha 2010). Although it can occur in other sites of the head and neck, oral cavity cases represent around three quarters of the total number (Barnes 2005). It tends to have a more indolent growth compared to other SCCs and may require multiple biopsies before the diagnosis is confirmed. Local invasion does occur, but locoregional spread through metastasis is rare. There are reports of squamous cell carcinoma arising from within verrucous carcinoma (Terada 2012).

2.1.3 Adenosquamous carcinoma (ICD-O code: 8560/3)

This is a rare cancer of the oral cavity. It is a tumour showing areas of adenocarcinoma arising within an SCC. This most often occurs in larger tumours (Barnes 2005).

2.1.4 Spindle cell carcinoma (ICD-O code: 8074/3)

Although much more commonly seen arising in the larynx, this rare biphasic (comprising both epithelial and mesenchymal components) tumour is reported to occur within the oral cavity. It is a poorly differentiated tumour with a more aggressive behaviour Oktay 2011).

2.1.5 Preneoplastic lesions

Preneoplastic lesions have traditionally been divided into precancerous lesions, for example leukoplakia (white patch), erythroplakia (red patch), and precancerous conditions, such as submucous fibrosis and lichen planus (although the malignant potential of some forms of lichen planus is still debated) (van der Waal 2010; ; Warnakulasuriya 2007). The distinction implying that in the former a cancer develops from within the lesion itself, whereas in the latter a cancer may develop in an adjacent or even more distant site within the upper aerodigestive tract because of the overall increased risk the condition confers on the patient. More recently, it has been shown that in patients with a precancerous lesion clinically normal mucosa from the contralateral side of the oral cavity may also show signs of dysplasia or molecular alterations, implying progression along a malignant pathway (Thomson 2002). For this reason, the suggestion of a recent working group was to refer to any clinical presentations that carry a risk of cancer under the term “oral potentially malignant disorders” (Warnakulasuriya 2007).
The presence of oral epithelial dysplasia (OED) significantly increases the malignant potential of leukoplakia/erythroplakia. The rate of OED in leukoplakia ranges from 5-25%, although rates of up to 46% have been reported in South-East Asian populations (Bouquot 1994; Bouquot 1986; Lee 2006). OED is most commonly graded histologically using the WHO system into mild, moderate, severe or carcinoma in situ (Barnes 2005). Malignant transformation rates increase with severity of WHO grade (Mehanna 2009). A binary OED grading system has more recently demonstrated superior prognostic ability (Kujan 2006; Nankivell 2013b). Despite having a much lower reported incidence and prevalence, erythroplakia is just as important clinically, as it displays higher rates of dysplasia, and consequently higher risk of malignant transformation (van der Waal 2010). Quoted malignant transformation rates vary but have been reported to be as high as 50% in some series (Amagasa 1985).

Table 1. WHO classification of tumours of the oral cavity.
Type of tumour Code*
Malignant epithelial tumours
Squamous cell carcinoma 8070/3
Verrucous carcinoma 8051/3
Basaloid squamous cell carcinoma 8083/3
Papillary squamous cell carcinoma 8052/3
Spindle cell carcinoma 8074/3
Acantholytic squamous cell carcinoma 8075/3
Adenosquamous carcinoma 8560/3
Carcinoma cuniculatum 8051/3
Lymphoepithelial carcinoma 8082/3
Salivary gland tumours
Acinic cell carcinoma 8550/3
Mucoepidermoid carcinoma 8430/3
Adenoid cystic carcinoma 8200/3
Polymorphous low-grade adenocarcinoma 8525/3
Basal cell adenocarcinoma 8147/3
Epithelial-myoepithelial carcinoma 8562/3
Clear cell carcinoma, not otherwise specified 8310/3
Cystadenocarcinoma 8450/3
Mucinous adenocarcinoma 8480/3
Oncocytic carcinoma 8290/3
Salivary duct carcinoma 8500/3
Myoepithelial carcinoma 8982/3
Carcinoma ex pleomorphic adenoma 8941/3
Soft tissue tumours
Kaposi sarcoma 9140/3
Haematolymphoid tumours
Diffuse large B-cell lymphoma (DLBCL) 9680/3
Mantle cell lymphoma 9673/3
Follicular lymphoma 9690/3
Extranodal marginal zone B-cell lymphoma of MALT type 9699/3
Burkitt lymphoma 9687/3
T-cell lymphoma (including anaplastic large cell lymphoma) 9714/3
Extramedullary plasmacytoma 9734/3
Langerhans cell histiocytosis 9751/1
Extramedullary myeloid sarcoma 9930/3
Follicular dendritic cell sarcoma/tumour 9758/3
Mucosal malignant melanoma 8720/3
Secondary tumours
*Morphology code of the International Classification of Diseases for Oncology (ICD-O) (Fritz 2000) and the Systematised Nomenclature of Medicine.

Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour (Barnes 2005).

2.2 Molecular abnormalities

There continues to be a rapid expansion in knowledge about the genomic basis for oral cancer development and behaviour. It is clear that disruption of the normal balance between tumour suppressor genes and oncogenes leads to a loss of cellular physiological and reproductive control. Early seminal studies identified loss of heterozygosity at particular chromosomal segments 3p, 5q, 7q, 8p, 9p, 11q, and 18q in addition to gains of regions of chromosomes 3q, 5p, 7p, 8q, and 11q to be important in the development of oral cancer (Califano 1996; Martin 2008). These changes are also identified in dysplastic lesions.
The correlation between over expression of EGFR and prognosis in oral cancer has been covered above. Other commonly mutated genes in head and neck cancer have been investigated using whole exome sequencing techniques. TP53, NOTCH1, CDKN2A, and PI3KCA were the most frequently mutated genes (Agrawal 2011; Stransky 2011).
Prognostic biomarkers in oral dysplasia have also been extensively investigated in an attempt to better identify the 15-20% of premalignant lesions that are at highest risk of malignant transformation. In addition to LOH at 3p, 9p and 11q, Survivin, MMP mRNA9, Aneuploidy, recurrence after surgery, ABCG2, DSPP, BMI-1, ΔNp63, BSP, EGFR copy number, p16 methylation, COX-2, CD9, and CD151 have been identified as potential biomarkers (Hogmo 1998; Jordan 2004; Lo Muzio 2003; Saintigny 2009; Taoudi Benchekroun 2010; Liu 2013; Ogbureke 2010; Yang 2010; Torres-Rendon 2009; Smith 2009; Nankivell 2013a).

3. Diagnosis

3.1 Presentation

Oral lesions may be incidentally noticed by the patients themselves, or may become apparent on visual inspection of the oral cavity by general dental or medical practitioners. Initial presentation may be as white, red or speckled areas of mucosa or non-healing ulceration. Presentation will also depend on the anatomical site of the tumour. For example, tumours occurring around dental sockets may present with the loosening of a tooth. As the tumour advances in stage, patients may experience referred otalgia (through cross innervation), bleeding, trismus or fetor. Due to the rich lymphatic supply, around 40% of patients will have cervical lymphadenopathy secondary to metastatic disease at presentation (Lea 2009; Fan 2011). However, the actual number of patients with locoregional spread at presentation is likely to be even higher with occult nodal metastasis occurring in >25% of patients that have clinically negative necks (Chaturvedi 2015).

3.2 History and examination

A thorough history and examination is crucial in the diagnostic evaluation of patients presenting with oral cancer. The focus of the history should be to elucidate and record symptoms associated with the primary cancer, to record any functional loss at this stage, to explore whether there are symptoms suggestive of locoregional or distant disease spread, and taking a complete medical history to assess the suitability to undergo what is often physiologically demanding treatment. Of particular importance is ascertaining the social history of the patient and their support network available through family and friends. This can have a large influence on the ease and success of recovery from treatment.
Examination should aim to gain a clear understanding of the location and extent of the primary tumour, the presence of locoregional disease, and the presence of a synchronous primary tumour. The risk of patients with head and neck cancer presenting with a synchronous primary tumour is around 10%. One study detected 12.1% of patients with oral cancer presenting with synchronous tumours on panendoscopy (Rodriguez-Bruno 2011).

3.3 Investigations

There are four important components to investigating a patient with suspected oral cancer. The first is to achieve a pathological confirmation of the diagnosis. This will involve a biopsy of the primary site – typically performed under local anaesthetic. The biopsy sample is most helpfully taken from the edge of the tumour mass or ulcer, so as to include the margin of the tumour and some surrounding normal mucosa, and should be deep enough to allow assessment of tumour thickness if possible. The anatomical location of the tumour or patient factors, such as severe trismus, may make biopsy under local anaesthesia impractical and, therefore, assessment and biopsy under general anaesthetic will be necessary. Because ulceration, on histological examination, may reveal atypical mucosa in keeping with changes seen in dysplasia (but non-neoplastic), a repeat biopsy may be required. Pathological confirmation of locoregional neck disease can be performed by fine needle aspiration cytology (FNAc). This may be performed with or without ultrasound guidance. A recent systematic review of 3459 FNAc from head and neck cancer cases reported in a total of 30 studies demonstrated sensitivity, specificity, accuracy, positive predictive value, and negative predictive values of 89.6%, 96.5%, 93.1%, 96.2%, and 90.3%, respectively (Tandon 2008).
Once a diagnosis of oral cancer has been made, the second component of investigation is to ascertain the extent of the primary tumour and the involvement of surrounding structures. Whilst this can be assessed by palpation, clinical examination has poor sensitivity. Therefore, this is best achieved through the use of cross sectional imaging, most commonly with high resolution computed tomography (CT) scanning. This modality has the advantage of giving an assessment of cortical bone involvement. However, with oral cavity tumours in particular, dental amalgam artefact can make assessment challenging. Magnetic resonance imaging (MRI) with T1 and short inversion time inversion recovery (STIR) fat suppression sequences may be preferable, as it is more sensitive, and better defines perineural spread and mandibular bone marrow involvement (Bolzoni 2004, Brown 1994).
The third aim of the investigations is to stage the disease, with respect to locoregional and distant disease. Again CT or MRI can be used to stage the neck, and CT is performed to assess for lung metastasis. Although reliable, a large institutional case series reported 2% of normal chest CT scans for head and neck cancer staging later developed a lung malignancy (Beech 2010). Some studies have suggested an additional role of 18-fluorodeoxyglucose positron emission tomography integrated with computed tomography (18-FDG-PETCT) in detecting distant metastases. A study from the Netherlands identified19 patients (21%) with distant metastases, with FDG-PET having a higher sensitivity (53% vs. 37%) and positive predictive value (80% vs. 75%) than CT. Combining CT and FDG-PET had the highest sensitivity (63%) (Senft 2008).
Finally, the last aim of investigations is to plan for the coming treatment. An orthopantomogram is often done partly to help assess mandibular invasion, but importantly also to help assess the state of the dentition (in case extraction is required ahead of post-operative radiotherapy) and to assess mandibular height for planning a mandibulotomy or rim resection. Depending on the planned reconstruction, a variety of additional tests may be required. If a radial forearm flap is planned, then assessment of patency of the ulnar artery can be assessed using the Allen’s test. Examination of the abdomen or hip may be required for iliac crest flap or anterolateral thigh flap respectively. An MR angiography or an angiogram would be required to assess the vascular anatomy for a fibular free flap.

4 Staging

4.1 General principles

In keeping with other tumour sites, oral cavity cancers are almost universally staged using the Tumour, Node, Metastasis (TNM) system. The system assesses the size/extent of the primary tumour, the degree of disease burden in the locoregional lymph nodes, and the presence or absence of distant metastases. This has been accepted by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) (Edge 2010).

4.2 Staging of oral cancer

4.2.1 TNM system
Table 2. Classification of tumours of the oral cavity by TNM system.
Primary tumour (T)
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour ≤2 cm in greatest dimension
T2 Tumour >2 cm but not more than 4cm in greatest dimension
T3 Tumour >4 cm in greatest dimension
T4a Moderately advanced, local disease
Lip: Tumour invades through cortical bone, inferior alveolar nerve, floor of mouth, skin of face
Oral cavity: Tumour invades adjacent structures (cortical bone into deep extrinsic muscle of the tongue, maxillary sinus, or skin of face)
T4b Very advanced, local disease: tumour invades masticator space, pterygoid plates, or skull base and/or encases internal carotid artery.
Regional lymph nodes (N)
Nx Regional nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph node ≤ 3cm in greatest dimension
N2a Metastasis in a single ipsilateral lymph node >3cm but ≤ 6cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none >6cm in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension
N3 Metastasis in a lymph node >6 cm in greatest dimension
Distant metastasis (M)
Mx Metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
4.2.2 Histological grade

Tumours may also be graded according to their degree of differentiation.

Table 3. Classification of tumours of the oral cavity by histological grade.
Grade Characteristics
Gx Grade cannot be assessed
G1 Well differentiated
G2 Moderately differentiated
G3 Poorly differentiated
G4 Undifferentiated
4.2.3 Anatomic stage/prognostic groups
Table 4. Classification of tumours of the oral cavity by anatomic stage.
Stage T N M
0 Tis N0 M0
I T1 N0 M0
II T2 N0 M0
III T3 N0 M0
T1 N1 M0
T2 N1 M0
T3 N1 M0
IVa T4a N0 M0
T4a N1 M0
T1 N2 M0
T2 N2 M0
T3 N2 M0
T4a N2 M0
IVb Any T N3 M0
T4b Any N M0
IVc Any T Any N M1

5. Prognosis

5.1 Overall survival

Data demonstrate an increase in disease specific survival (DSS) for oral cancer over the last 30 years. A UK study saw an increase in DSS of 18% between two periods of study (1992-1995 and 2000-2002) from 63% to 81% (Rogers 2009). Similar improvements in DSS have been shown from the US SEER database. This is predominantly seen in the subset of patients with tumours arising from the tongue, with survival from floor of mouth, gum and lip cancers remaining relatively constant (Mehta 2010).

5.2 Prognostic factors

5.2.1 Disease stage

Increasing disease stage results in reduced overall survival. The UK Data Audit for Head and Neck Oncology (DAHNO) figures demonstrate survival of over 90% at one year for early stage disease. Yet for late stage disease only two-thirds survive to one year. This effect is even more pronounced by three years, with over 80% of patients diagnosed with early stage still alive compared to less than half of those initially diagnosed at a later stage.

5.2.2 Tumour thickness

Tumour thickness, or depth of invasion, is directly correlated with the presence of locoregional metastases to the neck. The incidence of occult metastases in T1/T2 oral cavity tumours is reported between 27-40%. The decision to treat a clinically negative neck is currently made when the risk of occult disease reaches around 15%. A meta-analysis of 16 studies including1136 patients examined the effect of tumour thickness on the rates of occult nodal disease in the neck. With a tumour thickness of <4 mm, only 4.5% of patients had nodal metastases, with this rising to 16.6% with a tumour thickness of 5mm or more. This was a statistically significant difference, and this evidence now guides therapeutic decision making when planning elective neck dissections for oral cancer patients (Huang 2009).

5.2.3 Lymph node metastasis

The presence of cervical lymph node metastases is the single most important prognostic factor in oral cavity cancer. Extension of tumour outside the confines of the lymph node-termed extra-capsular spread (ECS) also significantly impacts overall survival. The 5-year survival in a cohort of 200 oral cancer patients was 81% for patients without metastasis and 64% for patients with intranodal metastases. In those patients with extra-capsular spread survival dropped dramatically to 21% (Woolgar 1999). The same authors present data suggesting even microscopic extra-capsular disease confers the same level of impact on survival, with 3-year survival similar for patients with macroscopic (33%) and microscopic extracapsular spread (36%), compared with 72% for patients with metastasis confined within the node (Woolgar 2003). However in a later study the same authors reported that 5-year overall survival of patients with macroscopic ECS was significantly worse than those with microscopic ECS (19% vs. 31%) (Shaw 2010).

5.2.4 Margins

Involved margins after surgical resection of the primary tumour conveys a significantly poorer prognosis to the patient. Margins as defined by the UK Royal College of Pathologists are divided into a histological distance from invasive carcinoma to surgical margins of more than 5 mm as clear, 1-5 as close and less than 1 mm as involved (Helliwell 1998). The proportion of patients with involved margins is around 20%, although this value varies depending on where in the oral cavity the tumour arises. A study of 301 consecutive radical oral cancer resections demonstrated an overall positive margin rate of 23%, with the tumours of the retromolar trigone having the highest positive margin rates (38%), followed by buccal mucosa (33%) alveolus (24%), floor of mouth (18.5%), and anterior tongue (10.5%) (Woolgar 2005). In a series of 522 cases, a positive margin doubled the risk of local recurrence. In addition, the presence of dysplasia in the margins also significantly increases the risk of local recurrence (18.9% vs. no dysplasia 6.7%; p <0.01) (Weijers 2002).
A general consensus exists to aim for resection of 1cm of normal tissue surrounding the tumour periphery to gain adequate histological margins. This allows for inevitable tissue shrinkage during the fixation steps prior to histological assessment, and still have a >5mm clear margin. Yuen et al. (Yuen 1998) examined 50 glossectomy specimens and demonstrated 96% of these had local spread to within 1.2 cm, with a maximum spread of 1.8 cm. This distance did not appear to be correlated with size, depth or volume of tumour. The recommendations from this study were for a minimum 1.5 cm margin (and maximum 2 cm).
The use of frozen section intraoperatively to aid adequate tumour clearance remains controversial. Using a micrographic approach to histological assessment remains impractical because of the size of the resection area. However, the recently concluded multicentre, randomised controlled Lugol’s iodine in head and neck cancer surgery (LIHNCS) trial, is assessing the effectiveness of Lugol’s iodine in assisting the excision of moderate dysplasia, severe dysplasia, and carcinoma in situ at mucosal resection margins of oral and oropharyngeal squamous cell carcinoma in over 400 patients (McCaul 2013). While the full study results are not yet available, the pilot phase reported on a decreased rate of dysplasia in the margins of oral cancer resections from 32% to 4% (p =0.001).

5.2.5 Molecular markers

Much research has been focused on identifying prognostic molecular markers in oral cancer. Unfortunately, the translation of these into clinically useful results has thus far been almost universally poor. TP53

The p53 gene is one of the most studied in oral cancer. Overexpression is associated with a poor prognosis (Oliveira 2007a; Oliveira 2007b). In another study, overexpression of p53 alone was not identified as an adverse prognostic feature. Yet coexpression, in conjunction with EGFR and cyclin D1, was significantly associated with shortened survival (p =0.02), and was an independent poor prognostic factor in a multivariate analysis (p =0.0002) (Shiraki 2005). In a prospective cohort study of 76 patients with histologically tumour-free margins, the presence of TP53-mutated DNA was determined in the surgical margins and correlated with clinical outcome. The absence of TP53-mutated DNA was significantly associated with remaining free of local and locoregional recurrence (p =0.027 and p = 0.028, respectively). The presence of TP53-mutated DNA in the surgical margins was an independent prognosticator for locoregional recurrence (relative risk: 7.1; p =0.021) (van Houten 2004). Epidermal Growth Factor Receptor

The role of the EGF receptor family has been covered in section 1.3. It is now widely accepted that overexpression of EGFR occurs in around 80%-90% of head and neck cancers (Grandis 1993). Expression of EGF receptors and copy number variations are correlated with clinical outcomes in head and neck cancer. In 82 cases of advanced head and neck cancer, increased EGFR expression remained an independent predictor of survival on multivariate analysis (relative risk 2.65; 95%CI 1.28-5.50), along with tumour stage, but not p53 expression (Etienne 1999). No correlation was evident between EGFR expression and tumour or nodal stage, or EGFR expression and distant metastases in 155 randomised patients selected from a phase III trial (Ang 2002). However, overall survival (p =0.0006), disease-free survival (p =0.0016) and locoregional recurrence (p =0.0031) were significantly associated with increased EGFR expression. Similar findings are seen in locally recurrent oral cancers, with EGFR positive cases having a 3-year cancer specific survival of 27.2% vs. a 3-year cancer specific survival of 64.3% in those cases negative for EGFR (p =0.001) (Agra 2008).
Her2 (erbB2) has mostly been studied in breast cancer, yet it is also overexpressed in head and neck cancer. In cancers of the oral cavity, its overexpression is associated with more advanced nodal stage and metastases and, correspondingly, overall survival is also reduced in these patients. Similar findings are reported for Her 3(erbB3) and HER 4 (erbB4), although the evidence is not as strong for the role the latter receptor plays in tumourigenesis. A longitudinal study of 47 oral squamous cell cancers not only identified the expression of EGFR, Her2 and Her3/ErbB3 as being linked to regional or distant metastases and decreased overall survival, but also that the combination of all three receptors predicted a worse overall survival than either receptor alone (Xia 1999). Cyclooxygenase 2 (COX-2)

COX-2 overexpression results in increased production of prostaglandins in tissues. PGE2 is the most abundant prostanoid detected in epithelial malignancies and has four receptor subtypes, EP1-4 (Dannenberg 2008). Overexpression of COX-2 is associated with poorer outcomes in patients with head and neck cancer. In 72 oral squamous cell cancers, overexpression was correlated with regional lymph node spread (p =0.011), local recurrence (p =0.025), disease-free and overall survival (p =0.039, p =0.043) (Itoh 2003). This prognostic significance is seen with overexpression in oral epithelial dysplasia leading to significantly higher risk of malignant transformation. In a study of 149 patients with oral epithelial dysplasia (OED), COX2 demonstrated an almost linear effect, with increasing expression correlated with an increasing risk of cancer (Nankivell 2013a). COX2 remained independently prognostic when accounting for the effect of other variables on multivariate analysis (HR 1.12; p <0.007). Other markers

Cyclin D1 amplification is commonly found in head and neck cancers. By itself it has not been shown to be prognostic, however it has been shown to be when considered in combination with other markers (EGFR and p53 as above) and with decreased expression of p16 (Jayasurya 2005). The family of matrix metalloproteinases (MMP) have been widely studied in oral cancer, although conflicting results are found. Survivin is generally undetectable in normal mucosa, but it is overexpressed in most head and neck cancers (Lippert 2007). Survivin expression is a potential biomarker of aggressive and invasive oral cancer (Lo Muzio 2005). This is not an exhaustive list, but many other biomarkers have been summarised in review papers (Oliveira 2011).

6. Treatment

6.1 General principles

The principal aim of treatment is complete resection to prevent recurrence of tumour at the primary site or in the locoregional lymphatic system. There remain no randomised controlled trials comparing different treatment modalities for oral cancer. Surgery remains the most common primary treatment modality, with radiotherapy (with or without adjuvant chemotherapy) often being reserved for post-operative adjuvant treatment in cases at high risk of locoregional recurrence (Type C basis). Whatever treatment strategy is employed, an attempt should be made to minimise functional morbidity – that is swallowing, speaking, breathing and disfigurement.
All patients should undergo pre-treatment dental assessment (Type C basis) in order to minimize the adverse effects of radiation induced xerostomia: dental caries, infection, and demineralization of the teeth. (Epstein 2012). Dental extractions, if required, can be performed at the same time as surgical treatment, or two weeks prior to the start of radiotherapy at the latest. This is necessary to prevent complications arising as a result of dental extractions in patients that have already undergone radiotherapy (leading to osteoradionecrosis). Further preventive measures include: oral hygiene, education, use of topical fluoride treatment during and after radiotherapy, monitoring and treating oral candidiasis. Post-treatment dental rehabilitation can also be planned before surgery, which may include the use of dental implants in selected cases. Irradiated patients need regular dental check-ups at least twice a year.
Part of the pre-treatment assessment should also include the involvement of dieticians to screen for correctable nutritional deficiencies. Patients who at the time of diagnosis have, or it is suspected will develop swallowing and speech dysfunctions during therapy, should be referred to a speech and swallowing therapists (Type C basis).

6.2 Early disease

Early disease, that is T1 or T2 tumours without clinical signs of regional node involvement, may be treated by surgical excision or radiotherapy, although the former is more common (Type C basis). The decision on which modality to use will depend on tumour factors, patient co-morbidity and pre-treatment function, and also patient wishes. In general, surgical approaches are favoured over radiotherapy because of the risk of osteoradionecrosis after radiotherapy to the oral cavity (incidence reported to vary widely between 0.4 and 56%) (Jereczek-Fossa 2002). However, there is no evidence of superiority for any particular surgical ablative modality over another, including scalpel, diathermy, LASER or coblation. The aim of surgery is to remove the tumour with an adequate margin (at least 1cm gross margin as has previously been discussed), while minimising morbidity. The majority of these tumours will be removed through the oral aperture, without the requirement for access procedures. However, this may not be possible in cases of posteriorly based tumours. For smaller tumours, wide local excision will give adequate margins with the resulting defect being either closed primarily or left to heal by secondary intention. If a hemiglossectomy is necessary, this may require free flap reconstruction – the options for which are discussed in a later section.
Post-operative radiotherapy or chemoradiotherapy is used only in cases with a high risk of local recurrence based on the histopathology report, and is discussed in detail below (Type 1 evidence).

6.3 Advanced disease

Combined treatment with surgical resection, neck dissection, and post-operative radiotherapy with or without chemotherapy is the standard of care for advanced oral cancer ST III – ST IV (Type C basis). Again, posteriorly placed tumours may require access procedures. This can be achieved through a paramedian or median mandibulotomy with lip split incision, or through a lingual release procedure. The latter provides excellent access with less external cosmetic deficit, but poorer post-operative functional outcomes (Devine 2001).
Adequate resection will likely leave large defects. There are a wide variety of reconstructive techniques described, ranging from primary closure and local flaps, to regional pedicle or free tissue transfer flaps. The reconstruction needs to be carefully tailored to each patient, depending on patient preference, anatomical location, and surgeon preference. With larger tumours, involving greater than 50% of the tongue or involvement of both the tongue and floor of mouth, or in cases of previously irradiated tissues attempts at direct closure without reconstruction using free tissue transfer may lead to immobility of the tongue and consequent problems with eating and speech.
It should be noted that in most studies, survival is correlated with bony invasion and margin status of soft tissue margins, but it is not correlated with extent of bony invasion or type of mandibular resection (Patel 2008; O’Brien 2003). Segmental resection of the mandible is required if there is invasion through the cortical bony cortex of the mandible into the medullary cortex. Reconstruction of the bony defect is usually undertaken using vascularised bony free tissue transfer (Hidalgo 1989). However, in some patients who are not suitable for vascularised reconstruction or where that is not possible, plating of the defect, sometimes covered by pedicled flaps, can be used. In patients with small T1 /T2 tumours with early invasion of the cortical bone, a rim resection is sufficient, and does not significantly influence local control rate or survival (O’Brien 2003). In a dentate mandible, where there is tumour abutting the mandible with no frank invasion, periosteal stripping – the so called “peek and shriek” technique – has been found to be more sensitive than radiographic assessment (Brown 1994; Werning 2001). This involves lifting the periosteum to examine whether invasion of the cortex is present, and only proceeding to marginal mandibulectomy if there are concerns regarding cortical invasion. Alternatively, and currently this is the recommended method (O’Brien 2003), where there is close abutment of the tumour to the mandible, a rim resection can be undertaken to provide adequate margin. If during the rim resection there is evidence of medullary cortical invasion, then the rim resection is converted to a segmental resection (Pandey 2009).
Many examples of free tissue reconstruction have been developed and described. Failure rates are low, often quoted at around 2-3% (Ren 2014). Those used most in the oral cavity include the radial forearm flap (Yang 1997; Mazeron 1990), the anterolateral thigh flap (Song 1984; Patil 2014) and the free fibula flap (Hidalgo 1989; Ma 2013).

6.3.1 Radial forearm free flap

First described in 1981, this flap may be raised as a fasciocutaneous flap, although a small amount of radial bone can be harvested along with it (Yang 1997). The radial artery provides the arterial supply with paired vena comitantes and/or cephalic vein providing the venous outflow. Particular advantages of the flap include the long pedicle, allowing greater access into the oral cavity from distant neck vessels, and also its low bulk, which otherwise may limit function. There is reasonable donor site morbidity with the need for a skin graft to cover, and the potential for functional loss in the hand.

6.3.2 Anterolateral thigh flap

First described by Song in1984, this flap can be raised as muscle only, or muscle and skin/subcutaneous fat (Song 1984). The arterial supply is from third perforator of profunda femoris artery with venous output from associated vena comitantes. The flap is robust, and can provide a large paddle of hairless skin for relining the oral cavity and the donor site morbidity is low. The pedicle is shorter than with a radial forearm flap and this may limit its use depending on the arrangement of available neck vessels.

6.3.3 Fibular flap

This flap, described by Hidalgo in1989, is particularly suitable where bony reconstruction is required (Hidalgo 1989). Bone reconstruction is required with segmental mandibular resection, or where less than 2cm of mandibular rim remains after a rim resection. A long length of bone (around 25 cm) can be harvested and moulded for use. Dental rehabilitation with osseointegrated implants is also possible after this reconstruction. Arterial supply is via the peroneal artery with vena comitantes providing the venous outflow. Peripheral vascular disease (not uncommon in oral cancer patients because of the shared risk factor exposure through smoking) may preclude the use of a fibular flap. Patients can complain of some ankle stiffness after the procedure. Other sources of bone for reconstruction are the iliac crest and scapula. The latter is particularly useful for complex defects involving both maxilla and mandible.

6.3.4 Other primary treatment options

Patient comorbidities may preclude management with radical surgery, in which case primary treatment with radical radiotherapy would be considered. Typical dosing schedules for primary treatment with locally advanced oral cancer would be 66-74 Gy in a fractionated dosing pattern. Concurrent chemotherapy improves outcome for patients when fit enough to tolerate the additional toxicity. There is no evidence for improved outcomes in those over 70 years of age (Pignon 2000; Lovelace 2014). Patients unfit for cisplatin, may be treated with cetuximab plus radiotherapy. Although oral cavity cancer patients were excluded from the Bonner trial, there is evidence that the addition of an EGFR antagonist (cetuximab) significantly improves locoregional control and progression-free survival compared to radiotherapy alone in oropharynx, hypopharynx and larynx cancer cases (Bonner 2006). Older age however, negatively influences the survival of cetuximab-treated patients (Perry 2013; van der Linden 2014).

6.4 Management of the neck

The nodal staging of the neck is described in section 4.2. In patients with a clinically and radiologically negative neck (i.e., N0) the risk of occult malignancy ranges between 27-34% (Woolgar 1995; Shah 1990; Baxi 2014). Of these, a proportion will also have extracapsular spread on histological examination (Coatesworth 2002). Incidence appears to be associated with size and depth of tumour. Depth of invasion of the tumour predicts the likelihood of nodal metastases. This is rare with tumours less than 2 mm deep (Spiro 1986). A meta-analysis of the incidence of occult metastasis in oral cancer showed that the incidence of occult metastasis increases with depth of tumour, from 5.3% if tumour thickness is less than 3 mm to 16% if >4 mm thick (p =0.007) (Huang 2009).
Controversy exists about the need to electively treat patients on the basis of the fact a third may have occult metastases. A study of 30 patients with T1/T2 N0 tumours demonstrated locoregional failure rate increased from 9% to 47% if the neck was not treated and underwent surveillance only. Elective neck dissection increased the 5-year disease-free survival to 86% from 55% in the surveillance group (Yuen 1997). More recently, the same author described a prospective randomised study of selective neck dissection versus surveillance for a similar group of 71 patients; 11 patients in the surveillance arm and 2 patients in the neck dissection arm developed nodal recurrence. However, unlike before, all 13 patients were successfully salvaged, with no deaths from nodal recurrence. This meant the 5-year disease-specific survival rate was similar at 87% for the surveillance arm and 89% for the neck dissection arm. The authors conclude that, if patients with N0 necks are not electively treated, then close follow-up is required to be able to successfully salvage those patients with recurrence (Yuen 2009).
However, another RCT of 67 patients reported a nodal recurrence rate of 33% in the surveillance arm compared to 12% in the elective neck dissection arm. The 40-month disease free survival rate was 49% compared to 72%, respectively (Kligerman 1994). An even earlier randomised study of 100 T1/T2 N0 tumours had shown that depth of tumour was the main determinant of outcome, with similar 2-year survival rates for the surveillance and neck dissection arms in tumours less than 4 mm in thickness. However, for tumours more than 4 mm in thickness, the 2-year survival rate differed (38% vs. 55%, respectively) (Fakih 1989).
Therefore, elective nodal dissection should be undertaken in T3-T4 oral cancers, and in T1-T2 cancers more than 4 mm in thickness (Type C basis). Bilateral neck dissections are required even in a clinically N0 neck in cases where the primary tumour crosses the midline, as it this was the most important predictor of contralateral nodal disease (Capote-Moreno 2010). For N0 necks, radiotherapy is as effective as surgery for local control (Chow 1989). Metastatic spread is most commonly to levels I-III. Although level IV may also be involved, a recent large series suggested that skip lesions to level IV did not occur and that level IV nodal involvement was always found with disease in other nodal levels. Level IIB and V were rarely involved (3.8 and 3.3%, respectively), and involvement of level IIA was a strong independent predictor for involvement of level IIB and V nodes (Pantvaidya 2014). This last finding has also been confirmed in a meta-analysis (Paleri 2008). Therefore, in an N0 neck, a selective neck dissection (level I-IV) appears adequate, with no evidence that a more radical neck dissection improves local control or overall survival (Brazilian 1998).

6.4.1 Sentinel node biopsy

Sentinel node biopsy is a technique to identify and sample the first echelon nodes draining a given primary tumour location. Evidence is accumulating that this may be a way of more accurately predicting those patients with N0 necks that are truly negative for metastatic disease. A European multicentre trial recruited 134 T1/T2 oral cancer patients with a minimum five-year follow-up. The negative predictive value (NPV) was 98%, although somewhat lower for floor of mouth tumours at 88% (Alkureishi 2010). A similar study from the U.S (ACOSOG trial – Z0360) included 140 patients with T1/T2 oral cavity cancer. The NPV here was 94 % (95%CI 0.88-0.98) although with the use of special immunohistochemical staining for cytokeratin this was improved to 96% (Civantos 2010). Two further meta-analyses have confirmed the findings from these studies, with pooled NPV estimates 93% (95%CI 85-96) and 96 % (95%CI 94-99) (Paleri 2005; Thompson 2013; Monroe 2014). Sentinel lymph node biopsy is an alternative to elective neck dissection in centres with expertise for this method for early (T1, T2) primary oral cavity cancers (Type 3 evidence).

 6.5 Post-operative adjuvant treatment

Post-operative radiotherapy is used in cases with a high risk of local recurrence. In one retrospective study, higher tumour grade and invasion depth over 0.5 cm were found to be the most important factors that affected prognosis after primary surgery in patients with T1-2/N0-1 oral tongue squamous cell carcinoma; in these patients, the authors recommended postoperative radiotherapy (Shim 2010). For all head and neck cancers (and not confined to oral cancers), evidence for adjuvant radiotherapy comes from non-randomised studies showing improved local control, disease-free and overall survival in patients with extracapsular spread and/or positive margins (Huang 1992). Other high risk features include advanced T stage, close (<5mm) or positive (<1mm) margins, lympho-vascular invasion (LVI), perineural invasion, any positive lymph node, especially when there are multiple positive nodes, and/or extracapsular spread (Parsons 1997; Hinerman 2004). Studies also demonstrate reduced locoregional control in the neck after adjuvant radiotherapy (Lundahl 1998).
Evidence for post-operative adjuvant treatment being superior to pre-operative neo-adjuvant treatment comes from a study of supraglottic larynx and hypopharynx cancers by Tupchong et al (Tupchong 1991). Locoregional control was found to be significantly better for 141 post-operative radiation therapy patients than for 136 preoperative radiation therapy patients (p =0.04), even though absolute survival was not affected (p =0.15).
Exact dosing schedules for radiotherapy differ, but would commonly deliver ≥60 Gy for tumours with R0 or R1 resection (i.e., 2 Gy/fraction or its biological equivalent dose), depending on whether there was extracapsular spread or involved margins or residual macroscopic tumour (R2 resection), which usually would receive 66Gy in 33 fractions.
The role of concomitant chemotherapy to adjuvant radiotherapy has been clarified by two large RCTs. Both the EORTC 22931 (Bernier 2005), and RTOG 9501 (Cooper 2004) trials showed significant improvements in 5-year locoregional control rates, from 69% to 82% (p =0.07) and 72% to 82% (p =0.01) respectively, with the addition of platinum-based chemotherapy to radiotherapy alone. However, this was at the expense of considerable additional morbidity through toxicity.
For small tumours in the anterior oral cavity, in particular the floor of mouth, brachytherapy may be used as primary therapy, or as adjuvant therapy after surgery – if residual disease or positive margin – or as a boost to external beam radiotherapy. (Mazeron 2009) A single institutional series of 429 patients revealed that local control could be achieved in over 80% of early oral cancers. Minimal additional improvement in survival was seen for doses over 65Gy, although the risks of osteoradionecrosis certainly increased. It is important to note that brachytherapy for oral cancer is not frequently performed and many new radiation oncology trainees are no longer trained and/or skilled in delivering brachytherapy for this indication.

6.6 Neoadjuvant treatment

There is some renewed interest in the role of neoadjuvant therapy in oral cancer. Although there is no good evidence to support the routine use of neoadjuvant chemotherapy in combination with surgery alone, a recent study of 721 patients with inoperable stage IV oral cavity cancer demonstrated that 43% of patients had a sufficient reduction in tumour size to allow attempt at surgical resection. Locoregional control at 24 months was 20.6% for the overall cohort and 32% in patients undergoing surgery (p =0.0001); median overall survival has also more than doubled (from 8 to 19 months) (Patil 2014). A recent meta-analysis of studies of induction chemotherapy followed by surgery showed no significant difference in overall survival, disease-free survival or recurrence between those treated with induction chemotherapy and those who were not. There was, however, a reduction in the distant metastasis rate (by 8%) in those treated with induction chemotherapy (Ma 2013).
The use of taxane-based neoadjuvant regimens (Vermorken 2007; Posner 2007) may allow for less destructive surgical approaches and help reduce the need for post-operative radiotherapy (Sturgis 2005). However, a recent RCT of induction docetaxel, cisplatin and 5-fluorouracil (TPF) vs. no induction followed by surgery and radiotherapy showed no significant improvement in overall survival or disease-free survival. However those patients who demonstrated a clinical or pathological response to induction chemotherapy had better overall survival and locoregional control (Zhong 2013). Clinical trials are currently ongoing to assess the role of neoadjuvant treatment in oral cancer.

7. Late sequelae

7.1 Treatment effect

7.1.1 Surgery

Because of their anatomical location, tumours arising in the oral cavity – perhaps more than most others – carry significant potential morbidity, both from direct effects of tumour invasion and from treatment side effects. Late effects from surgery include pain around the area of tumour resection, but also from the donor site for free tissue transfer. There may be numbness around the site of surgery or, more generally, in the oral cavity/tongue if neurological damage occurs as a result of tumour invasion or through iatrogenic injury. This neurological impairment may involve motor as well as sensory function, for example injury to the marginal mandibular branch of the facial nerve resulting in weakness to the lip, or shoulder weakness through injury to the spinal accessory nerve during neck dissection.
Loss of tongue function or power in the buccal musculature will lead to poor oral control of food and fluid. If adequate oral phase of swallowing cannot be achieved, patients may be unable to regain safe swallowing post procedure and require parenteral nutritional support. This same loss of function will impair the accurate production of speech. Late infection is a rare complication, however areas of bone may undergo necrosis, especially if a mandibulotomy has been performed.

7.1.2 Radiotherapy

Early side effects of radiation treatment include tiredness and erythema (sometimes with desquamation) to the skin surrounding the mouth/neck. Although mucositis and mucosal ulceration also tends to be an early feature, the latter may persist or even represent as a late side effect.
Difficulties in swallowing initially occur secondary to pain, however stricturing in the hypopharynx/post-cricoid area may lead to ongoing swallowing difficulties for many years after treatment. If strictures occur, surgical intervention with repeat dilatation may be necessary to enable a normal diet to be tolerated. A similar process of fibrosis occurs to affect mouth opening. Trismus may be severe enough to render eating impossible, and make dental and oral hygiene almost impossible.
Xerostomia through the collateral effect of radiation to both major and minor salivary glands is perhaps the most troublesome late sequelae after radiotherapy. This causes significant discomfort to patients, particularly at night, and leads to difficulty in eating. Artificial saliva products offer some relief, but this is temporary and not tolerated by all. Saliva production can return even after considerable time (many years in some instances). Efforts to protect against the damaging effects of radiotherapy on salivary tissue include the introduction of more accurate directed radiotherapy beams (Intensity Modulated Radiotherapy – IMRT) (Nutting 2011), the use of chemoprotectants, such as Amifostine, and devices to stimulate gums to help the production of saliva (being examined by the LEONIDAS-2 trial) (Lovelace 2014). Xerostomia also leads to increased rates of mouth infection and dental decay. If the latter occurs and requires dental extractions to be performed, there is a considerable risk of osteoradionecrosis.
Radiotherapy to the mouth often leads to alterations in taste and smell. This may present as a loss of taste, or altered taste (e.g., metallic or foul taste). These changes will impact appetite.

7.1.3 Chemotherapy

Most of the side effects of chemotherapy are acute, such as tiredness, nausea, vomiting, diarrhoea, hair loss, and haematological effects (neutropenia, anaemia). Importantly, chemotherapy potentiates the side effects of radiotherapy when given as concurrent treatment.

7.2 Second orimary tumours

Patients with oral cancer are at increased risk for the development of a second primary tumour. This is because of the exposure to the whole upper aerodigestive tract to the risk factors known to cause malignancy. This concept is in keeping with the theory of “field cancerisation” proposed by Slaughter et al (Slaughter 1953). Synchronous tumours are diagnosed simultaneously or within six months of the primary cancer, while metachronous tumours are diagnosed more than six months after the primary cancer. Second primary tumours are the second leading cause of death amongst head and neck cancer patients, although it should be noted that some second cancers will develop outside head and neck (Baxi 2014).
The risk of second primary tumours has increased compared with the age-matched general population and ranges from 2 to 7 percent per year (Kim 2007; Lee 2013). This level of risk continues through the patients’ lifetime (Gan 2013).

8. Follow-up

8.1 General principles

There are four major goals to be achieved in following up patients who have undergone treatment for oral cancer:

  • To reassure patients that they will remain disease free. This recognition of the importance to the psychological wellbeing of patients who have struggled with the uncertainty of a cancer diagnosis and treatment, and the ongoing concerns about disease recurrence is a crucial part of the holistic approach to patient care.
  • To achieve early identification of local or locoregional disease recurrence and the development of any second primary tumours. Early detection of either of these may facilitate successful salvage treatment. Late presentation almost invariably leads to loss of the opportunity to attempt curative treatment.
  • To monitor for treatment related side effects. These can be significant with treatments for oral cancer, including affecting speech, swallowing, voice, and cosmesis. These side effects need to be addressed and managed to improve patients’ specific and overall quality of life.
  • To achieve effective palliation. Unfortunately, many patients will develop non-curable recurrence or second primary disease and the support of patients and carers is vital.

8.2 Specific follow-up regimes

There is no good evidence for how often patients should undergo monitoring. Follow-up schedules are tailored according to the nature of the disease, specific patient factors and the capacity of the institution. Careful history and examination of all patients should be undertaken by trained head and neck surgeons. Specialised support may come from oncologists, speech and language therapists, dieticians, specialist cancer nurses, and clinical psychologists. Further investigations, including radiology, may be required as part of baseline monitoring or the investigation of specific symptoms.
A typical follow-up regime might be as follows:
Year 1: every 1-3 months;
Year 2: every 2-3 months;
Year 3: every 4 months;
Year 4/5: every 6 months;
After 5 years: discharge or every 12 months.
Most recurrence will occur within the first two years. This is also the period during which patients will have the most significant treatment-related side effects. This is the rationale for the short intervals between follow-up visits in the first few years, pragmatically lengthened out after 3 years of follow-up. Patients may be given the opportunity to be discharged after completing 5 years follow-up post treatment. Many will choose to remain on annual review.



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Anthony Kong (clinical oncologist)
Institute of Head and Neck Studies and Education,
University of Birmingham (UK)
e-mail address:

Hisham Mehanna (Senior author)
Institute of Head and Neck Studies and Education,
University of Birmingham (UK)
e-mail address:

Paul Nankivell (Author)
Institute of Head and Neck Studies and Education,
University of Birmingham (UK)
e-mail address:

Eva Remenar (reviewer)
Multidisciplinary Head and Neck Cancer Centre,
National Institute of Oncology, Budapest (HU)
e-mail address: