Description of the condition

Oropharyngeal tumours may arise from the tonsil, base of tongue, soft palate and posterior pharyngeal wall region. They are relatively infrequent, with an incidence of about 0.8 to 3.8 per 100,000 population per annum. However, in the head and neck this is now the most prevalent site for carcinomas and the number of cases appears to be rising (Dwivedi 2009; Evans 2010). The oropharynx plays an essential role in swallowing, speech and protecting the airway as it is situated at the bifurcation of the respiratory and digestive tract. Treatment modalities are influenced heavily by the aim to reduce the risk of functional disability where possible. Most tumours are locally advanced at the time of diagnosis, which may complicate the choice of primary treatment (Choi 2009; Meldenhall 2011).

Human papilloma virus (HPV) is a major carcinogen, with an estimated 4.8% of total worldwide cancers in 2008 linked to the virus (de Martel 2012). Essentially all cervical cancers (99.7%) are causally associated with HPV (Walboomers 1999). The association between high‐risk (carcinogenic) HPV and oropharyngeal cancer is now evident from data collected by independent controlled studies. The virus now fulfils epidemiological criteria for disease causality, especially in non‐smokers (Sudhoff 2011). A recent meta‐analysis of the world literature demonstrated that the proportion of oropharyngeal squamous cell carcinoma caused by HPV has increased from 40.5% in studies recruiting before the year 2000 to 72.2% in studies reporting after 2005 (Mehanna 2012). It is of interest to note that this group of patients have significantly improved rates of both overall survival and disease‐free survival compared to HPV‐negative tumour groups (Ang 2010; Fakhry 2008).

A significant proportion of oropharyngeal cancers (40% to 60%) have HPV16 DNA integrated within their genomic DNA, with minor contributions made by other oncogenic HPV subtypes (Gillison 2004). These HPV DNA sequences are transcriptionally active, which strongly suggests a functional influence within the host cancer cell (Van Houten 2001; Wiest 2002). The roles of the two HPV16 oncoproteins E6 and E7 have been studied extensively and include inhibition of p53 and pRb (retinoblastoma) tumour suppressor proteins (Hoffman 2010). Expression of the E6 protein will cause inhibition of p53, leading to loss of cell cycle arrest and apoptosis when DNA damage is detected within the cell. Expression of the E7 protein may cause degradation of pRb, leading to unopposed progression through the cell cycle. Laboratory studies have demonstrated that repression of E6 and E7 will lead to activation of the p53 and pRb pathways, decreased cellular proliferation and cellular growth arrest (Goodwin 2000; Wells 2000). This situation is quite different to HPV‐negative oropharyngeal squamous cell carcinoma, where an irreversible p53 mutation will normally be present and may contribute to the poorer survival observed in this patient cohort (Oliver 2002).

Description of the intervention

The current management of oropharyngeal carcinoma is dictated by the stage of the disease as well as clinician and patient preference. Early stage disease (T1 N0 and T2 N0) can be treated by a single modality, such as surgery or radiotherapy. The standard of care for local advanced disease may include primary chemoradiotherapy with or without selective neck dissection or primary surgical resection and reconstruction with adjuvant chemo‐radiotherapy (Mehanna 2011). The evidence would suggest that primary chemoradiation is more prevalent than surgery due to the perceived reduction in treatment‐related morbidity (Gregoire 2010). Biotherapy (sometimes called biological therapy or immunotherapy) is an emerging treatment that uses the immune system of the body to target cancer cells, decrease side effects or both.

Chemotherapy is the administration of cytotoxic medication that targets rapidly dividing cancer cells, disrupting growth and destroying them. Cancer cell DNA is usually disproportionately affected in comparison with normal cells and this results in decreased cellular division and increased cell death. Chemotherapy can be used in combination with radiotherapy (concurrent) to increase radiosensitivity or before radiotherapy (neoadjuvant) to reduce the tumour size. The combination of two or three chemotherapeutic medications can be more effective against the tumour as different agents interrupt the life cycle of malignant cells at different stages. The unwanted side effect of this approach may be increased toxicity, which can be exacerbated by the parallel use of radiotherapy.

Radiotherapy works by disrupting the DNA of rapidly dividing cells so that the normal repair mechanisms (normally less effective in cancer cells) are impeded and the cells die. It is the case that some physiological cells within the body also proliferate rapidly and as a consequence will be affected by the ionising radiation. In the head and neck region this most commonly will include the salivary glands and oral mucosa. Radiation therapy can also cause cancer and is no longer used for benign conditions.

Biological therapy will utilise the immune system to fight cancer. It does this by enhancing the patient's own immune system to target the cancer cells. This may be either through immunisation of the patient, in which case the patient's own immune system is trained to recognise tumour cells as targets to be destroyed, or through the administration of therapeutic antibodies which in turn co‐ordinate the body to destroy tumour cells. Cell‐based therapy involves activating immune cells (e.g. cytotoxic T lymphocytes or natural killer cells) by the use of cytokines such as the interleukins.

Growth factors activate cells by recognising specific receptors, which are present on the peripheral surface. A proportion of cancer cells exhibit rapid growth because they contain more of these receptors compared to healthy surrounding tissue. One of the growth factors that may be linked to oropharyngeal cancer is epidermal growth factor or EGF. High levels of EGF‐specific cell surface receptors (EGFR) are associated with a poor response to curative treatment; this knowledge has resulted in EGFR itself becoming an important therapeutic target (Haddad 2008).

How the intervention might work

It is usual to give two or more chemotherapy drugs together and this is referred to as combination therapy, e.g. cisplatin and 5‐fluorouracil. The temporal sequence of chemotherapy with other treatments can vary. It is most commonly delivered in combination with radiotherapy (concurrent, concomitant or synchronous chemoradiotherapy). Induction chemotherapy (neoadjuvant) is the early treatment of a tumour in order to physically reduce the size in preparation for radiotherapy, surgery or other interventions. Adjuvant chemotherapy is least common and refers to chemotherapy following the primary intervention (Pignon 2009). Sequential therapy usually refers to induction chemotherapy followed by concurrent chemoradiotherapy.

Chemotherapy drugs target all dividing cells in the body with the result that normal cells can also be adversely affected. It is therefore no surprise that chemotherapy is often associated with temporary side effects such as lethargy, nausea/vomiting, hair loss, susceptibility to infection, anaemia, diarrhoea, constipation or mucositis. The majority of these effects are mild but occasionally some can be severe. Less commonly, severe or permanent side effects can include cardiac impairment, peripheral neuropathy, nephrotoxicity or ototoxicity. Chemotherapeutic drug delivery is normally a cyclical administration over one to two days, followed by a rest period. The exact protocol will vary depending on the dosages used and the perceived interaction between the agents used.

Treatment of oropharyngeal cancer with radiotherapy has traditionally been given in a single dose of ˜2.0 Gy per day, five days a week to a total dose of 60 to 70 Gy. The precise method of dividing up the treatment dose, or fractionation, has changed over the years. This is a consequence of ongoing research looking at the biological interaction between the cancer cell and healthy surrounding tissue and has been recently reviewed (Dirix 2010).

The two main types of non‐conventional (altered) fractionation are accelerated and hyper‐fractionation. Accelerated fractionation will use a similar overall dose as conventional treatment but over a reduced time period. This fractionation regime has been developed to counteract tumour cell repopulation during the course of therapy (squamous cell cancers of the head and neck can double the number of cancerous cells in three days). The hyperfractionated regime utilises daily multiple attenuated doses over a similar duration as conventional fractionation to give a larger total dose, e.g. twice‐daily fractions of 1.1 to 1.2 Gy/fraction to a total dose of 74 to 80 Gy. Further developments in radiotherapy include intensity‐modulated radiotherapy (IMRT) and image‐guided radiotherapy which may improve precision and reduce side effects (Gregoire 2007; Nutting 2011).

Biological treatment of oropharyngeal cancer is primarily based on EGFR inhibition by the use of specific monoclonal antibodies (Bourhis 2010), tyrosine kinase inhibitors (e.g. erlotinib), immunotoxins (toxins bound to antibodies or growth factors) and antisense strategies (Modjtahedi 2009). Cetuximab is a monoclonal antibody that binds to EGFR and has been successful in shrinking and eliminating oropharyngeal cancers when combined with radiation (Bonner 2010). Patients who develop severe complications or febrile neutropenia (FN) during chemotherapy frequently suffer delays to their chemotherapy. As this may impact on the overall success of treatment, recent guidelines have been introduced regarding the use of granulocyte‐colony stimulating factors which have been shown to mitigate the toxic effects of chemotherapeutic regimens, e.g. docetaxel, cisplatin and 5‐fluorouracil (TPF), in the head and neck region (Aapro 2006).

Biological therapies may benefit a patient with cancer in various ways by 1) preventing local or distant metastatic spread of the disease; 2) stopping, controlling or suppressing the processes that permit cancer growth; 3) altering the cancer cell growth pattern to promote normal physiological behaviour; 4) enhancing the capability of the immune system cells, such as macrophages, NK‐cells and T‐cells by improved immunological targeting of oropharyngeal cancer cells; 5) blocking or reversing the process that transforms a pre‐cancerous cell into a cancerous cell; and 6) protecting or repairing normal cells that are damaged or destroyed by other forms of cancer treatment, such as chemotherapy or radiation.

Why it is important to do this review

The data now suggest that HPV‐associated oropharyngeal squamous cell carcinomas (SCC) are a distinct subgroup of tumours, and that this recognition is particularly important because the prognosis may be better than the traditional tobacco and alcohol‐associated tumours (Gillison 2004). It has been reported that there is a 60% improvement in survival when a tumour is HPV‐positive (Licitra 2006). Prospective randomised controlled clinical trials with retrospective analysis of pre‐treatment biopsies have now established that the detection of HPV in the tumour confers a survival advantage to the patient (Ang 2010; Fakhry 2008). These intriguing data now point to the importance of HPV status when managing patients.

How can we utilise current knowledge about the importance of HPV status? Treatment for local advanced head and neck cancer can result in very intensive treatment, usually by chemoradiation. Many patients require insertion of a percutaneous gastrostomy tube, intravenous fluids or both, with the potential for infection or electrolyte imbalance. Iatrogenic complications are estimated to cause mortality of ˜2%, which clinicians reluctantly accept as the majority of treated patients will be cured (Lee 2011). As patients with HPV‐associated cancers demonstrate improved survival (primarily due to the increased susceptibility of the tumour to curative treatment), can we safely de‐escalate the intensive therapies that could, in fact, unnecessarily endanger them? A primary aim of this review will be to assess not just overall survival but also toxicity profiles in all eligible trials.