General principles of management

Early stage (T1–T2 N0 M0) oropharyngeal carcinoma should ideally be treated with single modality therapy, either primary surgery or RT. There are no high-quality comparative studies of the two treatment modalities within the same population. Retrospective case series demonstrate five-year disease-specific survival rates of 81–100 per cent for primary surgeryReference Cosmidis, Rame, Dassonville, Temam, Massip and Poissonnet ¹⁵ (with adjuvant therapy where appropriate) and 77–89 per cent for primary RT, with surgical salvage.Reference Mendenhall, Morris, Amdur, Hinerman, Malyapa and Werning ¹⁶ Treatment decisions are made based on the size and position of the tumour overall functional deficit.

Surgical management of early (T1–T2 N0) oropharyngeal cancer

Surgery for T1–T2 N0 OPSCC should usually be carried out transorally, either by transoral laser microsurgery (TLM) or transoral robotic surgery (TORS). Oncologic results after transoral resection of the oropharynx appear to be comparable to open surgery and good functional outcomes have been reported after transoral surgery in retrospective series.Reference Moore and Hinni ¹⁷ Open approaches are associated with increased severe morbidity and treatment complications and have now fallen out of favour for early stage disease.

During TLM, tumours are removed in several (at least two) planned pieces following trans-tumoural resection. This can cause difficulty in pathological scrutiny of the resected tissue to determine margins, which is compounded by laser artefact and difficulty in orientation. Representative marginal biopsies, taken from the peripheral mucosal resection margins and tumour bed can be carried out and examined pathologically to help rule out the presence of residual microscopic disease after TLM. In contrast to TLM, TORS involves en bloc removal of the tumour in the majority of cases. As a result, surgical margins can be more easily interpreted.

About 10–31 per cent of patients who are clinically T1–T2 N0 will have occult nodal disease. Therefore, patients having surgery to the primary should also undergo ipsilateral selective neck dissection. Surgery to the contralateral neck may also be considered in tumours arising at or very near the midline (in the soft palate, tongue base or posterior pharyngeal wall) in order to obtain pathological staging of the contralateral neck. Evidence suggests dissecting levels II, III and IV and possibly level I if there is anterior extension.Reference Lim, Koo, Lee, Lim and Choi ¹⁸ Retrospective studies suggest that level IIb does not need to be dissected, as long as there are no findings pre-operatively of level IIa disease. For transoral resections, the neck dissection may be performed at the same time, or as a staged procedure, around two weeks before transoral resection of the primary. A staged approach may help prevent the development of a fistula if there is lateral pharyngeal wall transoral resection. Concomitant transoral resection and neck dissection can also be carried out and good results have been reported. In the latter, local muscle transposition (digastric or sternomastoid) can be performed to augment any defect and decrease risk of fistula. For any transoral resection of the oropharynx, ligation of the individual feeding vessels from the external carotid artery should be performed (ascending pharyngeal, lingual and facial branches) to limit the risk of potentially life-threatening haemorrhage. This should be done in any neck dissection performed as a prior staged procedure.

Although the goal for T1–T2 N0 disease should be single modality treatment, adjuvant RT and/or chemoradiotherapy may be required due to adverse pathological features for recurrence following surgery. Post-operative RT should be planned using the same principles as radical RT; a dose of 60 Gy in 30 fractions is typically recommended. Adjuvant treatment may affect functional outcomes following surgery.

Radical RT for early oropharyngeal cancer

Prior to RT, patients should undergo dietetic, speech and language therapy and dental review. A total dose equivalent of 70 Gy in 35 fractions is used in radical treatment. Hypofractionated schedules (typically 65–66 Gy in 30 fractions) are frequently used. Patients are managed as category 1 patients and RT should be completed on time.

Target volume definition is performed using a contrast-enhanced planning CT scan. Co-registration of the planning CT scan with the diagnostic MRI scan can aid target volume delineation. An anatomical (inclusion of the whole oropharynx) or geometric (inclusion of gross tumour volume with a defined margin) approach may be used for primary target volume delineation. Prophylactic RT should be given to the ipsilateral cervical lymph nodes for lateralised (e.g. tonsillar) tumours and to both sides of the neck for non-lateralised tumours (defined as tumours which involve greater than 1 cm of a midline structure e.g. soft palate and/or tongue base). Radiotherapy to levels II, III and IVa is recommended; level Ib may also be included in cases with anterior extension of tumour and/or involvement of the anterior tonsillar pillar. Planning can be carried out using three-dimensional conformal planning (typically using a ‘wedged pair’ of RT fields) or intensity modulated radiotherapy (IMRT) and/or Arc therapy.

General principles of management

A thorough review of the literature relating to the management of oropharyngeal cancer was published as a Cochrane report in 2009. The only evidence of statistically significant benefit was for the addition of concomitant chemotherapy to post-operative RT.Reference Furness, Glenny, Worthington, Pavitt, Oliver and Clarkson ¹⁹ All other treatment comparisons did not show any statistical differences.

In recent years, there has been a tendency to offer primary RT and/or chemoradiotherapy for oropharyngeal carcinoma, as part of an ‘organ preservation’ strategy. Although there are no good head-to-head comparisons of primary surgery and chemoradiotherapy for stage III/IV OPSCC, outcomes from randomised trials of chemoradiotherapy (e.g. RTOG 0129) are at least comparable to the results of surgical series. One potential concern with an organ preservation approach is that although salvage surgery has been shown to have a high success rate for laryngeal cancer, the success rate of salvage surgery is not the same in other head and neck sites, such as the oropharynx.

The 2013 National Head and Neck Cancer Audit (9th DAHNO Report) concluded that variation in treatment strategies for OPSCC is evident across cancer networks in England and Wales. This is not surprising in view of the fact that current published evidence does not provide a consensus view to define the most appropriate treatment strategy. Treatment decisions for individual patients will depend on the size, position and overall functional deficit, as well as on patient preference and local expertise. Human papilloma virus status has a profound influence on prognosis, and in future, could potentially affect selection of treatment modality. Recruitment into randomised controlled clinical trials addressing these issues is highly recommended.

Surgical management of advanced oropharyngeal carcinoma

Where facilities and expertise exist, transoral resection (by TLM or TORS) of base of tongue, tonsil and pharyngeal wall primary tumours (usually with post-operative (chemo)radiotherapy) has been shown to offer rates of cure which appear to be as good as primary chemoradiotherapy in non-randomised comparisons, with promising functional results. Transoral resection is generally restricted to T1–T2 tumours, although resection of some T3 tumours may be considered if it is anticipated that negative margins can be achieved via a transoral approach. Transoral resection is rarely appropriate for T4 primary tumours. Also, where a larger resection of the soft palate is required, the general consensus is that surgery gives a poor functional outcome. It should be noted that approximately 80 per cent of patients who undergo primary surgery will also receive post-operative RT or chemoradiotherapy.

If transoral resection is not appropriate, e.g. for large primary tumours, then chemoradiotherapy should be considered. Alternatively, open surgical procedures may be considered, which usually require paramedian mandibulotomy for access and reconstruction with a flap. Trans-cervical pharyngotomy alone can be used for tongue base resections. Other approaches, such as glossotomy and lingual release can be used but are not often employed. Reconstruction is generally performed using radial artery free flaps or anterolateral thigh free flaps. Reconstruction using pedicled flaps, such as pectoralis major should be considered sub-optimal. Functional results following open surgery can be poor, particularly when followed by adjuvant therapy.

There are several published case series that report the likelihood of nodal metastasis for advanced oropharyngeal carcinoma to be over 50 per cent. When managing T3 and T4 oropharyngeal cancers, the N0 neck should be treated electively. When managing the N0 neck surgically, a selective level II, III and IV neck dissection is generally recommended, and in some cases level I may be included. All patients with node positive disease should have a modified neck dissection or at least level I–IV selective neck dissection.

Primary chemoradiotherapy for loco-regionally advanced (stage III–IVb) oropharyngeal carcinoma

Chemoradiotherapy (organ preservation) is an effective treatment choice for advanced head and neck tumours. A RT dose equivalent of 70 Gy in 2 Gy fractions with concurrent cisplatin chemotherapy is considered standard for stage III and/or IV OPSCC. Concurrent weekly cetuximab (a monoclocal antibody targeting the epidermal growth factor receptor) may be given with RT if there is a contraindication to platinum chemotherapy (e.g. renal dysfunction or hearing impairment). Alternatively, radical RT alone can be given for patients with advanced disease who are not fit for concurrent treatment, particularly if they are over 70 years of age when the benefits of concurrent chemotherapy are reduced. Induction chemotherapy may be considered for patients with advanced (T4, N3, N2c) disease to reduce the risk of distant metastasesReference O'Sullivan, Huang, Siu, Waldron, Zhao and Perez-Ordonez ²⁰ and for selected other patients with bulky primary (T4) and/or nodal disease (N3), but there is currently no high-quality evidence of its efficacy in these indications.

The principles of RT outlining and planning are as described for earlier stage disease. Neck nodes should be included in the treatment fields depending on their probability of involvement and according to the DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines and atlas which were updated in 2013.Reference Gregoire, Ang, Budach, Grau, Hamoir and Langendijk ²¹ Radiotherapy to levels Ib–IVa, V(a,b) and the retropharyngeal nodes (level VIIa) at the level of the oropharynx is generally recommended in a node positive neck. The retrostyloid space (level VIIb) is included when level II is involved and the supraclavicular fossa (levels IVb and  Vc) is included when level IVa or V is involved. Radiotherapy should be given to at least the ipsilateral cervical lymph nodes for lateralised tumours and to both sides of the neck for non-lateralised tumours. The issue of whether the contralateral neck should be treated in patients with lateralised oropharyngeal tumours and advanced (N2+) nodal disease remains controversial and will depend on local practice.

Chemoradiotherapy is associated with greater toxicity than RT alone and late toxicity, particularly swallowing dysfunction, can have a significant impact on quality of life.Reference Machtay, Moughan, Trotti, Garden, Weber and Cooper ²² Gastrostomy tube dependence rates of up to 24 per cent at 1 year and 14 per cent at 2 years post-chemoradiotherapy have been reported, although others have reported much lower rates. Improvements in RT techniques (including IMRT) have been shown to reduce late complications following RT. The UK PARSPORT randomised study showed a significant reduction in xerostomia rates with parotid sparing IMRT compared with conventional RT (using parallel opposed fields) in patients with advanced OPSCC.Reference Nutting, Morden, Harrington, Urbano, Bhide and Clark ²³ Ongoing studies are exploring the role of IMRT in improving swallowing function following RT, by reducing radiation dose delivery to the pharyngeal constrictor muscles and other swallowing structures.

Traditionally, patients with advanced nodal disease (N2 or N3) being treated by chemoradiotherapy required a planned neck dissection, with little evidence to support whether neck dissection before or after chemoradiotherapy is more effective. There is now level I evidence from the PET-Neck trial that a PET–CT guided active surveillance policy, with neck dissection only being carried out if residual abnormal or equivocal nodes are present on imaging 10–12 weeks after the end of chemoradiotherapy, results in similar survival rates to a planned neck dissection, with less morbidity, and with higher cost effectiveness.Reference Mehanna, Wong, McConkey, Rahman, Robinson and Hartley ⁵

Post-operative radiotherapy and chemoradiotherapy for advanced oropharyngeal carcinoma

The indications for post-operative RT and chemoradiotherapy for OPSCC depend on pathological risk factors for recurrence common to most head and neck squamous carcinomas. Randomised controlled trials and a meta-analysis of results confirm that patients with extra-capsular invasion and/or microscopically involved (<1 mm) surgical resection margins around the primary tumour experience significant benefit in terms of overall and disease free survival from post-operative chemoradiotherapy compared with RT alone.Reference Bernier, Cooper, Pajak, van Glabbeke, Bourhis and Forastiere ²⁴ Post-operative chemoradiotherapy is associated with significant acute and late toxicity and is not generally recommended in patients over 70 years of age and/or patients with poor performance status. Indications for post-operative RT alone include multiple nodal metastasis, T3 or T4 tumours, and tumours with other adverse features, including perineural or lymphovascular invasion. Patients with close (1–5 mm) surgical margins around the primary tumour may be treated with post-operative chemoradiotherapy or RT alone according to the presence or absence of other risk factors for recurrence. Patients should start their adjuvant RT as soon as possible after surgery (ideally within five weeks (35 days) and no later than six weeks (42 days)) to avoid reduced local control and survival due to protracted treatment.

The relevance of traditional risk factors for recurrence (including extra-capsular spread) and the benefit of adjuvant chemotherapy with RT in the context of HPV-positive OPSCC has been questioned by some studies. However, no change in management of patients should occur outside clinical trials. Clinical trials which aim to modify adjuvant treatment based on HPV status are currently ongoing in the UK and USA.