the historical standard of 70 gy have been carried out. a study using 54–60 gy (a 15–20% reduction, stratified by response to initial induction chemotherapy) demonstrated comparable levels of disease control with much lower complication rates, when compared to similar studies, using 70 gy, such as ecog 2399. the percentage of patients alive after 2 years were 95% at the higher dose and 98% at the lower dose. similarly for the percentage free of disease (86 and 92%). toxicities were greatly reduced from an incidence of grade 3 or greater dysphagia and mucositis of 54 and 53% respectively, to 9%. a lower incidence and severity of dysphagia also means that less patients require gastrostomy feeding. a similar comparison can be made with the pooled data from two rtog studies which utilized 70 gy (0129 and 0522). no new guidelines dealing specifically with hpv+opc have yet been developed, outside of clinical trials. indirect data suggests the efficacy of less intense treatment. a retrospective analysis of advanced (n+) hpv+opc suggested 96% 5 year local control with de-intensified radiation of 54 gy and concurrent cisplatin based chemotherapy. the conclusions of the above pair of similar phase ii trials have been supported by several other phase ii trials. a prospective trial (ecog 1308) demonstrated similar locoregional control with 54 gy, and another study, a high pathological complete response rate at 60 gy. the quarterback trial showed comparable outcomes between 56 and 70 gy. and was followed by quarterback 2, comparing 50 to 56 gy. similarly, the optima trial showed good disease control with doses between 45 and 50 gy. ongoing studies, following the experience of the mayo clinic trial (mc1273), such as that the memorial sloan kettering cancer center are exploring doses as low as 30gy. these studies all used well below the previous standard dose of 70 gy. since long-term toxicity is associated with radiation dose, determining the efficacy of lower and hence less morbid doses of radiation is a priority, since many hpv+ patients can be expected to have long-term survival. radiation is commonly utilised in combination with chemotherapy, but also may be used as a single modality, especially in earlier stages, e.g. t1-t2, n0-1, and its use in later stages is being explored in clinical trials such as rtog 1333 which compares radiation alone to radiation with reduced chemotherapy, in non or light smokers. chemotherapy as with the radiotherapy data, most of the available knowledge on the efficacy of chemotherapy derives from the treatment of advanced head and neck cancer rather than specific studies of hpv+opc. since 1976, many clinical studies have compared crt to rt alone in the primary management of locally advanced head and neck cancers and have demonstrated an advantage to crt in both survival and locoregional control. cisplatin is considered the standard agent, and a survival advantage was seen for those patients who received radiation with concurrent cisplatin. despite this no trials directly comparing cisplatin with other agents in this context have been conducted. the other agent that is widely used is cetuximab, a monoclonal antibody directed at the epidermal growth factor receptor (egfr). a 10% survival advantage at three years was noted when cetuximab was given concurrently with radiation (bioradiation). cetuximab trials were completed prior to knowledge of hpv status. laboratory and clinical studies on the utility of cetuximab in this context are conflicting. the main toxicity is an acneiform rash, but it had not been compared directly to cisplatin in hpv+opc, until rtog 1016 (see talk) addressed this question. analysis of the results three years after the trial was completed demonstrate that cetuximab is inferior to cisplatin. concurrent chemotherapy is also superior to chemotherapy alone (induction chemotherapy) followed by radiation. cetuximab shows no advantage when added to cisplatin in combination with radiation. although chemoradiation became a treatment standard based on clinical trials and in particular, meta-analyses, a subsequent population based study of patients with opc, indicated no advantage to the addition of chemotherapy to radiation in either hpv+opc or hpv-opc, and significant concerns about added toxicity. chemotherapy also has a role, combined with radiation, in the postoperative setting (adjuvant therapy). generally it is used where the pathology of the resected specimen indicates features associated with high risk of locoregional recurrence (e.g. extracapsular extension through involved lymph nodes or very close margins). it has shown improved disease-free survival and locoregional control in two very similar clinical trials in such high risk patients, eortc 22931 (1994–2000) and rtog 9501 (1995–2000). however, for hpv+opc patients, such extracapsular spread does not appear to be an adverse factor and the addition of chemotherapy to radiation in this group provided no further advantage. since the sample size to detect a survival advantage is large, given the small number of events in this group, these studies may have been underpowered and the question of the utility of adding chemotherapy is being addressed in a randomized clinical trial (adept) with two year locoregional control and disease free survival as the endpoint. the addition of chemotherapy to radiation increases acute and late toxicity. in the gortec trial, chemotherapy with docetaxel provided improved survival and locoregional control in locally advanced opc, but was associated with increased mucositis and need for feeding by gastrostomy. chemotherapy and radiation are associated with a risk of death of 3–4% in this context. it is unclear whether the added toxicity of adding chemotherapy to radiation is offset by significant clinical benefit in disease control and survival. it is thought that hpv+opc patients benefit better from radiotherapy and concurrent cetuximab treatment than hpv-opc patients receiving the same treatment, and that radiation and cisplatin induce an immune response against an antigenic tumour which enhances their effect on the cancer cells. although the incidence of hpv positivity is low (10–20%), an advantage for hpv+opc was seen in trials of both cetuximab and panitumumab, a similar anti-egfr agent, but not a consistent interaction with treatment, although hpv+opc appears not to benefit to the same extent as hpv-opc to second line anti-egfr therapy, possibly due to lower egfr expression in hpv+opc. choice of treatment approach in the absence of high quality evidence comparing a primary surgical approach to other modalities, decisions are based on consideration of factors such as adequate surgical exposure and anatomically favourable features for adequate resection, post treatment function and quality of life. such patient selection may enable them to avoid the morbidity of additional adjuvant treatment. in the absence of favourable surgical features the primary treatment of choice remains radiation with or without chemotherapy. tumor characteristics which favour a non-surgical approach include invasion of the base of the tongue to the extent of requiring resection of 50% or more of the tongue, pterygoid muscle involvement, extension into the parapharyngeal fat abutting the carotid, involvement of the mandible or maxilla or invasion of the prevertebral space. the adequacy of surgical resection is a major factor in determining the role of postoperative adjuvant therapy. in the presence of a positive margin on pathological examination, most radiation oncologists recommend radiation to the primary site, and concurrent chemotherapy. a negative margin is more likely to be treated with lower doses and a smaller treatment volume. also the removal of a bulky tumour may allow reduced dosage to adjacent uninvolved pharyngeal structures and hence less effect on normal swallowing. the cancer outcomes (local control, regional control, and survival) for transoral resection followed by adjuvant therapy are comparable to primary chemoradiation, so that treatment decisions depend more on treatment-related morbidity, functional outcome, and quality of life. patient factors also need to be taken into account, including general baseline functionality, smoking history, anesthesia risk, oropharyngeal function, swallowing and airway protection and potential for rehabilitation. patient preference is equally important. many clinical trials are under way focussing on deintensification, often with risk stratification, e.g. low, intermediate and high risk (see fundakowski and lango, table i). clinical decisions also take into account morbidities, particularly if cancer outcomes are comparable for instance surgery is associated with a risk of bleeding between 5–10%, and a 0.3% risk of fatal postoperative haemorrhage. surgery may also be complicated by dysphagia, and while most patients can tolerate a diet on the first postoperative day, long-term use of a feeding tube has been reported as high as 10%. patients with larger tumours, involvement of base of tongue and requiring postoperative adjuvant therapy are more likely to require a long-term feeding tube. overall, function and quality of life appear relatively similar between surgery with postoperative radiation, and primary chemoradiation, but hpv+opc patients tend to have better quality of life at diagnosis than hpv-opc but may sustain greater loss following treatment. anatomical considerations may also dictate preference for surgical or non-surgical approaches. for instance trismus, a bulky tongue, limited extension of the neck, prominent teeth, torus mandibularis (a bony growth on the mandible) or limited width of the mandible would all be relative contraindications to surgery. tumour related considerations include invasion of the mandible, base of skull and extensive involvement of the larynx or more than half of the base of tongue. technical considerations in offering surgery as a primary modality include the presumed ability to achieve adequate margins in the resected specimen and the degree of resulting defect, since close or positive margins are likely to result in subsequent adjuvant therapy to achieve disease control, with resultant increased morbidity. costs are difficult to estimate but one us study, based on estimates of 25% of all opc patients receiving surgery alone and 75% surgery followed by adjuvant therapy, using the criteria of the nccn, found that this approach was less expensive than primary chemoradiation. early stage disease is associated with a relatively favourable outcome, for which single modality therapy is recommended, the choice depending on tumour location and accessibility. for instance unilateral tonsil or tongue base tumours will generally be treated with transoral resection and selective ipsilateral neck dissection. on the other hand, a large midline tongue lesion would require bilateral neck dissection, but in the absence of what are considered adverse pathology (positive margins, extracapsular extension) will likely be treated by surgery alone or radiation including ipsilateral or bilateral neck radiation fields, with surgery for those instances where the likelihood of adjuvant therapy is low. but many hpv+opc present with involvement of the lymph nodes in the neck, and hence a higher stage of disease, generally referred to as locally advanced disease. this group is mostly treated with multimodality therapy, with the exception of one of the more favourable subgroups with small primary tumours and lymph node involvement confined to a single node no larger than 3 cm in size, which as noted are considered early stage disease. the three main options for locally advanced but operable disease are resection, neck dissection and adjuvant therapy; chemoradiation (with possible salvage surgery); induction chemotherapy followed by radiation or chemoradiation. however the last option has not been supported in clinical trials that tested it. the primary consideration of surgery for locally advanced disease is to obtain adequate negative margins and spare the patient postoperative chemoradiation. but this must be balanced against the morbidity and functional loss from extensive resection, particularly where the tongue base is involved. to avoid such morbidity, primary chemoradiation is preferred. the management of disease within the cervical lymph nodes has to be taken into account in treating locally advanced disease. guidelines for all opc dictate that ectracapsular extension be given postoperative chemoradiation. where gross neck disease is evident initially primary chemoradiation is usually given. patient preferences current guidelines are based on data for opc as a whole, so that patients are generally being treated regardless of hpv status, yet many clinicians and researchers are considering deintensification. it is likely that treatment of this condition will continue to evolve in the direction of deintensification, in order to minimize loss of function but maintain disease control. in the absence of specific clinical trials and guidelines, patient preferences need to be taken into consideration to minimise short- and long-term toxicity and functional loss and optimize quality of life, given the prolonged survival frequently seen. this may involve exploring patients' values regarding trade-offs of disease control against adverse effects of treatment. patients who have received crt as primary treatment for opc place a high value on survival, and although agreeing that deintensification is desirable, were reluctant to trade