The goals of treatment are to optimise survival and locoregional disease control, and prevent spread to distant areas of the body (metastasis), while minimising short- and long-term morbidity. There is no high quality Level I evidence from prospective clinical trials in<unk> +OPC, therefore treatment guidelines must rely on data from treatment of OPC in general and from some retrospective unplanned subsetting of those studies, together with data for head and neck<unk>  in general. Treatment for OPC has traditionally relied on radiotherapy, chemotherapy and/or other systemic treatments, and surgical resection. Depending on stage and other factors treatment may include a combination of modalities. The mainstay has been radiotherapy in most cases. a pooled analysis of published studies suggested comparable disease control between radiation and surgery, but higher complication rates for surgery +/- radiation. Ideally a single modality approach is preferred, since triple modality is associated with much more toxicity, and a multidisciplinary team in a large centre with high patient volumes is recommended. Differences in response to treatment between<unk> -OPC and<unk> +OPC may include differences in the extent and manner in which cellular growth-regulatory pathways are altered in the two forms of OPC. For instance in<unk> +OPC the<unk>  E6 and E7 oncogenes merely render the p53 and pRb pathways dormant, leaving open the possibility of reactivation of these pathways by down-regulating (reducing) expression of the oncogenes. This is in contrast to the mutant form of p53 found in<unk> -OPC that is associated with treatment resistance. Furthermore, it is suggested that the effects of E6 and E7 on these pathways renders the tumour more radiosensitive, possibly by interference with mechanisms such as DNA repair, repopulation signalling, and cell-cycle redistribution. The microenvironment is also important, with radiation increasing host immune response to viral antigens expressed on the tumour. Also, there is an association between an increase in tumour-infiltrating lymphocytes and in circulating white blood cells in<unk> +OPC patients and better prognosis. This implies a role for an adaptive immune system in suppressing tumour progression. Surgery Historically, surgery provided the single approach to head and neck<unk> . Surgical management of OPC carried significant morbidity with a transcervical (through the neck) approach, often involving mandibulotomy, in which the jawbone (mandible) is split. This is referred to as an open surgical technique. Consequently, surgical approaches declined in favour of radiation. In the United States, the use of surgery declined from 41% of cases in 1998 to 30% by 2009, the year that the Food and Drug Administration approved the use of the newer techniques. These improvements in surgical techniques have allowed many tumours to be resected (removed) by transoral (through the mouth) surgical approaches (TOS), using transoral endoscopic head and neck surgery (HNS). Consequently, surgery became used more, increasing to 35% of cases by 2012. This approach has proven safety, efficacy and tolerability, and includes two main minimally invasive techniques, transoral robotic surgery (TORS) and transoral laser microsurgery (TLM). No direct comparisons of these two techniques have been conducted, and clinical trials in head and neck<unk>  such as ECOG 3311 allow either. They are associated with substantial postoperative morbidity, depending on extent of resection but compared to older techniques have shorter hospital stay, faster recovery, less pain, and less need for gastrostomy or tracheostomy, and less long-term effects, which are minimal in the absence of postoperative radiation (RT), or chemoradiation (CRT). TORS has the practical advantage that angled telescopes and rotating robotic surgical arms provide better line of sight. Outcomes of minimally invasive procedures also compare favourably with more invasive ones. In early stage disease, including involvement of neck nodes, TORS produces a 2-year survival of 80–90%. TLM similarly, is reported to have a five-year survival of 78% and local control rates of 85–97%. In addition to early disease, minimally invasive surgery has been used in advanced cases, with up to 90% local control and disease specific survival. Postoperative swallowing was excellent in 87%, but long-term dysphagia was associated with larger (T4)<unk> s, especially if involving the base of the tongue. The details of the surgical approach depend on the location and size of the primary tumour and its N stage. Neck dissection to examine the draining lymph nodes may be carried out simultaneously or as a second staging procedure. For tumours of the tonsil and lateral pharyngeal wall, and clinically node negative (N0) disease, dissection of the neck typically involves levels 2–4 (see diagram in Dubner 2017) ipsilaterally. Where nodes are involved clinically, dissection will depend on the location and size of the node or nodes. In the case of tongue base primaries, close to the midline, bilateral dissection is recommended. Pathological staging An advantage of a primary surgical approach is the amount of pathological information made available, including grade, margin status, and degree of involvement of lymph nodes. This may change the staging, as up to 40% of patients may have a different postoperative pathological stage compared to their preoperative clinical stage. In one study, 24% had their stage reduced (downstaged), which may impact subsequent decision making, including reduction in intensity and morbidity. In the United Kingdom, the Royal College of Pathologists (1998) has standardised the reporting of surgical margins, with two categories, "mucosal" and "deep", and for each created groups based on the microscopic distance from invasive<unk>  to the margin, as follows: more than 5 mm (clear), 1–5 mm (close) and less than 1 mm (involved). Adjuvant postoperative therapy Data on the use of postoperative radiation therapy (PORT) is largely confined to historical or retrospective studies rather than high quality randomized clinical trials and are based on the overall population of patients with head and neck<unk> , rather than specific studies of<unk> +OPC, which would have formed a very small proportion of the population studied. Despite surgical excision, in the more advanced cases local and regional recurrence of the<unk> , together with spread outside of the head and neck region (metastases) are frequent. The risk of subsequent recurrent disease has been considered highest in those tumours where the pathology shows tumour at the margins of the resection<unk>  margins), multiple involved regional lymph nodes and extension of the tumour outside of the capsule of the lymph node (extracapsular extension), based on historical experience with head and neck<unk> . PORT was introduced in the 1950s in an attempt to reduce treatment failure from surgery alone. Although never tested in a controlled setting, PORT has been widely adopted for this purpose. In an analysis of surgical treatment failure at Memorial Sloan-Kettering<unk>  Center, patients treated with surgery alone between 1960–1970 had failure rates of 39 and 73% for those with negative and<unk>  surgical margins respectively. These were compared to those who received PORT (with or without chemotherapy) from 1975–1980. The latter group had lower failure rates of 2% and 11% respectively. In addition, one randomised study from the 1970s (RTOG 73-03) compared preoperative radiation to PORT, and found lower failure rates with the latter. The addition of another modality of treatment is referred to as adjuvant (literally helping) therapy, compared to its use as the initial (primary) therapy, also referred to as radical therapy. Consequently, many of these patients have been treated with adjuvant radiation, with or without chemotherapy. In the above series of reports of minimally invasive surgery, many (30–80%) patients received adjuvant radiation. However, functional outcomes were worse if radiation was added to surgery and worst if both radiation and chemotherapy were used. Radiation dosage has largely followed that derived for all head and neck<unk> s, in this setting, based on risk. Historically only one randomised clinical trial has addressed optimal dosage, allocated patients to two dosage levels, stratified by risk, but showed no difference in<unk>  control between the low and high doses (63 and 68.4 Gy), but a higher incidence of complications at the higher doses. Consequently, the lower dose of 57.6 Gy was recommended. Because the authors used a fractionation scheme of 1.8 Gy per treatment, this dosage was not widely adopted, practitioners preferring a larger fraction of 2 Gy to produce a shorter treatment time, and a slightly higher dose of 60 Gy in 2 Gy fractions (30 daily treatments). Yet 57.6 Gy in 1.8 Gy fractions is equivalent (iso-effective dose) to only 56 Gy in 2 Gy fractions. 60 Gy corresponds to the 63 Gy used as the low dose in the high risk group. 60 Gy was also the dose used in RTOG 73-03. Subsequently, there was a tendency to intensify treatment in head and neck<unk> , and a number of centres adopted a dose of 66 Gy, at least for those patients with adverse tumour features. The effectiveness of PORT in<unk> +OPC receives some support from a cohort study (Level 2b), although the number of patients was low, and the number of events (recurrent disease or death) only 7%. Another retrospective population-level study (Level 4) of the SEER database (1998–2011) concluded that there was an overall survival but not disease-specific survival effect of radiation in 410 patients with a single lymph
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