1. Signs and symptoms

2. Cause

3. Pathology
     Anatomy    Patterns of spread   Mechanism   Virology    Oncogenesis  

4. Diagnosis
     Staging  

5. Prevention

6. Treatment
     Surgery    Pathological staging    Adjuvant postoperative therapy    Deintensification    Radiotherapy    Dosimetry    Deintensification    Chemotherapy    Choice of treatment approach    Patient preferences    Carcinoma of unknown primary  

7. Prognosis

8. Epidemiology
     Trends  

9. See also

10. Notes

11. References

12. Bibliography
      Articles    Human Papilloma Virus (HPV) and molecular biology    Diagnosis and staging    Treatment    Surgery    Radiation    Chemotherapy and chemoradiation    Deintensification    Prognosis    Epidemiology    Books and conference proceedings    Chapters, monographs, reports and theses    Websites    Treatment guidelines  

13. External links

Human papillomavirus-positive oropharyngeal cancer (HPV+OPC) is a subtype of oropharyngeal squamous cell carcinomas (OSCC), associated with the human papillomavirus type 16 virus (HPV16). Historically, cancer of the throat oropharynx (throat) was associated with the use of alcohol and tobacco, but the majority of cases are now associated with the HPV virus. HPV+OPC differs in a number of respects from OPC not associated with HPV (HPV-OPC), and is considered a separate disease. HPV has long been associated with cancers in the anogenital region, but in 2007 it was also recognized as a cause of oropharyngeal cancer. HPV is common among healthy adults and is largely transmitted through sexual contact, but tobacco use increases the risk of cancer.

Detection of a tumour suppressor protein, known as p16, is commonly used to diagnose an HPV associated OPC. The extent of disease is described in the standard cancer staging system, using the AJCC TNM system, based on the T stage (size and extent of tumour), N stage (extent of involvement of regional lymph nodes) and M stage (whether there is spread of the disease outside the region or not), and combined into an overall stage from I–IV. In 2016, a separate staging system was developed for HPV+OPC, distinct from HPV-OPC.

The historical treatment of OPC was surgical, with an approach through the neck and splitting of the jaw bone, which resulted in a considerable risk of death. Later, radiotherapy with or without the addition of chemotherapy, provided a less invasive alternative, and the results in terms of treating the cancer, were comparable. Newer minimally invasive surgical techniques through the mouth have improved outcomes, and surgery is often followed by radiation and or chemotherapy in high risk cases. In the absence of high quality evidence, management decisions are often based on technical factors, likely functional loss and patient preferences. Some HPV+OPC may first appear in lymph nodes in the neck, without an obvious source (cancer of unknown primary origin) but removal of tonsil tissue from the oropharynx will often show hidden disease. The presence of HPV in the tumour is associated with a better response to treatment and a better outcome, independent of the treatment methods used and a nearly 60% reduced risk of dying from the cancer. Most recurrence occurs locally and within the first year after treatment. The use of tobacco decreases the chances of survival. While most head and neck cancer has been declining with reduced smoking rates, HPV+OPC has been increasing. Compared to HPV-OPC patients, HPV+OPC patients tend to be younger, have a higher socioeconomic status and are less likely to smoke. In addition they tend to have smaller tumours, but are more likely to have involvement of the cervical lymph nodes. In the United States and other countries, the number of cases of oropharyngeal cancer has been increasing steadily, with the incidence of HPV+OPC increasing faster than the decline in HPV-OPC. The increase is seen particularly in young men in developed countries, and HPV+OPC now accounts for the majority of all OPC cases.

Attempts are being made to reduce the incidence of HPV+OPC by introducing vaccination that includes HPV types 16 and 18, found in 95% of these cancers, prior to exposure to the virus. Early data suggest a reduction in infection rates.

Signs and symptoms

Like other cancers arising in the head and neck region, HPV+OPC may be an asymptomatic incidental finding of an abnormality in the mouth, by the patient or a health professional, present with local symptoms such as difficulties with speech, swallowing, and breathing as well as pain and infection, or as a swelling in the neck if the cancer has spread to lymph nodes there. These may be accompanied by more general symptoms such as loss of appetite, weight loss and weakness.{{sfn|Vokes et al|2015}}

Cause

Most mucosal squamous cell head and neck cancers, including oropharyngeal cancer (OPC), have historically been attributed to tobacco and alcohol use. However this pattern has changed considerably since the 1980s. It was realised that some cancers occur in the absence of these risk factors and

an association between human papilloma virus (HPV) and various squamous cell cancers, including OPC, was first described in 1983.{{sfn|Syrjänen et al|1983}}{{sfn|Mannarini|2009}} Since then both molecular and epidemiological evidence has been accumulating, with the International Agency for Research on Cancer (IARC) stating that high-risk HPV types 16 and 18 are carcinogenic in humans, in 1995,{{sfn|IARC| 1995}} and In 2007 that HPV was a cause for oral cancers.{{sfn|IARC| 2007}}{{sfn|Chaturvedi|Gillison|2010}} Human papillomavirus (HPV)-positive cancer (HPV+OPC) incidence has been increasing while HPV-negative (HPV-OPC) cancer incidence is declining, a trend that is estimated to increase further in coming years.{{sfn|Gillison et al|2000}} Since there are marked differences in clinical presentation and treatment relative to HPV status, HPV+OPC is now viewed as a distinct biologic and clinical condition.{{sfn|Westra|2009}}{{sfn|Lowy|Munger|2010}}{{sfn|Fundakowski|Lango|2016}}

Human HPV has long been implicated in the pathogenesis of several anogenital cancers including those of the anus, vulva, vagina, cervix, and penis.{{sfn|Ramqvist|Dalianis|2010}} In 2007 it was also implicated by both molecular and epidemiological evidence in cancers arising outside of the anogenital tract, namely oral cancers. HPV infection is common among healthy individuals, and is acquired largely through sexual contact. Although less data is available, prevalence of HPV infection is at least as common among men as among women, with 2004 estimates of about 27% among US women aged 14–59.{{sfn|Chaturvedi|Gillison|2010}}

HPV oral infection precedes the development of HPV+OPC.{{sfn|Chaturvedi|Gillison|2010}}{{sfn|Mannarini|2009}} Slight injuries in the mucous membrane serve as an entry gate for HPV, which thus works into the basal layer of the epithelium.{{sfn|Michl et al|2010}}{{sfn|Vidal | Gillison|2008}} People testing positive for HPV type 16 virus (HPV16) oral infection have a 14 times increased risk of developing HPV+OPC.{{sfn|Michl et al|2010}} Immunosuppression seems to be an increased risk factor for HPV+OPC.{{sfn|Mannarini|2009}} Individuals with TGF-β1 genetic variations, specially T869C, are more likely to have HPV16+OPC.{{sfn|Guan et al|2010}} TGF-β1 plays an important role in controlling the immune system. In 1993 it was noted that patients with human papillomavirus (HPV)-associated anogenital cancers had a 4-fold increased risk of tonsillar squamous-cell carcinoma.{{sfn|Frisch et al|1999}} Although evidence suggests that HPV16 is the main cause of OPC in humans not exposed to smoking and alcohol, the degree to which tobacco and/or alcohol use may contribute to increase the risk of HPV+OPC has not always been clear{{sfn|Mannarini|2009}} but it appears that both smoking and HPV infection are independent and additive risk factors for developing OPC.{{sfn|Anantharaman et al|2016}} The connection between HPV-infection and oropharyngeal cancer is stronger in regions of lymphoepithelial tissue (base of tongue and palatine tonsils) than in regions of stratified squamous epithelium (soft palate and uvula).^[1] Human herpesvirus-8 infection can potentiate the effects of HPV-16.{{sfn|Underbrink et al|2008}}

Risk factors include a high number of sexual partners (25% increase >= 6 partners), a history of oral-genital sex (125% >= 4 partners), or anal–oral sex, a female partner with a history of either an abnormal Pap smear or cervical dysplasia,{{sfn|Hemminki et al|2000}} chronic periodontitis,{{sfn|Tezal et al|2009}}{{sfn|Tezal et al|2009a}} and, among men, decreasing age at first intercourse and history of genital warts.{{sfn|Smith et al|2004}}{{sfn|Schwartz et al|1998}}{{sfn|D'Souza et al|2007}}{{sfn|Heck et al|2010}}

Pathology

Cancers of the oropharynx primarily arise in lingual and palatine tonsil lymphoid tissue that is lined by respiratory squamous mucosal epithelium, which may be invaginated within the lymphoid tissue. Therefore, the tumour first arises in hidden crypts. OPC is graded on the basis of the degree of squamous and keratin differentiation into well, moderate or poorly (high) differentiated grades. Other pathological features include the presence of finger-like invasion, perineural invasion, depth of invasion and distance of the tumour from resection margins. Phenotypic variants include basaloid squamous carcinoma, a high grade form (see Chung Fig. 35-3(C){{sfn|Chung et al|2016}} and illustration here). They are most commonly non-keratinising. HPV+OPC also differs from HPV-OPC in being focal rather than multifocal and not being associated with pre-malignant dysplasia. HPV+OPC patients are therefore at less risk of developing other malignancies in the head and neck region, unlike other head and neck primary tumours that may have associated second neoplasms, that may occur at the same time (synchronous) or a distant time (metachronous), both within the head and neck region or more distantly. This suggests that the oncogenic alterations produced by the virus are spatially limited rather than related to a field defect.{{sfn|Gillison|2006}}{{sfn|Chung et al|2016}}{{sfn|Martel et al|2017}}

Anatomy

The oropharynx, at the back of the mouth, forms a circle and includes the base of the tongue (posterior third) below, the tonsils on each side, and the soft palate above, together with the walls of the pharynx, including the anterior epiglottis, epiglottic valleculae and branchial cleft at its base. The oropharynx is one of three divisions of the interior of the pharynx based on their relation to adjacent structures (nasal pharynx (nasopharynx), oral pharynx (oropharynx) and laryngeal pharynx (laryngopharynx - also referred to as the hypopharynx), from top to bottom). The pharynx is a semicircular fibromuscular tube joining the nasal cavities above to the larynx (voice box) and oesophagus (gullet), below, where the larynx is situated in front of the oesophagus.{{sfn|Teach Me|2017}}

The oropharynx lies between the mouth (oral cavity) to the front, and the laryngopharynx below, which separates it from the larynx. The upper limit of the oropharynx is marked by the soft palate, and its lower limit by the epiglottis and root of the tongue. The oropharynx communicates with the mouth, in front through what is known as the oropharyngeal isthmus, or isthmus of the fauces. The isthmus (i.e. connection) is formed above by the soft palate, below by the posterior third of the tongue, and at the sides by the palatoglossal arches. The posterior third of the tongue, or tongue base contains numerous follicles of lymphatic tissue that form the lingual tonsils. Adjacent to the tongue base, the lingual surface of the epiglottis, which curves forward, is attached to the tongue by median and lateral glossoepiglottic folds. The folds form small troughs known as the epiglottic valleculae. The lateral walls are marked by two vertical pillars on each side, the pillars of the fauces, or palatoglossal arches. More properly they are separately named the palatoglossal arch anteriorly and the palatopharyngeal arch posteriorly. The anterior arch is named from the palatoglossal muscle within, running from the soft palate to the tongue (glossus), while the posterior arch similarly contains the palatopharyngeal muscle running from the soft palate to the lateral pharynx. Between the arches lies a triangular space, the tonsillar fossa in which lies the palatine tonsil, another lymphoid organ. {{sfn|Joshi et al|2013}}

The external pharyngeal walls consisting of the four constrictor muscles form part of the mechanism of swallowing. The microscopic anatomy is composed of four layers, being from the lumen outwards, the mucosa, submucosa, muscles and the fibrosa, or fibrous layer. The mucosa consists of stratified squamous epithelium, that is generally non-keratinised, except when exposed to chronic irritants such as tobacco smoke. The submucosa contains aggregates of lymphoid tissue.{{sfn|Joshi et al|2013}}{{sfn|McHanwell|2015}}

Patterns of spread

Cancers arising in the tonsillar fossa spread to the cervical lymph nodes, primarily the subdigastric (upper jugular) lymph nodes (level II), with secondary involvement of the mid (level III) and low (level IV) jugular nodes and sometimes the posterior cervical nodes (level V). Base of tongue cancers spread to the subdigastric and mid jugular nodes, and occasionally posterior cervical nodes but being closer to the midline are more likely to have bilateral nodal disease. Tonsillar cancers rarely spread to the contralateral side unless involving the midline.{{sfn|Lindberg|1972}}

Mechanism

Virology

HPV associated cancers are caused by high-risk strains of HPV, mainly HPV-16 and HPV-18.{{sfn|Ault|2006}} HPV is a small non-enveloped DNA virus of the papillomavirus family. Its genome encodes the early (E) oncoproteins E5, E6 and E7 and the late (L) capsid proteins L1 and L2. The virus gains access to the mucosa through microlesions, where it infects the basal layer of cells, which are still able to proliferate. While the virus does not replicate in these cells, expression of its early genes stimulates proliferation and lateral expansion of the basal cells. As this moves the virus particles into the overlying suprabasal layers, late viral gene expression occurs, enabling replication of the circular viral genome (see figure) and structural proteins. As these are pushed into the most superficial mucosal layers, complete viral particles are assembled and released.{{sfn|zur Hausen|2002}}

Oncogenesis

An increased risk of HPV+OPC is observed more than 15 years after HPV exposure,{{sfn|Chaturvedi|Gillison|2010}} pointing to a slow development of the disease, similar to that seen in cervical cancer. Relative to HPV-OPC, the oncogenic molecular progression of HPV+OPC is poorly understood.{{sfn|Chung et al|2016}} The two main viral oncoproteins of the high risk HPV types are E6 and E7. These are consistently expressed in malignant cell lines, and if their expression is inhibited the malignant phenotype of the cancer cells is blocked. Either of these oncoproteins can immortalise cell lines,{{sfn|Smeets et al|2010}} but are more efficient when both are expressed, since their separate molecular roles are synergistic.{{sfn|Ault|2006}}{{sfn|zur Hausen|2002}} The E6 and E7 oncogenes become integrated into host-cell DNA, and the oncoproteins they express interfere with a variety of predominantly antiproliferative cellular regulatory mechanisms. They bind to and inactivate the best known of these mechanisms, the tumor suppressor proteins p53 and retinoblastoma protein pRB (pRb) leading to genomic instability and then cell cycle deregulation (see Chung et al., 2016 Fig. 35.2).{{sfn|Chung et al|2016}} Further, yet to be elicited, mechanisms are required for the final steps of malignant transformation of HPV infected cells.{{sfn|Chung et al|2016}}

HPV- and HPV+OPC are distinguishable at the molecular level. The naturally occurring (wild type) p53 is widely involved in cellular processes, including autophagy, response to DNA damage, cell cycle regulation and senescence, apoptosis and the generation of adenosine triphosphate (ATP) through oxidative phosphorylation.{{sfn|Maslon|Hupp|2010}} The gene encoding p53 is inactivated by E6 at the protein level and is found as the wild type in HPV+OPC but mutated in HPV-OPC. In HPV+OPC p53 protein undergoes accelerated degradation by E6, drastically reducing its levels, while in HPV-OPC it undergoes genetic mutation, which may result in synthesis of an abnormal p53 protein, that may not only be inactive as a tumour suppressor, but can also bind and inactivate any non-mutated wild type p53, with an increase in oncogenic activity.{{sfn|Chung|Gillison|2009}} Although p53 mutations occur in HPV+OPC, they are far less common than in HPV-OPC (26% vs 48%), and do not appear to affect clinical outcome.{{sfn|Hong et al|2016}}

The pRb protein is inactivated by E7 in HPV+OPC, but in HPV-OPC it is the p16 tumour suppressor part of the pRb tumour suppressor network that is inactivated. Also the pRb pathway is inactivated by E7 instead of Cyclin D1 amplification.{{sfn|Chaturvedi|Gillison|2010}}{{sfn|An et al|2016}} CDKN2A is a tumour suppressor gene that encodes a tumor suppressor protein, p16 (cyclin-dependent kinase inhibitor 2A) and inhibits the kinase activity of the cyclin-dependant kinases CDK4 and CDK6, which in turn induce cell cycle arrest.{{sfn|Maslon|Hupp|2010}} p16 expression is cell cycle dependent and is expressed focally in only about 5–10% of normal squamous epithelium. Like most HPV+ cancers, HPV+OPC express p16 but the latter does not function as a tumour-suppressor, because the mechanism by which this is achieved, pRb, has been inactivated by E7. p16 is upregulated (over-expressed) due to E7-related loss of pRB with reduced negative feedback,{{sfn|Chung|Gillison|2009}}{{sfn|Lawrence et al|2015}} whereas it is downregulated in up to 90% of HPV-OPC.{{sfn|Ha|Califano|2006}} This diffuse over-expression in the tumour cells provides a diagnostic marker for HPV involvement.{{sfn|Marur et al|2010}}{{sfn|Hunt|2010}} Although HPV E6 and E7 reduce tumour suppressor activity, they do so less than genetic and epigenetic processes do in HPV-OPC.{{sfn|Howard|Chung|2012}}{{sfn|Licitra et al|2006}}{{sfn|Lowy|Munger|2010}}

The tonsillar epithelia (palatine and lingual) share similar nonkeratinization characteristics with the cervix, where HPV infection plays the major role in cases of cervical cancer.{{sfn|Michl et al|2010}}{{sfn|Salem|2010}} Also E6 and E7 may make HPV+OPC more immunogenic than HPV-OPC, since anti-E6 and E7 antibodies may be detected in these patients. This in turn could restrict the malignant behaviour of HPV+OPC and the presence of antibodies has been associated with a better prognosis, while treatment may enhance the immunogenicity of the tumour, and hence improve response, although to what extent is not clear.{{sfn|Spanos et al|2009}}{{sfn|Lowy|Munger|2010}} Outcomes are also associated with improved adaptive immunity.{{sfn|Wansom et al|2010}}

Diagnosis

Initial diagnosis requires visualisation of the tumour either through the mouth or endoscopically through the nose using a rhinoscope, illustrated here, followed by biopsy. HPV+OPC is usually diagnosed at a more advanced stage than HPV-OPC,{{sfn|Chaturvedi|Gillison|2010}} with 75–90% having involvement of regional lymph nodes.{{sfn|Sinha et al|2015}} Genetic signatures of HPV+ and HPV- OPC are different.{{sfn|Klussmann et al|2009}}{{sfn|Lohavanichbutr et al|2009}}{{sfn|Schlecht et al|2007}}{{sfn|Weinberger et al|2009}}{{sfn|Martinez et al|2007}} HPV+OPC is associated with expression level of the E6/E7 mRNAs and of p16.{{sfn|Jung et al|2009}} Nonkeratinizing squamous cell carcinoma strongly predicts HPV-association.{{sfn|Chernock et al| 2009}}{{sfn|Elmofty| Patil|2006}} HPV16 E6/E7-positive cases are histopathologically characterized by their verrucous or papillary (nipple like) structure and koilocytosis of the adjacent mucosa. Approximately 15% of HNSCCs are caused by HPV16 infection and the subsequent constitutive expression of E6 and E7, and some HPV-initiated tumors may lose their original characteristics during tumor progression.{{sfn|Yamakawa-Kakuta et al|2009}} High-risk HPV types may be associated with oral carcinoma, by cell-cycle control dysregulation, contributing to oral carcinogenesis and the overexpression of mdm2, p27 and cathepsin B.{{sfn|Cristina Mazon|2011}}

HPV+OPC is not merely characterized by the presence of HPV-16. Only the expression of viral oncogenes within the tumor cells plus the serum presence of E6 or E7 antibodies is unambiguously conclusive.{{sfn|Michl et al|2010}} There is not a standard HPV testing method in head and neck cancers,{{sfn|Robinson et al|2010}} both in situ hybridization (ISH) and polymerase chain reaction (PCR) are commonly used.{{sfn|Marur et al|2010}}{{sfn|Munck-Wikland|2010}} Both methods have comparable performance for HPV detection, however it is important to use appropriate sensitivity controls.{{sfn|Agoston et al|2010}} Immunohistochemistry (IHC) staining of the tissue for p16 is frequently used as a cost effective surrogate for HPV in OPC, compared to ISH or PCR{{sfn|Seiwert|2014}}{{sfn|O'Sullivan et al|2016}}{{sfn|NCCN|2018}} but there is a small incidence of HPV-negative p16-positive disease accounting for about 5% of HPV-OPC.{{sfn|Seiwert|2014}}

Staging

Staging is generally by the UICC/AJCC TNM (Tumour, Nodes, Metastases) system.{{sfn|NCCN|2018}} Staging is based on clinical examination, diagnostic imaging, and pathology. On imaging, involved lymph nodes may appear cystic, a characteristic of HPV+OPC.{{sfn|Goldenberg et al|2008}}

HPV+OPC has been treated similarly to stage-matched and site-matched HPV unrelated OPC, but its unique features, which contrast smoking-related HPV-OPC head and neck cancers, for which patients' demographics, comorbidities, risk factors, and carcinogenesis differ markedly, suggest that a distinct staging system be developed to more appropriately represent the severity of the disease and its prognosis.{{sfn|Porceddu|2016}} Standard AJCC TNM staging, such as the seventh edition (2009){{sfn|TNM 7|2010}} while predictive for HPV-OPC has no prognostic value in HPV+OPC.{{sfn|Keane et al|2015}}{{sfn|Huang et al|2015a}}{{sfn|O'Sullivan et al|2016}}{{sfn|Porceddu|2016}} The 8th edition of the AJCC TNM Staging Manual (2016){{sfn|TNM 8|2017}} incorporates this specific staging for HPV+OPC.{{sfn|Lydiatt et al|2017}} As of 2018, treatment guidelines are evolving to account for the different outcomes observed in HPV+OPC. Consequently, less intensive (de-intensification) use of radiotherapy or chemotherapy,{{sfn|Quon|Richmon|2012}} as well as specific therapy, is under investigation, enrolling HPV+OPC in clinical trials to preserve disease control and minimise morbidity in selected groups based on modified TNM staging and smoking status.{{sfn|Psyrri|2009}}{{sfn|Lassen|2010}}{{sfn|Fakhry|Gillison|2006}}{{sfn|Brockstein|Vokes|2011}}{{sfn|Givens et al|2009}}

HPV+ cancer of the oropharynx are staged as (AJCC 8th ed. 2016):{{sfn|Lydiatt et al|2017}}

Tumour stage

• T0 no primary identified
• T1 2 cm or less in greatest dimension
• T2 2–4 cm
• T3 >4 cm, or extension to lingual surface of epiglottis
• T4 moderately advanced local disease, invading larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible or beyond

Nodal stage

• Nx regional lymph nodes cannot be assessed
• N0 no regional lymph nodes involved
• N1 one or more ipsilateral nodes involved, less than 6 cm
• N2 contralateral or bilateral lymph nodes, less than 6 cm
• N3 lymph node(s) larger than 6 cm

Clinical stage

• Stage I: T0N1, T1–2N0–1
• Stage II: T0N2, T1–3N2, T3N0–2
• Stage III: T0–3N3, T4N0-3
• Stage IV: any metastases (M1)

However, the published literature and ongoing clinical trials use the older seventh edition that does not distinguish between HPV+OPC and HPV-OPC - see Oropharyngeal Cancer - Stages.{{sfn|NCI|2016}}{{sfn|NCI|2016a}} The T stages are essentially similar between AJCC 7 and AJCC 8. with two exceptions. Tis (carcinoma in situ) has been eliminated and the division of T4 into substages (e.g. T4a) has been removed. The major changes are in the N stages, and hence the overall clinical stage. N0 remains the same, but as with the T stage, substages such as N2a have been eliminated. Extracapsular extension (ECE), also referred to as extranodal extension (ENE), which is invasion by the tumour beyond the capsule of the lymph node has been eliminated as a staging criterion.{{efn|name=AJCC7|N stage, AJCC 7th ed.{{sfn|Lydiatt et al|2017}}
N1: one ipsilateral node involved, 3 cm or smaller, ECE negative (ECE-)
N2a: one ipsilateral node 3–6 cm, ECE-
N2b: more than one ipsilateral node, less than 6 cm, ECE-
N2c: bilateral nodes, less than 6 cm, ECE-
N3a: any lymph node larger than 6 cm, ECE-
N3b: any lymph node ECE+}}

This results in a HPV+OPC tumour being given a lower stage than if it were HPV-OPC. For instance, a 5 cm tumour with one ipsilateral node involved that is 5 cm in size but has ECE would be considered T3N3bM0 Stage IVB if HPV- but T3N1M0 Stage II if HPV+.{{sfn|Lydiatt et al|2017}}

Prevention

Prevention of HPV+OPC involves avoiding or reducing exposure to risk factors where possible. About 90% of HPV+OPC carry HPV 16, and another 5% type 18. These two types are both targets of available vaccines. HPV vaccines given prior to exposure can prevent persistent genital infection and the consequent precancerous state.{{sfn|Lowy|Munger|2010}} Therefore, they have a theoretical potential to prevent oral HPV infection.{{sfn|Chaturvedi|Gillison|2010}} A 2010 review study has found that HPV16 oral infection was rare (1.3%) among the 3,977 healthy subjects analyzed.{{sfn|Kreimer et al|2010}}

Treatment

The goals of care 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.{{sfn|Posner et al|2011}} There is no high quality Level I evidence from prospective clinical trials in HPV+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 cancer in general.{{sfn|NCCN|2018}} 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.{{sfn|Parsons et al|2002}} The mainstay has been radiotherapy in most cases.{{sfn|O'Sullivan et al|2016}} a pooled analysis of published studies suggested comparable disease control between radiation and surgery, but higher complication rates for surgery +/- radiation.{{sfn|Parsons et al|2002}}{{sfn|Bourhis et al|2006}} 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.{{sfn|NCCN|2018}}{{sfn|Corry et al|2015}}{{sfn|Fundakowski|Lango|2016}}

Differences in response to treatment between HPV-OPC and HPV+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 HPV+OPC the HPV 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 HPV-OPC that is associated with treatment resistance.{{sfn|Lowy|Munger|2010}} 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.{{sfn|Dok et al|2014}}{{sfn|Chen et al|2017}} The microenvironment is also important, with radiation increasing host immune response to viral antigens expressed on the tumour.{{sfn|Wansom et al|2010}}{{sfn|Spanos et al|2009}} Also, there is an association between an increase in tumour-infiltrating lymphocytes and in circulating white blood cells in HPV+OPC patients and better prognosis. This implies a role for an adaptive immune system in suppressing tumour progression.{{sfn|Huang et al|2015b}}{{sfn|Ward et al|2014}}{{sfn|Chen et al|2017}}

Surgery

Historically, surgery provided the single approach to head and neck cancer. 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.{{sfn|Routman et al|2017}}

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).{{sfn|Adelstein et al|2012}} Consequently surgery became used more, increasing to 35% of cases by 2012.{{sfn|Routman et al|2017}} This approach has proven safety, efficacy and tolerability, and includes two main minimally invasive techniques, transoral robotic surgery (TORS){{sfn|Cohen et al|2011}}{{sfn|Genden et al|2011}}{{sfn|White et al|2010}}{{sfn|Rinaldi|2013}}{{sfn|Weinstein et al|2012}}{{sfn|Chia et al|2013}} and transoral laser microsurgery (TLM).{{sfn|Rich et al|2009}}{{sfn|Moore|Hinni|2013}}{{sfn|Canis|2012}} No direct comparisons of these two techniques have been conducted, and clinical trials in head and neck cancer 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).{{sfn|Moore et al|2012}}{{sfn|Choby et al|2015}} 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%.{{sfn|Dowthwaite et al|2012}} TLM similarly, is reported to have a five-year survival of 78% and local control rates of 85–97%.{{sfn|Steiner et al|2003}}{{sfn|Haughey et al|2011}} In addition to early disease, minimally invasive surgery has been used in advanced cases, with up to 90% local control and disease specific survival.{{sfn|Cohen et al|2011}}{{sfn|Haughey et al|2011}} Postoperative swallowing was excellent in 87%, but long term dysphagia was associated with larger (T4) cancers, especially if involving the base of the tongue.{{sfn|Haughey et al|2011}} {{sfn|Fundakowski|Lango|2016}}

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.{{sfn|Fundakowski|Lango|2016}}

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.{{sfn|Walvekar et al|2008}}{{sfn|Fundakowski|Lango|2016}} In the United Kingdom, the Royal College of Pathologists (1998){{sfn|Helliwell|Woolgar|1998}}{{efn|Revised 3rd edition, 2013}} 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 cancer to the margin, as follows: more than 5 mm (clear), 1–5 mm (close) and less than 1 mm (involved).{{sfn|Woolgar|Triantafyllou|2005}}

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 cancer, rather than specific studies of HPV+OPC, which would have formed a very small proportion of the population studied.{{sfn|Fundakowski|Lango|2016}} Despite surgical excision, in the more advanced cases local and regional recurrence of the cancer, 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 (positive 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 cancer.{{sfn|Bernier et al|2004}} PORT was introduced in the 1950s in an attempt to reduce treatment failure from surgery alone.{{sfn|Maccomb|Fletcher|1957}} Although never tested in a controlled setting, PORT has been widely adopted for this purpose.{{sfn|Kramer et al|1987}} In an analysis of surgical treatment failure at Memorial Sloan-Kettering Cancer Center, patients treated with surgery alone between 1960–1970 had failure rates of 39 and 73% for those with negative and positive 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.{{sfn|Vikram et al|1984}} In addition, one randomised study from the 1970s (RTOG 73-03) compared preoperative radiation to PORT, and found lower failure rates with the latter.{{sfn|Kramer et al|1987}}{{sfn|Tupchong et al|1991}}

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.{{sfn|Fundakowski|Lango|2016}} Radiation dosage has largely followed that derived for all head and neck cancers, 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 cancer 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.{{sfn|Peters et al|1993}}{{sfn|Rosenthal et al|2017}} 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).{{sfn|An et al|2016}} Yet 57.6 Gy in 1.8 Gy fractions is equivalent (iso-effective dose) to only 56 Gy in 2 Gy fractions.{{sfn|ASTRO|2017}} 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 cancer, and a number of centres adopted a dose of 66 Gy, at least for those patients with adverse tumour features.{{sfn|Chin et al|2016}} The effectiveness of PORT in HPV+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%.{{sfn|Haughey|Sinha|2012}} 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 node involved, but used only univariate statistical analysis and contained no information on HPV status.{{sfn|Monroe et al|2017}} A subsequent much larger study on a similar population in the National Cancer Database (2004–2013) of over 9,000 patients found a survival advantage but this was only in HPV-OPC, not in 410 HPV+OPC patients,{{sfn|Olson|Clayburgh|2017}} and a subsequent study of 2,500 low and intermediate risk HPV+OPC patients showed similar overall survival whether PORT was given or not.{{sfn|Cramer et al|2018}}

Deintensification

While less studies have been completed examining deintensification (de-escalation) in this setting, than in primary radical radiation for this cancer (see below), it is an area of active investigation.{{sfn|Kelly et al|2016}} In one single institution study, a decision was made to reduce the radiation dose in high risk patients with HPV+OPC from 66 to 60 Gy, corresponding to the actual evidence, and follow up has shown no decrease in cancer control.{{sfn|Chin et al|2016}} Current trials, both in North America and Europe (such as ECOG 3311{{efn|ECOG 3311 (NCT01706939) was activated in 2013 and completed accrual of 511 patients and is now in follow up - see Talk }} and PATHOS{{efn|Planned accrual of 242 patients to PATHOS commenced in late 2014 - see Talk{{sfn|Owadally et al|2015}}}}) use 50 Gy as the comparison arm.{{sfn|Masterson et al|2014}} The comparator of 50 Gy was chosen on the grounds of (i) the exquisite sensitivity of HPV+OPC to radiation, both in vitro and in vivo; ECOG 1308 showing excellent disease control at 54 Gy; and data{{sfn|Bedi et al|2012}} suggesting that 50 Gy in 1.43 Gy (iso-effective dose 43 Gy in 2.0 Gy) was sufficient to electively treat the neck.{{sfn|Owadally et al|2015}} Other studies, such as MC1273 and DART-HPV have evaluated doses as low as 30–36 Gy.{{sfn|Ma et al|2017}} Lowering the radiation dose to 54 Gy was identified as one of the important Clinical Cancer Advances of 2018 by the

American Society of Clinical Oncology, under the general theme of "Less Is More: Preserving Quality of Life With Less

Treatment".{{sfn|Heymach et al|2018}}

Chemotherapy has been used concurrently with radiation in this setting, as in primary treatment with radical radiation, particularly where pathological features indicated a higher risk of cancer recurrence. A number of studies have suggested that this does not improve local control, although adding toxicity.{{sfn|Su et al|2016}}

Radiotherapy

Concerns over the morbidity associated with traditional open surgical en-bloc resection, led to exploring alternative approaches using radiation.{{sfn|Haughey|Sinha|2012}} Intensity modulated radiation therapy (IMRT) can provide good control of primary tumours while preserving excellent control rates, with reduced toxicity to salivary and pharyngeal structures relative to earlier technology. HPV+OPC has shown increased sensitivity to radiation with more rapid regression, compared to HPV-OPC.{{sfn|Chen et al|2013}} Generally, radiation can safely be delivered to the involved side alone (ipsilateral), due to the low rate of recurrent cancer on the opposite side (contralateral), and significantly less toxicity compared to bilateral treatment.{{efn|Contralteral recurrence after unilateral treatment has been reported in only 2.4% of cases{{sfn|Al-Mamgani et al|2017}}}}{{sfn|O’Sullivan et al|2001}}{{sfn|Al-Mamgani et al|2017}} IMRT has a two-year disease free survival between 82 and 90%, and a two-year disease specific survival up to 97% for stage I and II.{{sfn|Maxwell et al|2014}}{{sfn|Hunter et al|2013}}

Reported toxicities include dry mouth (xerostomia) from salivary gland damage, 18% (grade 2);{{efn|Adverse effects are usually reported as grades 0–5, where 0 represents none and 5 represents death, corresponding to 1. mild, 2. moderate, 3. severe and 4. life-threatening. These are standardised as the Common Terminology Criteria for Adverse Events (CTCAE){{sfn|CTCAE|2010}}}} difficulty swallowing (dysphagia) from damage to the constrictor muscles, larynx and oesophageal sphincter, 15% (grade 2); subclinical aspiration up to 50% (reported incidence of aspiration pneumonia approximately 14%); hypothyroidism 28–38% at three years (may be up to 55% depending on amount of the thyroid gland exposed to over 45 Gy radiation; esophageal stenosis 5%; osteonecrosis of the mandible 2.5%; and need for a gastrostomy tube to be placed at some point during or up to one year after treatment 4% (up to 16% with longer follow up).{{sfn|Fundakowski|Lango|2016}}{{sfn|Forastiere et al|2013}}{{sfn|Hunter et al|2013}}{{sfn|de Almeida et al|2014}}{{sfn|Al-Mamgani et al|2013}} Concerns have been expressed regarding excessive short and long term toxicity, especially dysphagia and xerostomia,{{sfn|Fu et al|2000}}{{sfn|Langendijk et al|2008}}{{sfn|Ang et al|2014}} and hence whether standard doses expose patients with better prognoses are being exposed to overtreatment and unnecessary side effects.{{sfn|Marur et al|2017}}{{sfn|Chen et al|2017}}

Dosimetry

The probability of xerostomia at one year increases by 5% for every 1Gy increase in dose to the parotid gland. Doses above 25–30 Gy are associated with moderate to severe xerostomia. Similar considerations apply to the submandibular gland, but xerostomia is less common if only one parotid gland is included in the radiated field{{sfn|Deasy et al|2010}} and the contralateral submandibular gland is spared (less than 39 Gy){{sfn|Robin et al|2016}} In the same manner, radiation dose to the pharyngeal constrictor muscles, larynx, and cricopharyngeal inlet determine the risk of dysphagia (and hence dependence on gastrostomy tube feeds). The threshold for this toxicity is volume-dependent at 55–60 Gy,{{sfn|Feng et al|2007}}{{sfn|Li et al|2009}}{{sfn|Caudell et al|2010}}{{sfn|Chen et al|2017}} with moderate to severe impairment of swallowing, including aspiration, stricture and feeding tube dependence above a mean dose of 47 Gy, with a recommended dose to the inferior constrictor of less than 41 Gy.{{sfn|Eisbruch et al|2004}}{{sfn|Vlacich et al|2014}} Dose-toxicity relationships for the superior and middle constrictors are steep, with a 20% increase in the probability of dysphagia for each 10 Gy.{{sfn|Levendag et al|2007}} For late dysphagia, threshold mean total constrictor doses, to limit rates of greater than or equal to grade 2 and 3 below 5% were 58 and 61 Gy respectively. For grade 2 dysphagia, the rate increased by 3.4% per Gy.{{sfn|Tsai et al|2017}} Doses above 30 Gy to the thyroid are associated with moderate to severe hypothyroidism.{{sfn|Diaz et al|2010}} Subjective, patient-reported outcomes of quality of life also correlate with radiation dose received.{{sfn|Langendijk et al|2008}}

Altered fractionation schemes, such as RTOG 9003 {{efn|RTOG 9003 - see Talk}}{{sfn|Fu et al|2000}} and RTOG 0129{{efn|RTOG0129 - see Talk}} have not conferred additional benefit.{{sfn|Beitler et al|2014}}{{sfn|Nguyen-Tan et al|2014}} Radiation dose recommendations were largely determined empirically in clinical studies with few HPV+OPC patients, and have remained unchanged for half a century,{{sfn|Chen et al|2017}} making it difficult to determine the optimum dose for this subgroup. A common approach uses 70 Gy bilaterally and anteriorly, such as RTOG 9003 (1991–1997){{sfn|Fu et al|2000}}{{sfn|Beitler et al|2014}} and RTOG 0129 (2002–2005).{{sfn|Ang et al|2010}}{{sfn|Nguyen-Tan et al|2014}} For lateralized tonsil cancer unilateral neck radiation is usually prescribed, but for tongue base primaries bilateral neck radiation is more common, but unilateral radiation may be used where tongue base lesions are lateralised.{{sfn|Fundakowski|Lango|2016}}

Deintensification

Concerns have been expressed regarding excessive short and long term toxicity, especially dysphagia and xerostomia,{{sfn|Fu et al|2000}}{{sfn|Langendijk et al|2008}}{{sfn|Ang et al|2014}} and hence whether standard doses expose patients with better prognoses to overtreatment and unnecessary side effects.{{sfn|Marur et al|2017}}{{sfn|Chen et al|2017}} Current toxicities have been described as "not tolerable",{{sfn|Bath|2017}} and hence an intense interest in de-escalation.{{sfn|Masterson et al|2014}}

While comparison with historical controls has limited value compared to randomised clinical trials (phase III), phase II studies using reduced doses of radiation compared to 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,{{sfn|Chen et al|2017}} when compared to similar studies, using 70 Gy, such as ECOG 2399.{{sfn|Cmelak et al|2007}}{{sfn|Fakhry et al|2008}} 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.{{sfn|Chen et al|2017}} A similar comparison can be made with the pooled data from two RTOG studies which utilized 70 Gy (0129 and 0522).{{sfn|Fakhry et al|2014}}

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 deintensified radiation of 54 Gy and concurrent cisplatin based chemotherapy.{{sfn|Woody et al|2016}} 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,{{sfn|Marur et al|2017}} and another study, a high pathological complete response rate at 60 Gy.{{sfn|Chera et al|2015}} The Quarterback trial{{efn|NCT01706939 - see Talk}} showed comparable outcomes between 56 and 70 Gy.{{sfn|Mirghani et al|2018}} and was followed by Quarterback 2, comparing 50 to 56 Gy.{{efn|NCT02945631 - see Talk}} Similarly, the Optima trial showed good disease control with doses between 45 and 50 Gy.{{sfn|Seiwert et al|2018}} Ongoing studies, following the experience of the Mayo Clinic trial (MC1273),{{sfn|Ma et al|2017}} such as that the Memorial Sloan Kettering Cancer Center are exploring doses as low as 30Gy.{{efn|NCT03323463 - see Talk}} 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.{{sfn|Fundakowski|Lango|2016}}

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.{{sfn|Fundakowski|Lango|2016}}

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.{{sfn|Blanchard et al|2011}}{{sfn|Pignon et al|2007}} Cisplatin is considered the standard agent, and a survival advantage was seen for those patients who received radiation with concurrent cisplatin.{{sfn|Adelstein et al|2003}} 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).{{sfn|Bonner et al|2010}} Cetuximab trials were completed prior to knowledge of HPV status.{{sfn|Szturz et al|2017}} 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, till RTOG 1016 (see Talk) addressed this question.{{sfn|Fundakowski|Lango|2016}}{{sfn|Mirghani et al|2018}} Analysis of the results three years after the trial was completed demonstrate that cetuximab is inferior to cisplatin.{{sfn|NIH|2018}} Concurrent chemotherapy is also superior to chemotherapy alone (induction chemotherapy) followed by radiation.{{sfn|Blanchard et al|2011}}{{sfn|Fundakowski|Lango|2016}} Cetuximab shows no advantage when added to cisplatin in combination with radiation.{{sfn|Ang et al|2014}} 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,{{sfn|Hall et al|2017}} and significant concerns about added toxicity.{{sfn|Hall et al|2015}}

Chemotherapy also has a role, combined with radiation, in the postoperative setting (adjuvant therapy).{{sfn|Bachaud et al|1996}} 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){{sfn|Bernier et al|2004}} and RTOG 9501 (1995–2000).{{efn|RTOG 9501 randomized 459 patients with head and neck cancer and any or all of the following high risk features identified on the basis of previous trials: histologic evidence of invasion of two or more regional lymph nodes, extracapsular extension of nodal disease, and microscopically involved mucosal resection margins, between radiation and chemoradiation with cisplatin postoperatively. At five years, locoregional control was improved with chemotherapy but adverse events were greater. Distant metastases were not affected. Longer follow up to ten years showed that these differences were only seen in two high risk subgroups, those with positive margins and those with extracapsular extension}}{{efn|:EORC 22931, also published in 2004, used a similar design but differing definition of high risk. It showed a similar early advantage for combined therapy}}{{efn|RTOG 9501 - see Talk}}{{sfn|Cooper et al|2004}}{{sfn|Cooper et al|2012}}{{sfn|Bernier et al|2005}} However, for HPV+OPC patients, such extracapsular spread does not appear to be an adverse factor{{sfn|Lewis et al|2011}}{{sfn|Sinha et al|2012}}{{sfn|Maxwell et al|2013}} and the addition of chemotherapy to radiation in this group provided no further advantage.{{sfn|Sinha et al|2012}} 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.{{efn|ADEPT - see Talk}} 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.{{sfn|Calais et al|2004}} Chemotherapy and radiation are associated with a risk of death of 3–4% in this context.{{sfn|Machtay et al|2008}} It is unclear whether the added toxicity of adding chemotherapy to radiation is offset by significant clinical benefit in disease control and survival.{{sfn|Fundakowski|Lango|2016}}

It is thought that HPV+OPC patients benefit better from radiotherapy and concurrent cetuximab treatment than HPV-OPC patients receiving the same treatment,{{sfn|Erikson et al|2010 }} and that radiation and cisplatin induce an immune response against an antigenic tumour which enhances their effect on the cancer cells.{{sfn|Spanos et al|2009}} 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.{{sfn|Szturz et al|2017}}

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.{{sfn|Fundakowski|Lango|2016}}

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 treted 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.{{sfn|Quon|Richmon|2012}}{{sfn|Fundakowski|Lango|2016}}

The cancer outcomes (local control, regional control, and survival) for transoral resection followed by adjuvant therapy are comparable to primary chemoradiation,{{sfn|Moore|Hinni|2013}}{{sfn|Rinaldi|2013}}{{sfn|de Almeida et al|2014}} 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).{{sfn|Fundakowski|Lango|2016}}{{efn|For instance ECOG 3311 stratifies HPV+OPC with AJCC 7 Stages III and IV 1-2, N1-2b into three risk groups postoperatively. Low risk is T1-T2 N0-N1 with negative margins. Intermediate risk is clear or close margins with the presence of adverse features on pathology such as perineural invasion or lymphovascular invasion, <1 mm ECE or 2–4 nodes involved. High risk is positive margins or greater than 1 mm ECE or at least 5 nodes involved.}}

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.{{sfn|Canis|2012}}{{sfn|Pollei|2013}}{{sfn|Weinstein et al|2012}}{{sfn|Chia et al|2013}} 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%.{{sfn|Haughey et al|2011}}{{sfn|Weinstein et al|2012}}{{sfn|Chia et al|2013}} Patients with larger tumours, involvement of base of tongue and requiring postoperative adjuvant therapy are more likely to require a long term feeding tube.{{sfn|Sinclair et al|2011}}{{sfn|Dziegielewski et al|2013}} Overall, function and quality of life appear relatively similar between surgery with postoperative radiation, and primary chemoradiation,{{sfn|More et al|2013}}{{sfn|Chen et al|2015}}{{sfn|Fundakowski|Lango|2016}} but HPV+OPC patients tend to have better quality of life at diagnosis than HPV-OPC but may sustain greater loss following treatment.{{sfn|Sharma et al|2012}}

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.{{sfn|Rich et al|2009}} 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.{{sfn|Moore|Hinni|2013}} 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.{{sfn|Moore et al|2009}}{{sfn|Moore et al|2009a}}{{sfn|Moore et al|2012a}}

Early stage disease{{efn|Early stage disease is considered as AJCC 7 as T1–22 N0–1 M0, approximately equivalent to T1–2 N0–2 M0 by AJCC 8}} 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.{{sfn|Fundakowski|Lango|2016}}

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.{{efn|Clinical trials, such as PARADIGM{{sfn|Haddad et al|2013}} and DeCIDE{{sfn|Cohen et al|2014}}}} 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.{{sfn|Fundakowski|Lango|2016}}

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.{{sfn|Mehanna et al|2016}} 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.{{sfn|Mirghani et al|2015}} 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.{{sfn|Fundakowski|Lango|2016}} 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 off much survival advantage for lower toxicity, though would be more likely to forgo chemotherapy than accept reduced radiation.{{sfn|Brotherston et al|2013}}

Carcinoma of unknown primary

In some situations HPV+OPC may present with cervical lymph nodes but no evident disease of a primary tumour (T0 N1-3) and is therefore classed as Squamous Cell Carcinoma of Unknown Primary Origin. The lack of any such evidence of a primary tumour occurs in 2-4% of patients presenting with metastatic cancer in the cervical nodes. The incidence of HPV positivity is increasing at a similar rate to that seen in OPC. In such situations, resection of the lingual and palatine tonsils, together with neck dissection may be diagnostic and constitute sufficient intervention, since recurrence rates are low.{{sfn|Durmus et al|2014}}{{sfn|Graboyes et al|2015}}{{sfn|Mehta et al|2013}}{{sfn|Patel et al|2013}}{{sfn|Galloway|Ridge|2015}}{{sfn|Fundakowski|Lango|2016}}

Prognosis

The presence of HPV within the tumour has been realised to be an important factor for predicting survival since the 1990s.{{sfn|Rischin et al|2010}} Tumor HPV status is strongly associated with positive therapeutic response and survival compared with HPV-negative cancer, independent of the treatment modality chosen and even after adjustment for stage.{{sfn|Mehanna|2016}} While HPV+OPC patients have a number of favourable demographic features compared to HPV-OPC patients, such differences account for only about ten per cent of the survival difference seen between the two groups.{{sfn|Lowy|Munger|2010}} Response rates of over 80% are reported in HPV+ cancer and three-year progression free survival has been reported as 75–82% and 45–57%, respectively, for HPV+ and HPV- cancer, and improving over increasing time.{{sfn|Fundakowski|Lango|2016}}{{sfn|Dayyani et al|2010}}{{sfn|de Jong et al|2010}}{{sfn|Ragin|Taioli|2007}} It is likely that HPV+OPC is inherently less malignant than HPV-OPC, since patients treated by surgery alone have a better survival after adjustment for stage.{{sfn|Lowy|Munger|2010}} In one study, less than 50% of patients with HPV-OPC were still alive after five years, compared to more than 70% with HPV+OPC and an equivalent stage and disease burden.{{sfn|Huang et al|2015a}}

In RTOG clinical trial 0129,{{efn|RTOG 0129 - see Talk}} in which all patients with advanced disease received radiation and chemotherapy, a retrospective analysis (recursive-partitioning analysis, or RPA) at three years identified three risk groups for survival (low, intermediate, and high) based on HPV status, smoking, T stage and N stage (see Ang et al., Fig. 2).{{sfn|Ang et al|2010}} HPV status was the major determinant of survival, followed by smoking history and stage. 64% were HPV+ and all were in the low and intermediate risk group, with all non-smoking HPV+ patients in the low risk group. 82% of the HPV+ patients were alive at three years compared to 57% of the HPV- patients, a 58% reduction in the risk of death.{{efn|In RTOG 0129 the three prognostic groups were;

• Low risk: HPV-, and had either less than 10 pack years of smoking, or more than 10 pack years but low nodal status (confined to a single node, >3 cm but ≤6 cm in greatest dimension)
• Intermediate risk: HPV+ with >10 pack year smoking and more advanced nodal status, or HPV-, <10 pack years and tumour stage T2–T3
• High risk: All others (including remainder of HPV-, <10 pack years with T4 tumours, and all with >10 pack years)}}{{sfn|Ang et al|2010}} Locoregional failure is also lower in HPV+, being 14% compared to 35% for HPV-.{{sfn|Fakhry et al|2008}} HPV positivity confers a 50–60% lower risk of disease progression and death, but the use of tobacco is an independently negative prognostic factor.{{sfn|Ang et al|2010}}{{sfn|Gillison et al|2012}} A pooled analysis of HPV+OPC and HPV-OPC patients with disease progression in RTOG trials 0129 and 0522 showed that although less HPV+OPC experienced disease progression (23 v. 40%), the median time to disease progression following treatment was similar (8 months). The majority (65%) of recurrences in both groups occurred within the first year after treatment and were locoregional. Although the rate of failure in the opposite neck following treatment of only one side, is 2.4%, the rate of an isolated recurrence in the opposite neck is 1.7%, and these were mainly where the primary tumour involved the midline. However the rate of failure in the contralateral neck is also greater for HPV+.{{sfn|Kato et al|2018}} Of those that recur in this site, nearly all were successfully treated (salvaged) by further local treatment to the opposite neck.{{sfn|Al-Mamgani et al|2017}}

HPV+ did not reduce the rate of metastases (about 45% of patients experiencing progression), which are predominantly to the lungs (70%), although some studies have reported a lower rate.{{sfn|Trosman et al|2015}}{{sfn|Fakhry et al|2014}} with 3-year distant recurrence rates of about 10% for patients treated with primary radiation or chemoradiation.{{sfn|O'Sullivan et al|2013}} Even if recurrence or metastases occur, HPV positivity still confers an advantage.{{sfn|Fundakowski|Lango|2016}}{{sfn|Trosman et al|2015}}{{sfn|Sinha et al|2014}}

By contrast tobacco usage is an independently negative prognostic factor, with decreased response to therapy,{{sfn|Ang et al|2010}}{{sfn|Gillison et al|2012}} increased disease recurrence rates and decreased survival.{{sfn|Maxwell et al|2010}} The negative effects of smoking, increases with amount smoked, particularly

if greater than 10 pack-years.{{sfn|Ang et al|2010}}{{sfn|Gillison et al|2012}} For patients such as those treated on RTOG 0129 with primary chemoradiation, detailed nomograms have been derived from that dataset combined with RTOG 0522, enabling prediction of outcome based on a large number of variables. For instance, a 71 year old married non-smoking high school graduate with a performance status (PS) of 0, and no weight loss or anaemia and a T3N1 HPV+OPC would expect to have a progression-free survival of 92% at 2 years and 88% at 5 years. A 60 year old unmarried nonsmoking high school graduate with a PS of 1, weight loss and anaemia and a T4N2 HPV+OPC would expect to have a survival of 70% at two years and 48% at five years.{{sfn|Fakhry et al|2017}} Less detailed information is available for those treated primarily with surgery, for whom less patients are available,{{sfn|Haughey|Sinha|2012}} as well as low rates of recurrence (7–10%), but features that have traditionally been useful in predicting prognosis in other head and neck cancers, appear to be less useful in HPV+OPC.{{sfn|Sinha et al|2015}} These patients are frequently stratified into three risk groups:{{sfn|Routman et al|2017}}

• Low risk: No adverse pathological features
• Intermediate risk: T3–T4 primary, perineural or lymphovascular invasion, N2 (AJCC 7){{efn|name=AJCC7}}
• High risk: Positive margins, ECE

HPV+OPC patients are less likely to develop other cancers, compared to other head and neck cancer patients.{{sfn|Martel et al|2017}} A possible explanation for the favourable impact of HPV+ is "the lower probability of occurrence of 11q13 gene amplification, which is considered to be a factor underlying faster and more frequent recurrence of the disease"{{sfn|Michl et al|2010}} Presence of TP53 mutations, a marker for HPV- OPC, is associated with worse prognosis.{{sfn|Chaturvedi|Gillison|2010}} High grade of p16 staining is thought to be better than HPV PCR analysis in predicting radiotherapy response.{{sfn|Munck-Wikland|2010}}

The risk of regional cancer recurrence after neck dissection is often estimated{{sfn|Mirghani et al|2018}} from a large series based on all upper aerodigestive squamous cell cancers. In this series, the overall risks at three years by pathological stage (AJCC 7) were:{{sfn|Ambrosch et al|2001}}

• pN0 4.7%
• pN1 4.9%
• pN2 12.1%

Epidemiology

In 2015, squamous cell cancer of the head and neck region was the fifth most common cancer other than skin cancer, globally, with an annual incidence of 600,000 cases and about 60,000 cases annually in the United States and Europe.{{sfn|Siegel et al|2015}} The global incidence of pharyngeal cancer in 2013 was estimated at 136,000 cases.{{sfn|Fundakowski|Lango|2016}}{{sfn|Myers|Sturgis|2013}}{{sfn|Chaturvedi et al|2013}} For 2008 the Global Burden of Disease for OPC in 2008 is estimated at 85,000 cases, of which 22,000 were attributable to HPV, a population attributable fraction (PAF) of 26%. Of these, 17,000 were males and 4,400 females, 13,000 (60%) were aged between 50 and 69 years of age, and the majority of cases (15,000) were in developed regions compared to developing regions (6,400).{{sfn|de Martel et al|2017}}{{sfn|Forman et al|2012}} Age Standardised Incidence Rates (ASR) differ considerably by region and country (see de Martel et al., 2017 Fig. 2b).{{sfn|de Martel et al|2017}} ASRs for 2012 were highest in Europe (Hungary 3.0) and North America (United States 1.7) but much lower in Africa (≤ 0.3), Asia (≤ 0.6), Latin America (≤ 0.4) and Oceania (≤ 0.2) (other than Australasia, Australia 0.9).{{sfn|Johnson|Chaturvedi|2016}}{{sfn|de Martel et al|2017}} Estimated average numbers of cases and ASR for the US in the period 2008–2012 were 15,738 and 4.5 respectively. HPV+OPC was much more common in males than females (12,638, 7.6 and 3,100, 1.7). The highest incidence age group was 60–69, and was higher in Caucasians than in other races.{{sfn|Viens et al|2016}}

HPV+OPC patients tend to be younger than HPV- patients in general.{{sfn|Lajer et al|2010 }} The clinical presentation is also changing from the “typical” head and neck cancer patient with advanced age and major substance usage.{{sfn|Fundakowski|Lango|2016}} By contrast patients with HPV+ cancer are younger (4th–6th decades), male (ratio 8:1) with no or only a minimum history of smoking, generally Caucasian, reached higher education levels, are married, and have higher income.{{sfn|Chaturvedi et al|2011}} The risk factors for HPV-OPC and HPV+OPC tend to be independent, with the exception of smoking which has an adverse effect on both.{{sfn|Lowy|Munger|2010}} The presenting features are also different between HPV+ and HPV- OPC. HPV+ tumours have smaller primary lesions (less than 4 cm) but more advanced nodal disease resulting in higher TNM staging. This in turn may overestimate the severity of the disease status.{{sfn|Fischer et al|2010}}{{sfn|Hafkamp et al|2008}}

Trends

There has been a global trend in increasing OPC incidence, particularly in North America and northern Europe, but even in Taiwan, which has a very high rate for all cancers of the head and neck region, OPC rates increased increased more rapidly between 1995 and 2009 than any other cancer site.{{sfn|Hwang et al|2015}}{{sfn|Gillison et al|2015}} The Global Burden of HPV+OPC increased from 22,000 in 2008 to 29,000 by 2012, and the PAF from 26% to 31%,{{sfn|de Martel et al|2017}} and is considered an epidemic.{{sfn|Marur et al|2010}} In the United States the estimated number of cases was 12,410 in 2008,{{sfn|Jemal et al|2008}} 13,930 in 2013{{sfn|Siegel et al|2013}} and 17,000 for 2017.{{sfn|Siegel et al|2017}} Of these cases, HPV+ cancer has been increasing compared to HPV- cancer, but the increase in HPV+OPC exceeds the decline in HPV-OPC resulting an overall increase in OPC.{{sfn|Lowy|Munger|2010}} The rise in pharyngeal cancer incidence contrasts with a marginal decline in other head and neck cancers.{{sfn|Mehanna et al|2010}} As a result, the commonest head and neck cancer has shifted from larynx to oropharynx.{{sfn|Haughey|Sinha|2012}} A survey of 23 countries between 1983 and 2002 showed an increase in oropharyngeal squamous cell carcinoma that was particularly noticeable in young men in economically developed countries.{{sfn|Chaturvedi et al|2013}}{{sfn|Fundakowski|Lango|2016}} In the United Kingdom the incidence of oral and oropharyngeal cancer in men rose 51%, from 7/100,000 to 11/100,000 between 1989 and 2006.{{sfn|Mehanna et al|2010}} In the US there is a growing incidence of HPV associated oropharyngeal cancers,{{sfn|Chenevert|Chiosea|2012}} In the early 1980s HPV+ accounted for only 7.5% of cases in the US but by 2016 this was 70%,{{sfn|Fundakowski|Lango|2016}}{{sfn|Sturgis|Cinciripini|2007}}{{sfn|Ernster et al|2007}}{{sfn| Hammarstedt et al|2006}} perhaps as a result of changing sexual behaviors, decreased popularity of tonsillectomies, improved radiologic and pathologic evaluation, and changes in classification.{{sfn|Chenevert et al|2012}}{{sfn|Chaturvedi et al|2008}}{{sfn|Nguyen et al|2009}} Tonsil and oropharyngeal cancers increased in male predominance between 1975 and 2004, despite reductions in smoking.{{sfn|Cook et al|2009}} HPV-OPC decreased with decreasing smoking rates from 1988 to 2004, while HPV+OPC increased by almost 7.5% per year from about 16% of all cases of OPC in the early 1980s to almost 70% in 2004.{{sfn|Chaturvedi et al|2011}}{{sfn|Sturgis|Ang|2011}} The decline in smoking may be linked to the decreasing proportion of HPV negative cancers, while changes in sexual activity may be reflected in increasing proportion of HPV positive cancers.{{sfn|Chaturvedi et al|2011}} Recently, in the US, HPV associated OPC represent about 60% of OPC cases{{sfn|Fakhry et al|2008}}{{sfn|Adelstein|Rodriguez|2010}} compared with 40% in the previous decade.{{sfn|Mehanna et al|2010}} By 2007, in the US, incidence of general OPC, including non-HPV associated, is 3.2 cases per 100,000 males/year and 1.9 per 100,000 all-sexes/year.{{sfn|SEER|2010}} This makes HPV+OPC one of only five cancers that have increased in incidence in the US since 1975.{{sfn|Wirth|2016}} The largest increase in incidence has occurred in patients under age 50.{{sfn|Nguyen et al|2010}}

The increase in incidence of HPV associated OPC is also seen in other countries, like Sweden, with a 2007 incidence of over 80% for cancer in the tonsils,{{sfn|Nasman et al|2009}}{{sfn|Hammarstedt|2008}} Finland{{sfn|Syrjänen|2004}} and the Czech Republic.{{sfn|Tachezy|2005}} Partners of patients with HPV positive oropharyngeal cancer do not seem to have elevated oral HPV infection compared with the general population.{{sfn|D'Souza et al|2014}} In Australia the incidence of HPV associated OPC was 1.56 cases per 100,000 males/year (2001–2005), rising from 19% (1987–90), to 47% (2001–05) and 63.5% (2006–2010).{{sfn|Hong et al|2010}}{{sfn|Hong et al|2016}} In Canada the percentage of cases of OPC attributable to HPV increased from 47% in 2000 to 74% in 2012.{{sfn|Habbous et al|2017}}

See also

• Cancer
• Head and neck cancer
• Oropharyngeal cancer
• Human papilloma virus
• HPV-associated oropharyngeal cancer awareness and prevention

Notes

References

Bibliography

Articles

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Diagnosis and staging

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• {{cite journal |last1=Goldenberg |first1=David |last2=Begum |first2=Shahnaz |last3=Westra |first3=William H. |last4=Khan |first4=Zubair |last5=Sciubba |first5=James |last6=Pai |first6=Sara I. |last7=Califano |first7=Joseph A. |last8=Tufano |first8=Ralph P. |last9=Koch |first9=Wayne M. |title=Cystic lymph node metastasis in patients with head and neck cancer: An HPV-associated phenomenon |url=http://www.sbccp.org.br/arquivos/HN_07-2008_cystic_lymph_node_metastasis.pdf|journal=Head & Neck |date=July 2008 |volume=30 |issue=7 |pages=898–903 |doi=10.1002/hed.20796|pmid=18383529 |ref={{harvid|Goldenberg et al|2008}}}}
• {{cite journal|last1=Huang|first1=Shao Hui|last2=Xu|first2=Wei|last3=Waldron|first3=John|last4=Siu|first4=Lillian|last5=Shen|first5=Xiaowei|last6=Tong|first6=Li|last7=Ringash|first7=Jolie|last8=Bayley|first8=Andrew|last9=Kim|first9=John|last10=Hope|first10=Andrew|last11=Cho|first11=John|last12=Giuliani|first12=Meredith|last13=Hansen|first13=Aaron|last14=Irish|first14=Jonathan|last15=Gilbert|first15=Ralph|last16=Gullane|first16=Patrick|last17=Perez-Ordonez|first17=Bayardo|last18=Weinreb|first18=Ilan|last19=Liu|first19=Fei-Fei|last20=O'Sullivan|first20=Brian|display-authors=3|title=Refining American Joint Committee on Cancer/Union for International Cancer Control TNM Stage and Prognostic Groups for Human Papillomavirus–Related Oropharyngeal Carcinomas|journal=Journal of Clinical Oncology|date=10 March 2015|volume=33|issue=8|pages=836–845|doi=10.1200/JCO.2014.58.6412|pmid=25667292|ref={{harvid|Huang et al|2015a}}}}
• {{cite journal|last1=Keane|first1=Florence K.|last2=Chen|first2=Yui-Hui|last3=Neville|first3=Bridget A.|last4=Tishler|first4=Roy B.|last5=Schoenfeld|first5=Jonathan D.|last6=Catalano|first6=Paul J.|last7=Margalit|first7=Danielle N.|title=Changing prognostic significance of tumor stage and nodal stage in patients with squamous cell carcinoma of the oropharynx in the human papillomavirus era|journal=Cancer|date=1 August 2015|volume=121|issue=15|pages=2594–2602|doi=10.1002/cncr.29402|pmid=25873094|ref={{harvid|Keane et al|2015}}}}
• {{cite journal|last1=Lydiatt|first1=William M.|last2=Patel|first2=Snehal G.|last3=O'Sullivan|first3=Brian|last4=Brandwein|first4=Margaret S.|last5=Ridge|first5=John A.|last6=Migliacci|first6=Jocelyn C.|last7=Loomis|first7=Ashley M.|last8=Shah|first8=Jatin P.|title=Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual|journal=CA: A Cancer Journal for Clinicians|date=March 2017|volume=67|issue=2|pages=122–137|doi=10.3322/caac.21389|pmid=28128848|ref={{harvid|Lydiatt et al|2017}}}}
• {{cite journal|last1=O'Sullivan|first1=Brian|last2=Huang|first2=Shao Hui|last3=Su|first3=Jie|last4=Garden|first4=Adam S|last5=Sturgis|first5=Erich M|last6=Dahlstrom|first6=Kristina|last7=Lee|first7=Nancy|last8=Riaz|first8=Nadeem|last9=Pei|first9=Xin|last10=Koyfman|first10=Shlomo A|last11=Adelstein|first11=David|last12=Burkey|first12=Brian B|last13=Friborg|first13=Jeppe|last14=Kristensen|first14=Claus A|last15=Gothelf|first15=Anita B|last16=Hoebers|first16=Frank|last17=Kremer|first17=Bernd|last18=Speel|first18=Ernst-Jan|last19=Bowles|first19=Daniel W|last20=Raben|first20=David|last21=Karam|first21=Sana D|last22=Yu|first22=Eugene|last23=Xu|first23=Wei|display-authors=3|title=Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study|journal=The Lancet Oncology|date=April 2016|volume=17|issue=4|pages=440–451|doi=10.1016/S1470-2045(15)00560-4|pmid=26936027|ref={{harvid|O'Sullivan et al|2016}}}}
• {{cite journal|last1=Porceddu|first1=Sandro V|title=A TNM classification for HPV+ oropharyngeal cancer|journal=The Lancet Oncology|date=April 2016|volume=17|issue=4|pages=403–404|doi=10.1016/S1470-2045(15)00611-7|pmid=26936026|type=Editorial|ref=harv}}

Treatment

• {{cite journal|last1=Brockstein|first1=Bruce E.|last2=Vokes|first2=Everett E.|title=Head and neck cancer in 2010: Maximizing survival and minimizing toxicity|journal=Nature Reviews Clinical Oncology|date=February 2011|volume=8|issue=2|pages=72–74|doi=10.1038/nrclinonc.2010.226|pmid=21278773|ref=harv}}
• {{cite journal|last1=Corry|first1=June|last2=Peters|first2=Lester J.|last3=Rischin|first3=Danny|title=Impact of Center Size and Experience on Outcomes in Head and Neck Cancer|journal=Journal of Clinical Oncology|date=10 January 2015|volume=33|issue=2|pages=138–140|doi=10.1200/JCO.2014.58.2239|pmid=25488964|ref={{harvid|Corry et al|2015}}}}
• {{Cite journal| last1 = Fakhry | first1 = C.| last2 = Westra | first2 = W.| last3 = Li | first3 = S.| last4 = Cmelak | first4 = A.| last5 = Ridge | first5 = J.| last6 = Pinto | first6 = H.| last7 = Forastiere | first7 = A.| last8 = Gillison | first8 = M.| title = Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial| url = http://jnci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18270337| journal = Journal of the National Cancer Institute| volume = 100| issue = 4| pages = 261–269| date=Feb 2008 | issn = 0027-8874| pmid = 18270337 | doi = 10.1093/jnci/djn011|ref={{harvid|Fakhry et al|2008}} }}
• {{cite journal|last1=Fakhry|first1=Carole|last2=Zhang|first2=Qiang|last3=Nguyen-Tan|first3=Phuc Felix|last4=Rosenthal|first4=David|last5=El-Naggar|first5=Adel|last6=Garden|first6=Adam S.|last7=Soulieres|first7=Denis|last8=Trotti|first8=Andy|last9=Avizonis|first9=Vilija|last10=Ridge|first10=John Andrew|last11=Harris|first11=Jonathan|last12=Le|first12=Quynh-Thu|last13=Gillison|first13=Maura|display-authors=3|title=Human Papillomavirus and Overall Survival After Progression of Oropharyngeal Squamous Cell Carcinoma|journal=Journal of Clinical Oncology|date=20 October 2014|volume=32|issue=30|pages=3365–3373|doi=10.1200/JCO.2014.55.1937|pmid=24958820|pmc=4195851|ref={{harvid|Fakhry et al|2014}}}}
• {{cite journal|last1=Fundakowski|first1=Christopher E.|last2=Lango|first2=Miriam|title=Considerations in surgical versus non-surgical management of HPV positive oropharyngeal cancer|journal=Cancers of the Head & Neck|date=11 July 2016|volume=1|issue=1|doi=10.1186/s41199-016-0007-8|type=Review|ref=harv}}
• {{cite journal|last1=Galloway|first1=TJ|last2=Ridge|first2=JA|title=Management of Squamous Cancer Metastatic to Cervical Nodes With an Unknown Primary Site|journal=Journal of Clinical Oncology|date=10 October 2015|volume=33|issue=29|pages=3328–3337|doi=10.1200/JCO.2015.61.0063|pmid=26351351|type=Review|ref=harv|citeseerx=10.1.1.1029.7347}}
• {{cite journal|last1=Maxwell|first1=Jessica H.|last2=Mehta|first2=Vikas|last3=Wang|first3=Hong|last4=Cunningham|first4=Diana|last5=Duvvuri|first5=Umamaheswar|last6=Kim|first6=Seungwon|last7=Johnson|first7=Jonas|last8=Ferris|first8=Robert L.|title=Quality of life in head and neck cancer patients: Impact of HPV and primary treatment modality|journal=The Laryngoscope|date=July 2014|volume=124|issue=7|pages=1592–1597|doi=10.1002/lary.24508|pmid=24353066|ref={{harvid|Maxwell et al|2014}}}}
• {{cite journal|last1=Mehanna|first1=H|last2=Evans|first2=M|last3=Beasley|first3=M|last4=Chatterjee|first4=S|last5=Dilkes|first5=M|last6=Homer|first6=J|last7=O'Hara|first7=J|last8=Robinson|first8=M|last9=Shaw|first9=R|last10=Sloan|first10=P|title=Oropharyngeal cancer: United Kingdom National Multidisciplinary Guidelines|journal=The Journal of Laryngology & Otology|date=12 May 2016|volume=130|issue=S2|pages=S90–S96|doi=10.1017/S0022215116000505|pmid=27841123|pmc=4873902|ref={{harvid|Mehanna et al|2016}}}}
• {{cite journal|last1=More|first1=Yogesh I.|last2=Tsue|first2=Terance T.|last3=Girod|first3=Douglas A.|last4=Harbison|first4=John|last5=Sykes|first5=Kevin J.|last6=Williams|first6=Carson|last7=Shnayder|first7=Yelizaveta|title=Functional Swallowing Outcomes Following Transoral Robotic Surgery vs Primary Chemoradiotherapy in Patients With Advanced-Stage Oropharynx and Supraglottis Cancers|journal=JAMA Otolaryngology–Head & Neck Surgery|date=1 January 2013|volume=139|issue=1|pages=43–8|doi=10.1001/jamaoto.2013.1074|pmid=23247974|ref={{harvid|More et al|2013}}}}
• {{cite journal|last1=Sharma|first1=Arun|last2=Méndez|first2=Eduardo|last3=Yueh|first3=Bevan|last4=Lohavanichbutr|first4=Pawadee|last5=Houck|first5=John|last6=Doody|first6=David R.|last7=Futran|first7=Neal D.|last8=Upton|first8=Melissa P.|last9=Schwartz|first9=Stephen M.|last10=Chen|first10=Chu|title=Human Papillomavirus–Positive Oral Cavity and Oropharyngeal Cancer Patients Do Not Have Better Quality-of-Life Trajectories|journal=Otolaryngology–Head and Neck Surgery|date=24 January 2012|volume=146|issue=5|pages=739–745|doi=10.1177/0194599811434707|pmid=22275190|pmc=3535430|ref={{harvid|Sharma et al|2012}}}}
• {{cite journal|last1=Spanos|first1=William C.|last2=Nowicki|first2=Paul|last3=Lee|first3=Dong Wook|last4=Hoover|first4=Andrew|last5=Hostager|first5=Bruce|last6=Gupta|first6=Anjali|last7=Anderson|first7=Mary E.|last8=Lee|first8=John H.|title=Immune Response During Therapy With Cisplatin or Radiation for Human Papillomavirus–Related Head and Neck Cancer|journal=Archives of Otolaryngology–Head & Neck Surgery|date=1 November 2009|volume=135|issue=11|pages=1137–46|doi=10.1001/archoto.2009.159|pmid=19917928|ref={{harvid|Spanos et al|2009}}}}
• {{cite journal|last1=Wansom|first1=Derrick|last2=Light|first2=Emily|last3=Worden|first3=Frank|last4=Prince|first4=Mark|last5=Urba|first5=Susan|last6=Chepeha|first6=Douglas B.|last7=Cordell|first7=Kitrina|last8=Eisbruch|first8=Avraham|last9=Taylor|first9=Jeremy|last10=D’Silva|first10=Nisha|last11=Moyer|first11=Jeffrey|last12=Bradford|first12=Carol R.|last13=Kurnit|first13=David|last14=Kumar|first14=Bhavna|last15=Carey|first15=Thomas E.|last16=Wolf|first16=Gregory T.|display-authors=3|title=Correlation of Cellular Immunity With Human Papillomavirus 16 Status and Outcome in Patients With Advanced Oropharyngeal Cancer|journal=Archives of Otolaryngology–Head & Neck Surgery|date=20 December 2010|volume=136|issue=12|pages=1267–73|doi=10.1001/archoto.2010.211|pmc=3342998|ref={{harvid|Wansom et al|2010}}|pmid=21173378}}

Surgery

• {{cite journal|last1=Adelstein|first1=David J.|last2=Ridge|first2=John A.|last3=Brizel|first3=David M.|last4=Holsinger|first4=F. Christopher|last5=Haughey|first5=Bruce H.|last6=O'Sullivan|first6=Brian|last7=Genden|first7=Eric M.|last8=Beitler|first8=Jonathan J.|last9=Weinstein|first9=Gregory S.|last10=Quon|first10=Harry|last11=Chepeha|first11=Douglas B.|last12=Ferris|first12=Robert L.|last13=Weber|first13=Randal S.|last14=Movsas|first14=Benjamin|last15=Waldron|first15=John|last16=Lowe|first16=Val|last17=Ramsey|first17=Scott|last18=Manola|first18=Judith|last19=Yueh|first19=Bevan|last20=Carey|first20=Thomas E.|last21=Bekelman|first21=Justin E.|last22=Konski|first22=Andre A.|last23=Moore|first23=Eric|last24=Forastiere|first24=Arlene|last25=Schuller|first25=David E.|last26=Lynn|first26=Jean|last27=Ullmann|first27=Claudio Dansky|display-authors=3|title=Transoral resection of pharyngeal cancer: Summary of a National Cancer Institute Head and Neck Cancer Steering Committee Clinical Trials Planning Meeting, November 6-7, 2011, Arlington, Virginia|journal=Head & Neck|date=December 2012|volume=34|issue=12|pages=1681–1703|doi=10.1002/hed.23136|pmid=23015475|ref={{harvid|Adelstein et al|2012}}}}
• {{cite journal|last1=de Almeida|first1=John R.|last2=Byrd|first2=James K.|last3=Wu|first3=Rebecca|last4=Stucken|first4=Chaz L.|last5=Duvvuri|first5=Uma|last6=Goldstein|first6=David P.|last7=Miles|first7=Brett A.|last8=Teng|first8=Marita S.|last9=Gupta|first9=Vishal|last10=Genden|first10=Eric M.|title=A systematic review of transoral robotic surgery and radiotherapy for early oropharynx cancer: A systematic review|journal=The Laryngoscope|date=September 2014|volume=124|issue=9|pages=2096–2102|doi=10.1002/lary.24712|pmid=24729006|ref={{harvid|de Almeida et al|2014}}}}
• {{cite journal |last1=Ambrosch |first1=Petra |last2=Kron |first2=Martina |last3=Pradier |first3=O. |last4=Steiner |first4=W. |title=Efficacy of Selective Neck Dissection: A Review of 503 Cases of Elective and Therapeutic Treatment of the Neck in Squamous Cell Carcinoma of the Upper Aerodigestive Tract |journal=Otolaryngology–Head and Neck Surgery |date=2001 |volume=124 |issue=2 |pages=180–187 |doi=10.1067/mhn.2001.111598|pmid=11226954 |ref={{harvid|Ambrosch et al|2001}}}}
• {{cite journal|last1=Canis|first1=Martin|last2=Martin|first2=Alexios|last3=Kron|first3=Martina|last4=Konstantinou|first4=Alexandra|last5=Ihler|first5=Friedrich|last6=Wolff|first6=Hendrik A.|last7=Matthias|first7=Christoph|last8=Steiner|first8=Wolfgang|title=Results of transoral laser microsurgery in 102 patients with squamous cell carcinoma of the tonsil|journal=European Archives of Oto-Rhino-Laryngology|date=29 December 2012|volume=270|issue=8|pages=2299–2306|doi=10.1007/s00405-012-2335-6|pmid=23274878|pmc=3699702|ref={{harvid|Canis|2012}}}}
• {{cite journal|last1=Chen|first1=Allen M.|last2=Daly|first2=Megan E.|last3=Luu|first3=Quang|last4=Donald|first4=Paul J.|last5=Farwell|first5=D. Gregory|title=Comparison of functional outcomes and quality of life between transoral surgery and definitive chemoradiotherapy for oropharyngeal cancer|journal=Head & Neck|date=March 2015|volume=37|issue=3|pages=381–385|doi=10.1002/hed.23610|pmid=24431059|ref={{harvid|Chen et al|2015}}}}
• {{cite journal|last1=Chia|first1=Stanley H.|last2=Gross|first2=Neil D.|last3=Richmon|first3=Jeremy D.|title=Surgeon Experience and Complications with Transoral Robotic Surgery (TORS)|journal=Otolaryngology–Head and Neck Surgery|date=December 2013|volume=149|issue=6|pages=885–892|doi=10.1177/0194599813503446|pmid=24013139|ref={{harvid|Chia et al|2013}}}}
• {{cite journal|last1=Choby|first1=Garret W.|last2=Kim|first2=Jeehong|last3=Ling|first3=Diane C.|last4=Abberbock|first4=Shira|last5=Mandal|first5=Rajarsi|last6=Kim|first6=Seungwon|last7=Ferris|first7=Robert L.|last8=Duvvuri|first8=Umamaheswar|title=Transoral Robotic Surgery Alone for Oropharyngeal Cancer|journal=JAMA Otolaryngology–Head & Neck Surgery|date=1 June 2015|volume=141|issue=6|pages=499–504|doi=10.1001/jamaoto.2015.0347|pmid=25834991|ref={{harvid|Choby et al|2015}}}}
• {{cite journal|last1=Cohen|first1=Marc A.|last2=Weinstein|first2=Gregory S.|last3=O'Malley|first3=Bert W.|last4=Feldman|first4=Michael|last5=Quon|first5=Harry|title=Transoral robotic surgery and human papillomavirus status: Oncologic results|journal=Head & Neck|date=April 2011|volume=33|issue=4|pages=573–580|doi=10.1002/hed.21500|pmid=21425382|ref={{harvid|Cohen et al|2011}}}}
• {{cite journal|last1=Durmus|first1=K|last2=Rangarajan|first2=SV|last3=Old|first3=MO|last4=Agrawal|first4=A|last5=Teknos|first5=TN|last6=Ozer|first6=E|title=Transoral robotic approach to carcinoma of unknown primary.|journal=Head & Neck|date=June 2014|volume=36|issue=6|pages=848–52|pmid=23720223|doi=10.1002/hed.23385|ref={{harvid|Durmus et al|2014}}|pmc=4266274}}
• {{cite journal|last1=Dziegielewski|first1=Peter T.|last2=Teknos|first2=Theodoros N.|last3=Durmus|first3=Kasim|last4=Old|first4=Matthew|last5=Agrawal|first5=Amit|last6=Kakarala|first6=Kiran|last7=Marcinow|first7=Anna|last8=Ozer|first8=Enver|title=Transoral Robotic Surgery for Oropharyngeal Cancer|journal=JAMA Otolaryngology–Head & Neck Surgery|date=1 November 2013|volume=139|issue=11|pages=1099–108|doi=10.1001/jamaoto.2013.2747|pmid=23576186|pmc=4274181|ref={{harvid|Dziegielewski et al|2013}}}}
• {{cite journal|last1=Dowthwaite|first1=Samuel A.|last2=Franklin|first2=Jason H.|last3=Palma|first3=David A.|last4=Fung|first4=Kevin|last5=Yoo|first5=John|last6=Nichols|first6=Anthony C.|title=The Role of Transoral Robotic Surgery in the Management of Oropharyngeal Cancer: A Review of the Literature|journal=ISRN Oncology|date=2012|volume=2012|pages=945162|doi=10.5402/2012/945162|pmid=22606380|pmc=3347745|ref={{harvid|Dowthwaite et al|2012}}}}
• {{cite journal|last1=Genden|first1=Eric M.|last2=Kotz|first2=Tamar|last3=Tong|first3=Charles C. L.|last4=Smith|first4=Claris|last5=Sikora|first5=Andrew G.|last6=Teng|first6=Marita S.|last7=Packer|first7=Stuart H.|last8=Lawson|first8=William L.|last9=Kao|first9=Johnny|title=Transoral robotic resection and reconstruction for head and neck cancer|journal=The Laryngoscope|date=August 2011|volume=121|issue=8|pages=1668–1674|doi=10.1002/lary.21845|pmid=21792953|ref={{harvid|Genden et al|2011}}}}
• {{cite journal|last1=Graboyes|first1=EM|last2=Sinha|first2=P|last3=Thorstad|first3=WL|last4=Rich|first4=JT|last5=Haughey|first5=BH|title=Management of human papillomavirus-related unknown primaries of the head and neck with a transoral surgical approach.|journal=Head & Neck|date=November 2015|volume=37|issue=11|pages=1603–11|pmid=24931847|doi=10.1002/hed.23800|ref={{harvid|Graboyes et al|2015}}}}
• {{cite journal|last1=Haughey|first1=Bruce H.|last2=Hinni|first2=Michael L.|last3=Salassa|first3=John R.|last4=Hayden|first4=Richard E.|last5=Grant|first5=David G.|last6=Rich|first6=Jason T.|last7=Milov|first7=Simon|last8=Lewis|first8=James S.|last9=Krishna|first9=Murli|title=Transoral laser microsurgery as primary treatment for advanced-stage oropharyngeal cancer: A united states multicenter study|journal=Head & Neck|date=December 2011|volume=33|issue=12|pages=1683–1694|doi=10.1002/hed.21669|pmid=21284056|ref={{harvid|Haughey et al|2011}}}}
• {{cite journal|last1=Mehta|first1=V|last2=Johnson|first2=P|last3=Tassler|first3=A|last4=Kim|first4=S|last5=Ferris|first5=RL|last6=Nance|first6=M|last7=Johnson|first7=JT|last8=Duvvuri|first8=U|title=A new paradigm for the diagnosis and management of unknown primary tumors of the head and neck: a role for transoral robotic surgery|journal=The Laryngoscope|date=January 2013|volume=123|issue=1|pages=146–151|pmid=23154813|doi=10.1002/lary.23562|ref={{harvid|Mehta et al|2013}}}}
• {{cite journal|last1=Moore|first1=Eric J.|last2=Hinni|first2=Michael L.|last3=Olsen|first3=Kerry D.|last4=Price|first4=Daniel L.|last5=Laborde|first5=Rebecca R.|last6=Inman|first6=Jared C.|title=Cost Considerations in the Treatment of Oropharyngeal Squamous Cell Carcinoma|journal=Otolaryngology–Head and Neck Surgery|date=June 2012|volume=146|issue=6|pages=946–951|doi=10.1177/0194599812437534|pmid=22344182|ref={{harvid|Moore et al|2012a}}}}
• {{cite journal|last1=Moore|first1=Eric J.|last2=Henstrom|first2=Doug K.|last3=Olsen|first3=Kerry D.|last4=Kasperbauer|first4=Jan L.|last5=McGree|first5=Michaela E.|title=Transoral resection of tonsillar squamous cell carcinoma|journal=The Laryngoscope|date=March 2009|volume=119|issue=3|pages=508–515|doi=10.1002/lary.20124|pmid=19235742|ref={{harvid|Moore et al|2009}}}}
• {{cite journal|last1=Moore|first1=Eric J.|last2=Olsen|first2=Kerry D.|last3=Kasperbauer|first3=Jan L.|title=Transoral robotic surgery for oropharyngeal squamous cell carcinoma: A prospective study of feasibility and functional outcomes|journal=The Laryngoscope|date=November 2009|volume=119|issue=11|pages=2156–2164|doi=10.1002/lary.20647|pmid=19824067|ref={{harvid|Moore et al|2009a}}}}
• {{cite journal|last1=Moore|first1=Eric J.|last2=Olsen|first2=Steven M.|last3=Laborde|first3=Rebecca R.|last4=García|first4=Joaquín J.|last5=Walsh|first5=Francis J.|last6=Price|first6=Daniel L.|last7=Janus|first7=Jeffrey R.|last8=Kasperbauer|first8=Jan L.|last9=Olsen|first9=Kerry D.|title=Long-term Functional and Oncologic Results of Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma|journal=Mayo Clinic Proceedings|date=March 2012|volume=87|issue=3|pages=219–225|doi=10.1016/j.mayocp.2011.10.007|pmid=22386176|pmc=3538408|ref={{harvid|Moore et al|2012}}}}
• {{cite journal|last1=Moore|first1=Eric J.|last2=Hinni|first2=Michael L.|title=Critical Review: Transoral Laser Microsurgery and Robotic-Assisted Surgery for Oropharynx Cancer Including Human Papillomavirus Related Cancer|journal=International Journal of Radiation Oncology Biology Physics|date=April 2013|volume=85|issue=5|pages=1163–1167|doi=10.1016/j.ijrobp.2012.08.033|pmid=23182390|type=Review|ref=harv}}
• {{cite journal|last1=Patel|first1=SA|last2=Magnuson|first2=JS|last3=Holsinger|first3=FC|last4=Karni|first4=RJ|last5=Richmon|first5=JD|last6=Gross|first6=ND|last7=Bhrany|first7=AD|last8=Ferrell|first8=JK|last9=Ford|first9=SE|last10=Kennedy|first10=AA|last11=Méndez|first11=E|display-authors=3|title=Robotic surgery for primary head and neck squamous cell carcinoma of unknown site|journal=JAMA Otolaryngology–Head & Neck Surgery|date=November 2013|volume=139|issue=11|pages=1203–1211|doi=10.1001/Jamaoto.2013.5189|pmid=24136446|ref={{harvid|Patel et al|2013}}}}
• {{cite journal|last1=Pollei|first1=Taylor R.|last2=Hinni|first2=Michael L.|last3=Moore|first3=Eric J.|last4=Hayden|first4=Richard E.|last5=Olsen|first5=Kerry D.|last6=Casler|first6=John D.|last7=Walter|first7=Logan C.|title=Analysis of Postoperative Bleeding and Risk Factors in Transoral Surgery of the Oropharynx|journal=JAMA Otolaryngology–Head & Neck Surgery|date=1 November 2013|volume=139|issue=11|pages=1212–8|doi=10.1001/jamaoto.2013.5097|pmid=24113922|ref={{harvid|Pollei|2013}}}}
• {{cite journal|last1=Rinaldi|first1=V|last2=Pagani|first2=D|last3=Torretta|first3=S|last4=Pignataro|first4=L|title=Transoral robotic surgery in the management of head and neck tumours|journal=Ecancermedicalscience|date=26 September 2013|volume=7|pages=359|doi=10.3332/ecancer.2013.359|pmid=24073017|pmc=3782590|ref={{harvid|Rinaldi|2013}}}}
• {{cite journal|last1=Sinclair|first1=CF|last2=McColloch|first2=NL|last3=Carroll|first3=WR|last4=Rosenthal|first4=EL|last5=Desmond|first5=RA|last6=Magnuson|first6=JS|title=Patient-perceived and objective functional outcomes following transoral robotic surgery for early oropharyngeal carcinoma|journal=Archives of Otolaryngology–Head & Neck Surgery|date=November 2011|volume=137|issue=11|pages=1112–6|pmid=22106235|doi=10.1001/archoto.2011.172|ref={{harvid|Sinclair et al|2011}}}}
• {{cite journal|last1=Steiner|first1=Wolfgang|last2=Fierek|first2=Oliver|last3=Ambrosch|first3=Petra|last4=Hommerich|first4=Christian P.|last5=Kron|first5=Martina|title=Transoral Laser Microsurgery for Squamous Cell Carcinoma of the Base of the Tongue|journal=Archives of Otolaryngology–Head & Neck Surgery|date=1 January 2003|volume=129|issue=1|pages=36|doi=10.1001/archotol.129.1.36|ref={{harvid|Steiner et al|2003}}}}
• {{cite journal|last1=Walvekar|first1=Rohan R.|last2=Li|first2=Ryan J.|last3=Gooding|first3=William E.|last4=Gibson|first4=Michael K.|last5=Heron|first5=Dwight|last6=Johnson|first6=Jonas T.|last7=Ferris|first7=Robert L.|title=Role of Surgery in Limited (T1-2, N0-1) Cancers of the Oropharynx|journal=The Laryngoscope|date=December 2008|volume=118|issue=12|pages=2129–2134|doi=10.1097/MLG.0b013e3181857950|pmid=18948826|ref={{harvid|Walvekar et al|2008}}}}
• {{cite journal|last1=Weinstein|first1=Gregory S.|last2=O'Malley|first2=Bert W.|last3=Magnuson|first3=J. Scott|last4=Carroll|first4=William R.|last5=Olsen|first5=Kerry D.|last6=Daio|first6=Lixia|last7=Moore|first7=Eric J.|last8=Holsinger|first8=F. Christopher|title=Transoral robotic surgery: A multicenter study to assess feasibility, safety, and surgical margins|journal=The Laryngoscope|date=August 2012|volume=122|issue=8|pages=1701–1707|doi=10.1002/lary.23294|pmid=22752997|ref={{harvid|Weinstein et al|2012}}}}
• {{cite journal|last1=White|first1=Hilliary N.|last2=Moore|first2=Eric J.|last3=Rosenthal|first3=Eben L.|last4=Carroll|first4=William R.|last5=Olsen|first5=Kerry D.|last6=Desmond|first6=Reneé A.|last7=Magnuson|first7=J. Scott|title=Transoral Robotic-Assisted Surgery for Head and Neck Squamous Cell Carcinoma|journal=Archives of Otolaryngology–Head & Neck Surgery|date=20 December 2010|volume=136|issue=12|pages=1248–52|doi=10.1001/archoto.2010.216|pmid=21173375|ref={{harvid|White et al|2010}}}}
• {{cite journal|last1=Woolgar|first1=Julia Anne|last2=Triantafyllou|first2=Asterios|title=A histopathological appraisal of surgical margins in oral and oropharyngeal cancer resection specimens|journal=Oral Oncology|date=November 2005|volume=41|issue=10|pages=1034–1043|doi=10.1016/j.oraloncology.2005.06.008|pmid=16129652|ref=harv}}

Radiation

• {{cite journal|last1=Adelstein|first1=David J.|last2=Li|first2=Yi|last3=Adams|first3=George L.|last4=Wagner|first4=Henry|last5=Kish|first5=Julie A.|last6=Ensley|first6=John F.|last7=Schuller|first7=David E.|last8=Forastiere|first8=Arlene A.|title=An Intergroup Phase III Comparison of Standard Radiation Therapy and Two Schedules of Concurrent Chemoradiotherapy in Patients With Unresectable Squamous Cell Head and Neck Cancer|journal=Journal of Clinical Oncology|date=January 2003|volume=21|issue=1|pages=92–98|doi=10.1200/JCO.2003.01.008|pmid=12506176|ref={{harvid|Adelstein et al|2003}}}}
• {{cite journal|last1=Al-Mamgani|first1=Abrahim|last2=van Rooij|first2=Peter|last3=Verduijn|first3=Gerda M.|last4=Mehilal|first4=Robert|last5=Kerrebijn|first5=Jeroen D.|last6=Levendag|first6=Peter C.|title=The impact of treatment modality and radiation technique on outcomes and toxicity of patients with locally advanced oropharyngeal cancer|journal=The Laryngoscope|date=February 2013|volume=123|issue=2|pages=386–393|doi=10.1002/lary.23699|pmid=23404489|ref={{harvid|Al-Mamgani et al|2013}}}}
• {{cite journal|last1=Bedi|first1=Meena|last2=Firat|first2=Selim|last3=Semenenko|first3=Vladimir A.|last4=Schultz|first4=Christopher|last5=Tripp|first5=Patrick|last6=Byhardt|first6=Roger|last7=Wang|first7=Dian|title=Elective Lymph Node Irradiation With Intensity-Modulated Radiotherapy: Is Conventional Dose Fractionation Necessary?|journal=International Journal of Radiation OncologyBiologyPhysics|date=May 2012|volume=83|issue=1|pages=e87–e92|doi=10.1016/j.ijrobp.2011.12.016|pmid=22516389|ref={{harvid|Bedi et al|2012}}}}
• {{cite journal|last1=Beitler|first1=Jonathan J.|last2=Zhang|first2=Qiang|last3=Fu|first3=Karen K.|last4=Trotti|first4=Andy|last5=Spencer|first5=Sharon A.|last6=Jones|first6=Christopher U.|last7=Garden|first7=Adam S.|last8=Shenouda|first8=George|last9=Harris|first9=Jonathan|last10=Ang|first10=Kian K.|title=Final Results of Local-Regional Control and Late Toxicity of RTOG 9003: A Randomized Trial of Altered Fractionation Radiation for Locally Advanced Head and Neck Cancer|journal=International Journal of Radiation Oncology Biology Physics|date=May 2014|volume=89|issue=1|pages=13–20|doi=10.1016/j.ijrobp.2013.12.027|pmid=24613816|pmc=4664465|ref={{harvid|Beitler et al|2014}}}}
• {{cite journal|last1=Bourhis|first1=Jean|last2=Overgaard|first2=Jens|last3=Audry|first3=Hélène|last4=Ang|first4=Kian K|last5=Saunders|first5=Michele|last6=Bernier|first6=Jacques|last7=Horiot|first7=Jean-Claude|last8=Le Maître|first8=Aurélie|last9=Pajak|first9=Thomas F|last10=Poulsen|first10=Michael G|last11=O'Sullivan|first11=Brian|last12=Dobrowsky|first12=Werner|last13=Hliniak|first13=Andrzej|last14=Skladowski|first14=Krzysztof|last15=Hay|first15=John H|last16=Pinto|first16=Luiz HJ|last17=Fallai|first17=Carlo|last18=Fu|first18=Karen K|last19=Sylvester|first19=Richard|last20=Pignon|first20=Jean-Pierre|display-authors=3|title=Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis|journal=The Lancet|date=September 2006|volume=368|issue=9538|pages=843–854|doi=10.1016/S0140-6736(06)69121-6|pmid=16950362|ref={{harvid|Bourhis et al|2006}}}}
• {{cite journal|last1=Caudell|first1=Jimmy J.|last2=Schaner|first2=Philip E.|last3=Desmond|first3=Renee A.|last4=Meredith|first4=Ruby F.|last5=Spencer|first5=Sharon A.|last6=Bonner|first6=James A.|title=Dosimetric Factors Associated With Long-Term Dysphagia After Definitive Radiotherapy for Squamous Cell Carcinoma of the Head and Neck|journal=International Journal of Radiation OncologyBiologyPhysics|date=February 2010|volume=76|issue=2|pages=403–409|doi=10.1016/j.ijrobp.2009.02.017|pmid=19467801|ref={{harvid|Caudell et al|2010}}}}
• {{cite journal|last1=Chen|first1=Allen M.|last2=Li|first2=Judy|last3=Beckett|first3=Laurel A.|last4=Zhara|first4=Talia|last5=Farwell|first5=Gregory|last6=Lau|first6=Derick H.|last7=Gandour-Edwards|first7=Regina|last8=Vaughan|first8=Andrew T.|last9=Purdy|first9=James A.|title=Differential response rates to irradiation among patients with human papillomavirus positive and negative oropharyngeal cancer|journal=The Laryngoscope|date=January 2013|volume=123|issue=1|pages=152–157|doi=10.1002/lary.23570|pmid=23008061|ref={{harvid|Chen et al|2013}}}}
• {{cite journal|last1=Chin|first1=Re-I|last2=Spencer|first2=Christopher R.|last3=DeWees|first3=Todd|last4=Hwang|first4=Michael Y.|last5=Patel|first5=Pranav|last6=Sinha|first6=Parul|last7=Gay|first7=Hiram A.|last8=Haughey|first8=Bruce H.|last9=Nussenbaum|first9=Brian|last10=Adkins|first10=Douglas R.|last11=Lewis|first11=James S.|last12=Thorstad|first12=Wade L.|display-authors=3|title=Reevaluation of postoperative radiation dose in the management of human papillomavirus-positive oropharyngeal cancer|journal=Head & Neck|date=November 2016|volume=38|issue=11|pages=1643–1649|doi=10.1002/hed.24486|pmid=27152851|ref={{harvid|Chin et al|2016}}}}
• {{cite journal |last1=Cramer |first1=John David |last2=Ferris |first2=Robert L. |last3=Duvvuri |first3=Umamaheswar |title=Treatment deintensification to surgery only for stage I human papillomavirus-associated oropharyngeal cancer |journal=Journal of Clinical Oncology |date=20 May 2018 |volume=36 |issue=15 supplement |page=6003 |doi=10.1200/JCO.2018.36.15_suppl.6003 |ref={{harvid|Cramer et al|2018}}}}
• {{cite journal|last1=Daly|first1=Megan E.|last2=Le|first2=Quynh-Thu|last3=Maxim|first3=Peter G.|last4=Loo|first4=Billy W.|last5=Kaplan|first5=Michael J.|last6=Fischbein|first6=Nancy J.|last7=Pinto|first7=Harlan|last8=Chang|first8=Daniel T.|title=Intensity-Modulated Radiotherapy in the Treatment of Oropharyngeal Cancer: Clinical Outcomes and Patterns of Failure|journal=International Journal of Radiation OncologyBiologyPhysics|date=April 2010|volume=76|issue=5|pages=1339–1346|doi=10.1016/j.ijrobp.2009.04.006|pmid=19540068}}
• {{cite journal|last1=Deasy|first1=Joseph O.|last2=Moiseenko|first2=Vitali|last3=Marks|first3=Lawrence|last4=Chao|first4=K.S. Clifford|last5=Nam|first5=Jiho|last6=Eisbruch|first6=Avraham|title=Radiotherapy Dose–Volume Effects on Salivary Gland Function|journal=International Journal of Radiation OncologyBiologyPhysics|date=March 2010|volume=76|issue=3|pages=S58–S63|doi=10.1016/j.ijrobp.2009.06.090|pmid=20171519|pmc=4041494|ref={{harvid|Deasy et al|2010}}}}
• {{cite journal|last1=Dok|first1=Rüveyda|last2=Kalev|first2=Peter|last3=Van Limbergen|first3=Evert Jan|last4=Asbagh|first4=Layka Abbasi|last5=Vázquez|first5=Iria|last6=Hauben|first6=Esther|last7=Sablina|first7=Anna|last8=Nuyts|first8=Sandra|title=p16INK4a Impairs Homologous Recombination–Mediated DNA Repair in Human Papillomavirus–Positive Head and Neck Tumors|journal=Cancer Research|date=15 March 2014|volume=74|issue=6|pages=1739–1751|doi=10.1158/0008-5472.CAN-13-2479|pmid=24473065|ref={{harvid|Dok et al|2014}}}}
• {{cite journal|last1=Feng|first1=Felix Y.|last2=Kim|first2=Hyungjin M.|last3=Lyden|first3=Teresa H.|last4=Haxer|first4=Marc J.|last5=Feng|first5=Mary|last6=Worden|first6=Frank P.|last7=Chepeha|first7=Douglas B.|last8=Eisbruch|first8=Avraham|title=Intensity-Modulated Radiotherapy of Head and Neck Cancer Aiming to Reduce Dysphagia: Early Dose–Effect Relationships for the Swallowing Structures|journal=International Journal of Radiation OncologyBiologyPhysics|date=August 2007|volume=68|issue=5|pages=1289–1298|doi=10.1016/j.ijrobp.2007.02.049|pmid=17560051|ref={{harvid|Feng et al|2007}}}}
• {{cite journal|last1=Forastiere|first1=Arlene A.|last2=Zhang|first2=Qiang|last3=Weber|first3=Randal S.|last4=Maor|first4=Moshe H.|last5=Goepfert|first5=Helmuth|last6=Pajak|first6=Thomas F.|last7=Morrison|first7=William|last8=Glisson|first8=Bonnie|last9=Trotti|first9=Andy|last10=Ridge|first10=John A.|last11=Thorstad|first11=Wade|last12=Wagner|first12=Henry|last13=Ensley|first13=John F.|last14=Cooper|first14=Jay S.|display-authors=3|title=Long-Term Results of RTOG 91-11: A Comparison of Three Nonsurgical Treatment Strategies to Preserve the Larynx in Patients With Locally Advanced Larynx Cancer|journal=Journal of Clinical Oncology|date=March 2013|volume=31|issue=7|pages=845–852|doi=10.1200/JCO.2012.43.6097|pmid=23182993|pmc=3577950|ref={{harvid|Forastiere et al|2013}}}}
• {{cite journal|last1=Fu|first1=Karen K.|last2=Pajak|first2=Thomas F.|last3=Trotti|first3=Andy|last4=Jones|first4=Christopher U.|last5=Spencer|first5=Sharon A.|last6=Phillips|first6=Theodore L.|last7=Garden|first7=Adam S.|last8=Ridge|first8=John A.|last9=Cooper|first9=Jay S.|last10=Ang|first10=K.Kian|title=A radiation therapy oncology group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003|journal=International Journal of Radiation OncologyBiologyPhysics|date=August 2000|volume=48|issue=1|pages=7–16|doi=10.1016/S0360-3016(00)00663-5|pmid=10924966|ref={{harvid|Fu et al|2000}}}}
• {{cite journal|last1=Garden|first1=Adam S.|last2=Dong|first2=Lei|last3=Morrison|first3=William H.|last4=Stugis|first4=Erich M.|last5=Glisson|first5=Bonnie S.|last6=Frank|first6=Steven J.|last7=Beadle|first7=Beth M.|last8=Gunn|first8=Gary B.|last9=Schwartz|first9=David L.|last10=Kies|first10=Merill S.|last11=Weber|first11=Randal S.|last12=Ang|first12=K. Kian|last13=Rosenthal|first13=David I.|display-authors=3|title=Patterns of Disease Recurrence Following Treatment of Oropharyngeal Cancer With Intensity Modulated Radiation Therapy|journal=International Journal of Radiation OncologyBiologyPhysics|date=March 2013|volume=85|issue=4|pages=941–947|doi=10.1016/j.ijrobp.2012.08.004|pmid=22975604}}
• {{cite journal |last1=Heymach |first1=John |last2=Krilov |first2=Lada |last3=Alberg |first3=Anthony |last4=Baxter |first4=Nancy |last5=Chang |first5=Susan Marina |last6=Corcoran |first6=Ryan B. |last7=Dale |first7=William |last8=DeMichele |first8=Angela |last9=Magid Diefenbach |first9=Catherine S. |last10=Dreicer |first10=Robert |last11=Epstein |first11=Andrew S. |last12=Gillison |first12=Maura L. |last13=Graham |first13=David L. |last14=Jones |first14=Joshua |last15=Ko |first15=Andrew H. |last16=Lopez |first16=Ana Maria |last17=Maki |first17=Robert G. |last18=Rodriguez-Galindo |first18=Carlos |last19=Schilsky |first19=Richard L. |last20=Sznol |first20=Mario |last21=Westin |first21=Shannon Neville |last22=Burstein |first22=Harold |title=Clinical Cancer Advances 2018: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology |journal=Journal of Clinical Oncology |date=April 2018 |volume=36 |issue=10 |pages=1020–1044 |doi=10.1200/JCO.2017.77.0446|pmid=29380678 |ref={{harvid|Heymach et al|2018}}}}
• {{cite journal|last1=Kramer|first1=Simon|last2=Gelber|first2=Richard D.|last3=Snow|first3=James B.|last4=Marcial|first4=Victor A.|last5=Lowry|first5=Louis D.|last6=Davis|first6=Lawrence W.|last7=Chandler|first7=Richard|title=Combined radiation therapy and surgery in the management of advanced head and neck cancer: Final report of study 73-03 of the radiation therapy oncology group|journal=Head & Neck Surgery|date=September 1987|volume=10|issue=1|pages=19–30|doi=10.1002/hed.2890100105|ref={{harvid|Kramer et al|1987}}}}
• {{cite journal|last1=Langendijk|first1=Johannes A.|last2=Doornaert|first2=Patricia|last3=Verdonck-de Leeuw|first3=Irma M.|last4=Leemans|first4=Charles R.|last5=Aaronson|first5=Neil K.|last6=Slotman|first6=Ben J.|title=Impact of Late Treatment-Related Toxicity on Quality of Life Among Patients With Head and Neck Cancer Treated With Radiotherapy|journal=Journal of Clinical Oncology|date=August 2008|volume=26|issue=22|pages=3770–3776|doi=10.1200/JCO.2007.14.6647|pmid=18669465|ref={{harvid|Langendijk et al|2008}}}}
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• {{cite journal|last1=Li|first1=Baoqing|last2=Li|first2=Dan|last3=Lau|first3=Derick H|last4=Farwell|first4=D Gregory|last5=Luu|first5=Quang|last6=Rocke|first6=David M|last7=Newman|first7=Kathleen|last8=Courquin|first8=Jean|last9=Purdy|first9=James A|last10=Chen|first10=Allen M|title=Clinical-dosimetric analysis of measures of dysphagia including gastrostomy-tube dependence among head and neck cancer patients treated definitively by intensity-modulated radiotherapy with concurrent chemotherapy|journal=Radiation Oncology|date=2009|volume=4|issue=1|pages=52|doi=10.1186/1748-717X-4-52|pmid=19909531|pmc=2785826|ref={{harvid|Li et al|2009}}}}
• {{cite journal|last1=Maccomb|first1=WS|last2=Fletcher|first2=GH|title=Planned combination of surgery and radiation in treatment of advanced primary head and neck cancers.|journal=The American Journal of Roentgenology, Radium Therapy, and Nuclear Medicine|date=March 1957|volume=77|issue=3|pages=397–414|pmid=13403033|ref=harv}}
• {{cite journal|last1=Monroe|first1=Marcus M.|last2=Buchmann|first2=Luke O.|last3=Hunt|first3=Jason P.|last4=Hitchcock|first4=Ying J.|last5=Lloyd|first5=Shane|last6=Hashibe|first6=Mia|title=The Benefit of Adjuvant Radiation in Surgically-Treated T1-2 N1 Oropharyngeal Squamous Cell Carcinoma|journal=Laryngoscope Investigative Otolaryngology|date=April 2017|volume=2|issue=2|pages=57–62|doi=10.1002/lio2.64|pmid=28894823|pmc=5527368|ref={{harvid|Monroe et al|2017}}}}
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• {{cite journal|last1=Parsons|first1=James T.|last2=Mendenhall|first2=William M.|last3=Stringer|first3=Scott P.|last4=Amdur|first4=Robert J.|last5=Hinerman|first5=Russell W.|last6=Villaret|first6=Douglas B.|last7=Moore-Higgs|first7=Giselle J.|last8=Greene|first8=Bruce D.|last9=Speer|first9=Tod W.|last10=Cassisi|first10=Nicholas J.|last11=Million|first11=Rodney R.|display-authors=3|title=Squamous cell carcinoma of the oropharynx: Surgery, radiation therapy, or both|journal=Cancer|date=1 June 2002|volume=94|issue=11|pages=2967–2980|doi=10.1002/cncr.10567|pmid=12115386|ref={{harvid|Parsons et al|2002}}}}
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• {{cite journal|last1=Rich|first1=Jason T.|last2=Milov|first2=Simon|last3=Lewis|first3=James S.|last4=Thorstad|first4=Wade L.|last5=Adkins|first5=Douglas R.|last6=Haughey|first6=Bruce H.|title=Transoral laser microsurgery (TLM) ± adjuvant therapy for advanced stage oropharyngeal cancer|journal=The Laryngoscope|date=September 2009|volume=119|issue=9|pages=1709–1719|pmid=19572271|pmc=3877921|doi=10.1002/lary.20552|ref={{harvid|Rich et al|2009}}}}
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Chemotherapy and chemoradiation

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• {{cite journal|last1=Olson|first1=Brennan|last2=Clayburgh|first2=Daniel R|title=Utility of adjuvant therapy for pN1 oropharyngeal carcinoma|page=99|ref={{harvid|Olson|Clayburgh|2017}}}}, in {{harvtxt|AAO|2017}}
• {{cite journal|last1=Owadally|first1=Waheeda|last2=Hurt|first2=Chris|last3=Timmins|first3=Hayley|last4=Parsons|first4=Emma|last5=Townsend|first5=Sarah|last6=Patterson|first6=Joanne|last7=Hutcheson|first7=Katherine|last8=Powell|first8=Ned|last9=Beasley|first9=Matthew|last10=Palaniappan|first10=Nachi|last11=Robinson|first11=Max|last12=Jones|first12=Terence M.|last13=Evans|first13=Mererid|display-authors=3|title=PATHOS: a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV) positive oropharyngeal cancer|journal=BMC Cancer|date=27 August 2015|volume=15|issue=1|pages=602|pmid=26311526|pmc=4549836|doi=10.1186/s12885-015-1598-x|ref={{harvid|Owadally et al|2015}}}}
• {{cite journal|last1=Pignon|first1=Jean-Pierre|last2=le Maître|first2=Aurélie|last3=Bourhis|first3=Jean|title=Meta-Analyses of Chemotherapy in Head and Neck Cancer (MACH-NC): An Update|journal=International Journal of Radiation Oncology Biology Physics|date=October 2007|volume=69|issue=2|pages=S112–S114|doi=10.1016/j.ijrobp.2007.04.088|pmid=17848275|ref={{harvid|Pignon et al|2007}}}}
• {{cite journal|last1=Posner|first1=M. R.|last2=Lorch|first2=J. H.|last3=Goloubeva|first3=O.|last4=Tan|first4=M.|last5=Schumaker|first5=L. M.|last6=Sarlis|first6=N. J.|last7=Haddad|first7=R. I.|last8=Cullen|first8=K. J.|title=Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial|journal=Annals of Oncology|date=May 2011|volume=22|issue=5|pages=1071–1077|doi=10.1093/annonc/mdr006|pmid=21317223|pmc=4351352|ref={{harvid|Posner et al|2011}}}}
• {{cite journal |last1=Seiwert |first1=T. |last2=Melotek |first2=J.M. |last3=Foster |first3=C.C. |last4=Blair |first4=E.A. |last5=Karrison |first5=T.G. |last6=Agrawal |first6=N. |last7=Portugal |first7=L. |last8=Gooi |first8=Z. |last9=Stenson |first9=K.M. |last10=Brisson |first10=R.J. |last11=Arshad |first11=S. |last12=Dekker |first12=A. |last13=Kochanny |first13=S. |last14=Saloura |first14=V. |last15=Spiotto |first15=M.T. |last16=Villaflor |first16=V.M. |last17=Haraf |first17=D.J. |last18=Vokes |first18=E.E. |title=OPTIMA—A Phase 2 Trial of Induction Chemotherapy Response-Stratified Radiation Therapy Dose and Volume De-escalation for HPV+ Oropharyngeal Cancer: Efficacy, Toxicity, and HPV Subtype Analysis |journal=International Journal of Radiation Oncology Biology Physics |date=April 2018 |volume=100 |issue=5 |pages=1309 |doi=10.1016/j.ijrobp.2017.12.025|ref={{harvid|Seiwert et al|2018}}}}
• {{cite journal|last1=Su|first1=William|last2=Liu|first2=Jerry|last3=Miles|first3=Brett A.|last4=Genden|first4=Eric M.|last5=Misiukiewicz|first5=Krzysztof J.|last6=Posner|first6=Marshall|last7=Gupta|first7=Vishal|last8=Bakst|first8=Richard L.|last9=Chu|first9=Pei-Yi|title=Adjuvant Radiation Therapy Alone for HPV Related Oropharyngeal Cancers with High Risk Features|journal=PLOS One|date=8 December 2016|volume=11|issue=12|pages=e0168061|doi=10.1371/journal.pone.0168061|pmc=5145232|ref={{harvid|Su et al|2016}}|pmid=27930732|bibcode=2016PLoSO..1168061S}}
• {{cite journal|last1=Szturz|first1=Petr|last2=Seiwert|first2=Tanguy Y.|last3=Vermorken|first3=Jan B.|title=How Standard Is Second-Line Cetuximab in Recurrent or Metastatic Head and Neck Cancer in 2017?|journal=Journal of Clinical Oncology|date=10 July 2017|volume=35|issue=20|pages=2229–2231|doi=10.1200/JCO.2016.71.8072|pmid=28471725|ref={{harvid|Szturz et al|2017}}}}
• {{cite journal|last1=Vlacich|first1=Gregory|last2=Spratt|first2=Daniel E.|last3=Diaz|first3=Roberto|last4=Phillips|first4=John G.|last5=Crass|first5=Jostin|last6=Li|first6=Chung-I|last7=Shyr|first7=Yu|last8=Cmelak|first8=Anthony J.|title=Dose to the inferior pharyngeal constrictor predicts prolonged gastrostomy tube dependence with concurrent intensity-modulated radiation therapy and chemotherapy for locally-advanced head and neck cancer|journal=Radiotherapy and Oncology|date=March 2014|volume=110|issue=3|pages=435–440|doi=10.1016/j.radonc.2013.12.007|pmid=24440043|ref={{harvid|Vlacich et al|2014}}}}
• {{cite journal|last1=Wirth|first1=Lori J.|title=Cetuximab in Human Papillomavirus?Positive Oropharynx Carcinoma|journal=Journal of Clinical Oncology|date=20 April 2016|volume=34|issue=12|pages=1289–1291|doi=10.1200/JCO.2015.65.1414|pmid= 26884569|ref=harv}}

Deintensification

• {{cite journal|last1=An|first1=Yi|last2=Holsinger|first2=F. Christopher|last3=Husain|first3=Zain A.|title=De-intensification of adjuvant therapy in human papillomavirus-associated oropharyngeal cancer|journal=Cancers of the Head & Neck|date=20 December 2016|volume=1|issue=1|doi=10.1186/s41199-016-0016-7|type=Review|ref={{harvid|An et al|2016}}}}
• {{cite journal|last1=Arnaoutakis|first1=Demetri|last2=Sumer|first2=Baran D.|title=Treatment Deintensification for Human Papillomavirus-Associated Oropharyngeal Cancer|journal=Annals of Surgical Oncology|date=10 August 2017|volume=24|issue=12|pages=3463–3465|doi=10.1245/s10434-017-6045-6|pmid=28799138|ref={{harvid|Arnaoutakis et al|2017}}}}
• {{cite journal|last1=Brotherston|first1=Drew C.|last2=Poon|first2=Ian|last3=Le|first3=Tuyen|last4=Leung|first4=Martin|last5=Kiss|first5=Alex|last6=Ringash|first6=Jolie|last7=Balogh|first7=Judith|last8=Lee|first8=Justin|last9=Wright|first9=James R.|title=Patient preferences for oropharyngeal cancer treatment de-escalation|journal=Head & Neck|date=February 2013|volume=35|issue=2|pages=151–159|doi=10.1002/hed.22930|pmid=22431201|url=https://www.researchgate.net/publication/221723808|ref={{harvid|Brotherston et al|2013}}}}
• {{cite journal|last1=Chera|first1=Bhishamjit S.|last2=Amdur|first2=Robert J.|title=Current Status and Future Directions of Treatment Deintensification in Human Papilloma Virus-associated Oropharyngeal Squamous Cell Carcinoma|journal=Seminars in Radiation Oncology|date=January 2018|volume=28|issue=1|pages=27–34|doi=10.1016/j.semradonc.2017.08.001|pmid=29173753|ref={{harvid|Chera|Amdur|2018}}}}
• {{cite journal|last1=Kelly|first1=Jacqueline R.|last2=Husain|first2=Zain A.|last3=Burtness|first3=Barbara|title=Treatment de-intensification strategies for head and neck cancer|journal=European Journal of Cancer|date=November 2016|volume=68|pages=125–133|pmid=27755996|doi=10.1016/j.ejca.2016.09.006|ref={{harvid|Kelly et al|2016}}|pmc=5734050}}
• {{cite journal |last1=Ma |first1=D.J. |last2=Price |first2=K. |last3=Moore |first3=E.J. |last4=Patel |first4=S.H. |last5=Hinni |first5=M.L. |last6=Chintakuntlawar |first6=A.V. |last7=Garcia |first7=J.J. |last8=Graner |first8=D. |last9=Neben-Wittich |first9=M.A. |last10=Garces |first10=Y. |last11=Hallemeier |first11=C.L. |last12=Price |first12=D.L. |last13=Kasperbauer |first13=J.L. |last14=Janus |first14=J.R. |last15=Foster |first15=N.R. |last16=Foote |first16=R.L. |title=Two-Year Results for MC1273, a Phase 2 Evaluation of Aggressive Dose De- Escalation for Adjuvant Chemoradiation in HPV+ Oropharynx Squamous Cell Carcinoma (OPSCC) |journal=International Journal of Radiation Oncology Biology Physics |date=December 2017 |volume=99 |issue=5 |pages=1320 |doi=10.1016/j.ijrobp.2017.09.021|ref={{harvid|Ma et al|2017}}}}
• {{cite journal|last1=Masterson|first1=L|last2=Moualed|first2=D|last3=Liu|first3=ZW|last4=Howard|first4=JE|last5=Dwivedi|first5=RC|last6=Tysome|first6=JR|last7=Benson|first7=R|last8=Sterling|first8=JC|last9=Sudhoff|first9=H|last10=Jani|first10=P|last11=Goon|first11=PK|display-authors=3|title=De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis of current clinical trials.|journal=European Journal of Cancer|date=October 2014|volume=50|issue=15|pages=2636–48|doi=10.1016/j.ejca.2014.07.001|pmid=25091798|ref={{harvid|Masterson et al|2014}}}}
• {{cite journal|last1=Mirghani|first1=H.|last2=Amen|first2=F.|last3=Blanchard|first3=P.|last4=Moreau|first4=F.|last5=Guigay|first5=J.|last6=Hartl|first6=D.M.|last7=Lacau St Guily|first7=J.|title=Treatment de-escalation in HPV-positive oropharyngeal carcinoma: Ongoing trials, critical issues and perspectives|journal=International Journal of Cancer|date=April 2015|volume=136|issue=7|pages=1494–1503|doi=10.1002/ijc.28847|pmid=24622970|ref={{harvid|Mirghani et al|2015}}}}
• {{cite journal |last1=Mirghani |first1=Haitham |last2=Blanchard |first2=Pierre |title=Treatment de-escalation for HPV-driven oropharyngeal cancer: Where do we stand? |journal=Clinical and Translational Radiation Oncology |date=January 2018 |volume=8 |pages=4–11 |doi=10.1016/j.ctro.2017.10.005|pmid=29594236 |pmc=5862680 |ref={{harvid|Mirghani et al|2018}}}}
• {{cite journal|last1=Quon|first1=Harry|last2=Richmon|first2=Jeremy D.|title=Treatment Deintensification Strategies for HPV-Associated Head and Neck Carcinomas|journal=Otolaryngologic Clinics of North America|date=August 2012|volume=45|issue=4|pages=845–861|doi=10.1016/j.otc.2012.04.007|pmid=22793856|ref=harv}}

Prognosis

• {{cite journal |last1=Al-Mamgani |first1=Abrahim |last2=van Werkhoven |first2=Erik |last3=Navran |first3=Arash |last4=Karakullukcu |first4=Baris |last5=Hamming-Vrieze |first5=Olga |last6=Machiels |first6=Melanie |last7=van der Velden |first7=Lilly-Ann |last8=Vogel |first8=Wouter V. |last9=Klop |first9=W. Martin |title=Contralateral regional recurrence after elective unilateral neck irradiation in oropharyngeal carcinoma: A literature-based critical review |journal=Cancer Treatment Reviews |date=September 2017 |volume=59 |pages=102–108 |doi=10.1016/j.ctrv.2017.07.004|pmid=28779635 |ref={{harvid|Al-Mamgani et al|2017}}}}
• {{Cite journal |last1 = Ang |last11 = Kim |first6 = P. F. | last7 = Westra | last6 = Nguyen-Tân | first5 = D. I. | last5 = Rosenthal | first7 = W. H. | last8 = Chung |first9 = R. C. | last9 = Jordan | first8 = C. H. | first4 = R. | last4 = Weber | last10 = Lu | first10 = C.|first11 = H. | last12 = Axelrod | first12 = R. | last13 = Silverman | first13 = C. C. | last14 = Redmond | first14 = K. P. | last15 = Gillison | first15 = M. L. | first1 = K. K. | last2 = Harris | first3 = R. | last3 = Wheeler | first2 = J. |display-authors=3|title = Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer| journal = New England Journal of Medicine | volume = 363| issue = 1 | pages = 24–35 | year = 2010 | pmid = 20530316 | pmc = 2943767 | doi = 10.1056/NEJMoa0912217|ref={{harvid|Ang et al|2010}}}}
• {{cite journal |last1=Bhattasali |first1=O. |last2=Thompson |first2=L.D. |last3=Schumacher |first3=A. |last4=Iganej |first4=S. |title=Nodal Radiographic Prognostic Factors in the New Stage I p16-Positive Oropharyngeal Cancer of the AJCC 8th Edition: Is All N1 Disease the Same? |journal=International Journal of Radiation Oncology Biology Physics |date=April 2018 |volume=99 |issue=2 |pages=S137 |doi=10.1016/j.ijrobp.2017.06.317|ref={{harvid|Bhattasali et al|2018}}}}
• {{ Cite journal|last1 = Chernock|first1 = R. D.| last4 = Parvin | last2 = El-mofty| last5 = Lewis| last3 = Thorstad | first2 = S. K.| first3 = W. L.| first4 = C. A.| first5 = J. S.|title = HPV-Related Nonkeratinizing Squamous Cell Carcinoma of the Oropharynx: Utility of Microscopic Features in Predicting Patient Outcome| journal = Head and Neck Pathology| volume = 3|issue = 3| pages = 186–194| year = 2009 | doi = 10.1007/s12105-009-0126-1| pmid = 20596971| pmc = 2811624|ref={{harvid|Chernock et al| 2009}}}}
• {{cite journal|last1=Fakhry|first1=Carole|last2=Zhang|first2=Qiang|last3=Nguyen-Tân|first3=Phuc Felix|last4=Rosenthal|first4=David I.|last5=Weber|first5=Randal S.|last6=Lambert|first6=Louise|last7=Trotti|first7=Andy M.|last8=Barrett|first8=William L.|last9=Thorstad|first9=Wade L.|last10=Jones|first10=Christopher U.|last11=Yom|first11=Sue S.|last12=Wong|first12=Stuart J.|last13=Ridge|first13=John A.|last14=Rao|first14=Shyam S.D.|last15=Bonner|first15=James A.|last16=Vigneault|first16=Eric|last17=Raben|first17=David|last18=Kudrimoti|first18=Mahesh R.|last19=Harris|first19=Jonathan|last20=Le|first20=Quynh-Thu|last21=Gillison|first21=Maura L.|display-authors=3|title=Development and Validation of Nomograms Predictive of Overall and Progression-Free Survival in Patients With Oropharyngeal Cancer|journal=Journal of Clinical Oncology|date=4 August 2017|pages=4057–4065|doi=10.1200/JCO.2016.72.0748|pmid=28777690|pmc=5736236|ref={{harvid|Fakhry et al|2017}}|volume=35|issue=36}}
• {{cite journal|last1=Fischer|first1=C. A.|last2=Kampmann|first2=M.|last3=Zlobec|first3=I.|last4=Green|first4=E.|last5=Tornillo|first5=L.|last6=Lugli|first6=A.|last7=Wolfensberger|first7=M.|last8=Terracciano|first8=L. M.|title=p16 expression in oropharyngeal cancer: its impact on staging and prognosis compared with the conventional clinical staging parameters|journal=Annals of Oncology|date=27 April 2010|volume=21|issue=10|pages=1961–1966|doi=10.1093/annonc/mdq210|pmid=20423915|ref={{harvid|Fischer et al|2010}}}}
• {{cite journal|last1=Gillison|first1=Maura L.|title=Human Papillomavirus and Prognosis of Oropharyngeal Squamous Cell Carcinoma: Implications for Clinical Research in Head and Neck Cancers|journal=Journal of Clinical Oncology|type=Editorial|date=20 December 2006|volume=24|issue=36|pages=5623–5625|doi=10.1200/JCO.2006.07.1829|pmid=17179099|ref=harv}}
• {{cite journal|last1=Gillison|first1=Maura L.|last2=Zhang|first2=Qiang|last3=Jordan|first3=Richard|last4=Xiao|first4=Weihong|last5=Westra|first5=William H.|last6=Trotti|first6=Andy|last7=Spencer|first7=Sharon|last8=Harris|first8=Jonathan|last9=Chung|first9=Christine H.|last10=Ang|first10=K. Kian|title=Tobacco Smoking and Increased Risk of Death and Progression for Patients With p16-Positive and p16-Negative Oropharyngeal Cancer|journal=Journal of Clinical Oncology|date=10 June 2012|volume=30|issue=17|pages=2102–2111|doi=10.1200/JCO.2011.38.4099|pmid=22565003|pmc=3397696|ref={{harvid|Gillison et al|2012}}}}
• {{cite journal|last1=Hafkamp|first1=Harriët C.|last2=Manni|first2=J.J.|last3=Haesevoets|first3=A.|last4=Voogd|first4=A.C.|last5=Schepers|first5=M.|last6=Bot|first6=F.J.|last7=Hopman|first7=A.H.N.|last8=Ramaekers|first8=F.C.S.|last9=Speel|first9=Ernst-Jan M.|title=Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas|journal=International Journal of Cancer|date=15 June 2008|volume=122|issue=12|pages=2656–2664|doi=10.1002/ijc.23458|pmid=18360824|ref={{harvid|Hafkamp et al|2008}}}}
• {{cite journal|last1=Haughey|first1=Bruce H.|last2=Sinha|first2=Parul|title=Prognostic factors and survival unique to surgically treated p16+ oropharyngeal cancer|journal=The Laryngoscope|date=September 2012|volume=122|issue=S2|pages=S13–S33|doi=10.1002/lary.23493|pmid= 22926949|ref=harv}}
• {{cite journal|last1=Huang|first1=Shao Hui|last2=Waldron|first2=John N.|last3=Milosevic|first3=Michael|last4=Shen|first4=Xiaowei|last5=Ringash|first5=Jolie|last6=Su|first6=Jie|last7=Tong|first7=Li|last8=Perez-Ordonez|first8=Bayardo|last9=Weinreb|first9=Ilan|last10=Bayley|first10=Andrew J.|last11=Kim|first11=John|last12=Hope|first12=Andrew|last13=Cho|first13=B.C. John|last14=Giuliani|first14=Meredith|last15=Razak|first15=Albiruni|last16=Goldstein|first16=David|last17=Shi|first17=Willa|last18=Liu|first18=Fei-Fei|last19=Xu|first19=Wei|last20=O'Sullivan|first20=Brian|display-authors=3|title=Prognostic value of pretreatment circulating neutrophils, monocytes, and lymphocytes in oropharyngeal cancer stratified by human papillomavirus status|journal=Cancer|date=15 February 2015|volume=121|issue=4|pages=545–555|doi=10.1002/cncr.29100|pmid=25336438|ref={{harvid|Huang et al|2015b}}}}
• {{cite journal |last1=Huang |first1=K. |last2=Banerjee |first2=R.N. |last3=Debenham |first3=B. |last4=Patel |first4=A. |last5=Sabiq |first5=F. |last6=Harold |first6=L. |last7=Skarsgard |first7=D.P. |last8=Lysack |first8=J. |last9=Ghosh |first9=S. |last10=Quon |first10=H.C. |title=What's the Matter With Matted Nodes? Significance of Matted Lymph Nodes in HPV-Related Oropharyngeal Squamous Cell Carcinoma: A Multi-institutional Population-Based Cohort Study |journal=International Journal of Radiation Oncology Biology Physics |date=April 2018 |volume=100 |issue=5 |pages=1328 |doi=10.1016/j.ijrobp.2017.12.059|ref={{harvid|Huang et al|2018}}}}
• {{cite journal|last=de Jong|first=M. C.|last2=Pramana| first2=J.|last3=Knegjens | first3=J. L.|last4=Balm | first4=A. J. M.|last5=Van Den Brekel | first5=M. W. M.|last6=Hauptmann | first6=M.|last7=Begg | first7=A. C.|last8=Rasch | first8=C. R. N.|title=HPV and high-risk gene expression profiles predict response to chemoradiotherapy in head and neck cancer, independent of clinical factors|journal=Radiotherapy and Oncology|issn=1879-0887|date=24 March 2010 |issue=3|pages=365–370|doi =10.1016/j.radonc.2010.02.001|volume=95| pmid = 20346528|ref={{harvid|de Jong et al|2010}}}}
• {{cite journal |last1=Kato |first1=Masanari G. |last2=Ellis |first2=Mark A. |last3=Nguyen |first3=Shaun A. |last4=Day |first4=Terry A. |title=Predictors of contralateral-bilateral nodal disease in oropharyngeal cancer: A National Cancer Data Base Study |journal=Head & Neck |date=February 2018 |volume=40 |issue=2 |pages=338–348 |doi=10.1002/hed.24964|pmid=28963823 |ref={{harvid|Kato et al|2018}}}}
• {{cite journal|last1=Lewis|first1=James S|last2=Carpenter|first2=Danielle H|last3=Thorstad|first3=Wade L|last4=Zhang|first4=Qin|last5=Haughey|first5=Bruce H|title=Extracapsular extension is a poor predictor of disease recurrence in surgically treated oropharyngeal squamous cell carcinoma|journal=Modern Pathology|date=24 June 2011|volume=24|issue=11|pages=1413–1420|doi=10.1038/modpathol.2011.105|pmid=21701534|pmc=3925389|ref={{harvid|Lewis et al|2011}}}}
• {{cite journal|last1=Licitra|first1=Lisa|last2=Perrone|first2=Federica|last3=Bossi|first3=Paolo|last4=Suardi|first4=Simona|last5=Mariani|first5=Luigi|last6=Artusi|first6=Raffaella|last7=Oggionni|first7=Maria|last8=Rossini|first8=Chiara|last9=Cantù|first9=Giulio|last10=Squadrelli|first10=Massimo|last11=Quattrone|first11=Pasquale|last12=Locati|first12=Laura D.|last13=Bergamini|first13=Cristiana|last14=Olmi|first14=Patrizia|last15=Pierotti|first15=Marco A.|last16=Pilotti|first16=Silvana|display-authors=3|title=High-Risk Human Papillomavirus Affects Prognosis in Patients With Surgically Treated Oropharyngeal Squamous Cell Carcinoma|journal=Journal of Clinical Oncology|date=20 December 2006|volume=24|issue=36|pages=5630–5636|doi=10.1200/JCO.2005.04.6136|pmid=17179101|ref={{harvid|Licitra et al|2006}}}}
• {{Cite journal|last1 = Lowy|first1 = D.|last2 = Munger | first2 = K.| title = Prognostic Implications of HPV in Oropharyngeal Cancer |url = https://www.researchgate.net/publication/44656062|journal = The New England Journal of Medicine| year = 2010| volume = 363|issue = 1 | pages = 82–84| doi = 10.1056/NEJMe1003607| pmid = 20530315|type=Editorial|ref=harv }}
• {{cite journal|last1=Martel|first1=María|last2=Alemany|first2=Laia|last3=Taberna|first3=Miren|last4=Mena|first4=Marisa|last5=Tous|first5=Sara|last6=Bagué|first6=Silvia|last7=Castellsagué|first7=Xavier|last8=Quer|first8=Miquel|last9=León|first9=Xavier|title=The role of HPV on the risk of second primary neoplasia in patients with oropharyngeal carcinoma|journal=Oral Oncology|date=January 2017|volume=64|pages=37–43|doi=10.1016/j.oraloncology.2016.11.011|pmid=28024722|ref={{harvid|Martel et al|2017}}}}
• {{cite journal|last1=Maxwell|first1=J. H.|last2=Kumar|first2=B.|last3=Feng|first3=F. Y.|last4=Worden|first4=F. P.|last5=Lee|first5=J. S.|last6=Eisbruch|first6=A.|last7=Wolf|first7=G. T.|last8=Prince|first8=M. E.|last9=Moyer|first9=J. S.|last10=Teknos|first10=T. N.|last11=Chepeha|first11=D. B.|last12=McHugh|first12=J. B.|last13=Urba|first13=S. G.|last14=Stoerker|first14=J.|last15=Walline|first15=H. M.|last16=Kurnit|first16=D. M.|last17=Cordell|first17=K. G.|last18=Davis|first18=S. J.|last19=Ward|first19=P. D.|last20=Bradford|first20=C. R.|last21=Carey|first21=T. E.|display-authors=3|title=Tobacco Use in Human Papillomavirus-Positive Advanced Oropharynx Cancer Patients Related to Increased Risk of Distant Metastases and Tumor Recurrence|journal=Clinical Cancer Research|date=9 February 2010|volume=16|issue=4|pages=1226–1235|doi=10.1158/1078-0432.CCR-09-2350| pmid = 20145161| pmc = 2822887| ref={{harvid|Maxwell et al|2010}}}}
• {{cite journal|last1=Maxwell|first1=Jessica H.|last2=Ferris|first2=Robert L.|last3=Gooding|first3=William|last4=Cunningham|first4=Diana|last5=Mehta|first5=Vikas|last6=Kim|first6=Seungwon|last7=Myers|first7=Eugene N.|last8=Johnson|first8=Jonas|last9=Chiosea|first9=Simion|title=Extracapsular spread in head and neck carcinoma: Impact of site and human papillomavirus status|journal=Cancer|date=September 2013|volume=119|issue=18|pages=3302–3308|doi=10.1002/cncr.28169|pmid=23797868|ref={{harvid|Maxwell et al|2013}}|citeseerx=10.1.1.663.564}}
• {{cite journal|last1=Nguyen|first1=Nam P.|last2=Ly|first2=Bevan Hong|last3=Betz|first3=Michael|last4=Vinh-Hung|first4=Vincent|title=Importance of Age as a Prognostic Factor for Tonsillar Carcinoma|journal=Annals of Surgical Oncology|date=18 June 2010|volume=17|issue=10|pages=2570–2577|doi=10.1245/s10434-010-1167-0|pmid=20559738|ref={{harvid|Nguyen et al|2010}}}}
• {{cite journal|last1=O'Sullivan|first1=Brian|last2=Huang|first2=Shao Hui|last3=Siu|first3=Lillian L.|last4=Waldron|first4=John|last5=Zhao|first5=Helen|last6=Perez-Ordonez|first6=Bayardo|last7=Weinreb|first7=Ilan|last8=Kim|first8=John|last9=Ringash|first9=Jolie|last10=Bayley|first10=Andrew|last11=Dawson|first11=Laura A.|last12=Hope|first12=Andrew|last13=Cho|first13=John|last14=Irish|first14=Jonathan|last15=Gilbert|first15=Ralph|last16=Gullane|first16=Patrick|last17=Hui|first17=Angela|last18=Liu|first18=Fei-Fei|last19=Chen|first19=Eric|last20=Xu|first20=Wei|display-authors=3|title=Deintensification Candidate Subgroups in Human Papillomavirus–Related Oropharyngeal Cancer According to Minimal Risk of Distant Metastasis|journal=Journal of Clinical Oncology|date=10 February 2013|volume=31|issue=5|pages=543–550|doi=10.1200/JCO.2012.44.0164|pmid=23295795|ref={{harvid|O'Sullivan et al|2013}}}}
• {{cite journal|last1=Ragin|first1=Camille C. R.|last2=Taioli|first2=Emanuela|title=Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: Review and meta-analysis|journal=International Journal of Cancer|date=15 October 2007|volume=121|issue=8|pages=1813–1820|doi=10.1002/ijc.22851|pmid=17546592|ref=harv}}
• {{cite journal|last1=Rischin|first1=Danny|last2=Young|first2=Richard J.|last3=Fisher|first3=Richard|last4=Fox|first4=Stephen B.|last5=Le|first5=Quynh-Thu|last6=Peters|first6=Lester J.|last7=Solomon|first7=Ben|last8=Choi|first8=Jimin|last9=O'Sullivan|first9=Brian|last10=Kenny|first10=Lizbeth M.|last11=McArthur|first11=Grant A.|display-authors=3|title=Prognostic Significance of p16INK4A and Human Papillomavirus in Patients With Oropharyngeal Cancer Treated on TROG 02.02 Phase III Trial|journal=Journal of Clinical Oncology|date=20 September 2010|volume=28|issue=27|pages=4142–4148|doi=10.1200/JCO.2010.29.2904|pmid=20697079|pmc=2953971|ref={{harvid|Rischin et al|2010}} }}
• {{cite journal|last1=Routman|first1=David M.|last2=Funk|first2=Ryan K.|last3=Tangsriwong|first3=Kanograt|last4=Lin|first4=Alexander|last5=Keeney|first5=Michael G.|last6=García|first6=Joaquín J.|last7=Zarka|first7=Matthew A.|last8=Lewis|first8=Jason T.|last9=Stoddard|first9=David G.|last10=Moore|first10=Eric J.|last11=Day|first11=Courtney N.|last12=Zhai|first12=Qihui|last13=Price|first13=Katharine A.|last14=Lukens|first14=John N.|last15=Swisher-McClure|first15=Samuel|last16=Weinstein|first16=Gregory S.|last17=O'Malley|first17=Bert W.|last18=Foote|first18=Robert L.|last19=Ma|first19=Daniel J.|display-authors=3|title=Relapse Rates With Surgery Alone in Human Papillomavirus–Related Intermediate- and High-Risk Group Oropharynx Squamous Cell Cancer: A Multi-Institutional Review|journal=International Journal of Radiation OncologyBiologyPhysics|date=June 2017|doi=10.1016/j.ijrobp.2017.06.2453|pmid=28847412|ref={{harvid|Routman et al|2017}}|volume=99|issue=4|pages=938–946}}
• {{cite journal|last1=Sinha|first1=Parul|last2=Lewis|first2=James S.|last3=Piccirillo|first3=Jay F.|last4=Kallogjeri|first4=Dorina|last5=Haughey|first5=Bruce H.|title=Extracapsular spread and adjuvant therapy in human papillomavirus-related, p16-positive oropharyngeal carcinoma|journal=Cancer|date=15 July 2012|volume=118|issue=14|pages=3519–3530|doi=10.1002/cncr.26671|pmid=22086669|ref={{harvid|Sinha et al|2012}}}}
• {{cite journal|last1=Sinha|first1=P.|last2=Thorstad|first2=W.T.|last3=Nussenbaum|first3=B.|last4=Haughey|first4=B.H.|last5=Adkins|first5=D.R.|last6=Kallogjeri|first6=D.|last7=Lewis Jr.|first7=J.S.|title=Distant metastasis in p16-positive oropharyngeal squamous cell carcinoma: A critical analysis of patterns and outcomes|journal=Oral Oncology|date=January 2014|volume=50|issue=1|pages=45–51|doi=10.1016/j.oraloncology.2013.10.007|pmid=24211084|pmc=3942323|ref={{harvid|Sinha et al|2014}}}}
• {{cite journal|last1=Sinha|first1=Parul|last2=Kallogjeri|first2=Dorina|last3=Gay|first3=Hiram|last4=Thorstad|first4=Wade L.|last5=Lewis|first5=James S.|last6=Chernock|first6=Rebecca|last7=Nussenbaum|first7=Brian|last8=Haughey|first8=Bruce H.|title=High metastatic node number, not extracapsular spread or N-classification is a node-related prognosticator in transorally-resected, neck-dissected p16-positive oropharynx cancer|journal=Oral Oncology|date=May 2015|volume=51|issue=5|pages=514–520|doi=10.1016/j.oraloncology.2015.02.098|pmid=25771076|ref={{harvid|Sinha et al|2015}}}}
• {{cite journal|last1=Trosman|first1=Samuel J.|last2=Koyfman|first2=Shlomo A.|last3=Ward|first3=Matthew C.|last4=Al-Khudari|first4=Samer|last5=Nwizu|first5=Tobenna|last6=Greskovich|first6=John F.|last7=Lamarre|first7=Eric D.|last8=Scharpf|first8=Joseph|last9=Khan|first9=Mumtaz J.|last10=Lorenz|first10=Robert R.|last11=Adelstein|first11=David J.|last12=Burkey|first12=Brian B.|display-authors=3|title=Effect of Human Papillomavirus on Patterns of Distant Metastatic Failure in Oropharyngeal Squamous Cell Carcinoma Treated With Chemoradiotherapy|journal=JAMA Otolaryngology–Head & Neck Surgery|date=1 May 2015|volume=141|issue=5|pages=457–62|doi=10.1001/jamaoto.2015.136|pmid=25742025|ref={{harvid|Trosman et al|2015}}}}
• {{cite journal|last1=Ward|first1=M J|last2=Thirdborough|first2=S M|last3=Mellows|first3=T|last4=Riley|first4=C|last5=Harris|first5=S|last6=Suchak|first6=K|last7=Webb|first7=A|last8=Hampton|first8=C|last9=Patel|first9=N N|last10=Randall|first10=C J|last11=Cox|first11=H J|last12=Jogai|first12=S|last13=Primrose|first13=J|last14=Piper|first14=K|last15=Ottensmeier|first15=C H|last16=King|first16=E V|last17=Thomas|first17=G J|display-authors=3|title=Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer|journal=British Journal of Cancer|date=29 October 2013|volume=110|issue=2|pages=489–500|doi=10.1038/bjc.2013.639|pmid=24169344|pmc=3899750|ref={{harvid|Ward et al|2014}}}}

Epidemiology

• {{cite journal|last1=Anantharaman|first1=Devasena|last2=Muller|first2=David C|last3=Lagiou|first3=Pagona|last4=Ahrens|first4=Wolfgang|last5= Holcátová|first5=Ivana|last6=Merletti|first6=Franco|last7=Kjærheim|first7=Kristina|last8=Polesel|first8=Jerry|last9=Simonato|first9=Lorenzo|last10=Canova|first10=Cristina|last11=Castellsague|first11=Xavier|last12=Macfarlane|first12=Tatiana V|last13=Znaor|first13=Ariana|last14=Thomson|first14=Peter|last15=Robinson|first15=Max|last16=Conway|first16=David I|last17=Healy|first17=Claire M|last18=Tjønneland|first18=Anne|last19=Westin|first19=Ulla|last20=Ekström|first20=Johanna|last21=Chang-Claude|first21=Jenny|last22=Kaaks|first22=Rudolf|last23=Overvad|first23=Kim|last24=Drogan|first24=Dagmar|last25=Hallmans|first25=Göran|last26=Laurell|first26=Göran|last27=Bueno-de-Mesquita|first27=HB|last28=Peeters|first28=Petra H|last29=Agudo|first29=Antonio|last30=Göran|first30=Nerea|last31=Travis|first31=Ruth C|last32=Palli|first32=Domenico|last33=Barricarte|first33=Aurelio|last34=Trichopoulou|first34=Antonia|last35=George|first35=Saitakis|last36=Trichopoulos|first36=Dimitrios|last37=Quirós|first37=J Ramón |last38=Grioni|first38=Sara|last39=Sacerdote|first39=Carlotta|last40=Navarro|first40=Carmen|last41= Sánchez|first41=María-José |last42=Tumino|first42=Rosario|last43=Severi|first43=Gianluca|last44=Boutron-Ruault|first44=Marie-Christine|last45=Clavel-Chapelon|first45=Francoise|last46=Panico|first46=Salvatore|last47=Weiderpass|first47=Elisabete|last48=Lund|first48=Eiliv|last49=Gram|first49=Inger T|last50=Riboli|first50=Elio|last51=Pawlita|first51=Michael|last52=Waterboer|first52=Tim|last53=Kreimer|first53=Aim?e R|last54=Johansson|first54=Mattias|last55=Brennan|first55=Paul|display-authors=3|title=Combined effects of smoking and HPV16 in oropharyngeal cancer|journal=International Journal of Epidemiology|date=June 2016|volume=45|issue=3|pages=752–761|doi=10.1093/ije/dyw069|pmid=27197530|pmc=5841602|ref={{harvid|Anantharaman et al|2016}}}}
• {{Cite journal| last1 = Chaturvedi| first1 = A.| last2 = Engels| first2 = E.| last3 = Anderson| first3 = W.| last4 = Gillison| first4 = M.| title = Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States| journal = Journal of Clinical Oncology| volume = 26| issue = 4| pages = 612–619| date = Feb 2008| pmid = 18235120| doi = 10.1200/JCO.2007.14.1713| ref = {{harvid|Chaturvedi et al|2008}}}}
• {{cite journal|last1=Chaturvedi|first1=Anil K.|last2=Engels|first2=Eric A.|last3=Pfeiffer|first3=Ruth M.|last4=Hernandez|first4=Brenda Y.|last5=Xiao|first5=Weihong|last6=Kim|first6=Esther|last7=Jiang|first7=Bo|last8=Goodman|first8=Marc T.|last9=Sibug-Saber|first9=Maria|last10=Cozen|first10=Wendy|last11=Liu|first11=Lihua|last12=Lynch|first12=Charles F.|last13=Wentzensen|first13=Nicolas|last14=Jordan|first14=Richard C.|last15=Altekruse|first15=Sean|last16=Anderson|first16=William F.|last17=Rosenberg|first17=Philip S.|last18=Gillison|first18=Maura L.|display-authors=3|title=Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States|journal=Journal of Clinical Oncology|date=10 November 2011|volume=29|issue=32|pages=4294–4301|doi=10.1200/JCO.2011.36.4596|pmid = 21969503| pmc =3221528| ref={{harvid|Chaturvedi et al|2011}}}}
• {{cite journal|last1=Chaturvedi|first1=Anil K.|last2=Anderson|first2=William F.|last3=Lortet-Tieulent|first3=Joannie|last4=Curado|first4=Maria Paula|last5=Ferlay|first5=Jacques|last6=Franceschi|first6=Silvia|last7=Rosenberg|first7=Philip S.|last8=Bray|first8=Freddie|last9=Gillison|first9=Maura L.|title=Worldwide Trends in Incidence Rates for Oral Cavity and Oropharyngeal Cancers|journal=Journal of Clinical Oncology|date=20 December 2013|volume=31|issue=36|pages=4550–4559|doi=10.1200/JCO.2013.50.3870|pmid=24248688|pmc=3865341|ref={{harvid|Chaturvedi et al|2013}}}}
• {{cite journal|last1=Chenevert|first1=J|last2=Chiosea|first2=S|title=Incidence of human papillomavirus in oropharyngeal squamous cell carcinomas: now and 50 years ago|journal=Human Pathology|date=January 2012|volume=43|issue=1|pages=17–22|pmid=21777945|doi=10.1016/j.humpath.2011.03.009|ref=harv}}
• {{Cite journal| last1 = Cook | first1 = M.| last2 = Dawsey | first2 = S.| last3 = Freedman | first3 = N.| last4 = Inskip | first4 = P.| last5 = Wichner | first5 = S.| last6 = Quraishi | first6 = S.| last7 = Devesa | first7 = S.| last8 = McGlynn | first8 = K.| year = 2009| title = Sex disparities in cancer incidence by time period and age| journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 18 | issue = 4 | pages = 1174–1182| doi = 10.1158/1055-9965.EPI-08-1118| pmc = 2793271| pmid = 19293308|ref={{harvid|Cook et al|2009}}}}
• {{cite journal|last1=Dayyani|first1=Farshid|last2=Etzel|first2=Carol J|last3=Liu|first3=Mei|last4=Ho|first4=Chung-Han|last5=Lippman|first5=Scott M|last6=Tsao|first6=Anne S|title=Meta-analysis of the impact of human papillomavirus (HPV) on cancer risk and overall survival in head and neck squamous cell carcinomas (HNSCC)|journal=Head & Neck Oncology|date=2010|volume=2|issue=1|pages=15|doi=10.1186/1758-3284-2-15|pmid=20587061|pmc=2908081|ref={{harvid|Dayyani et al|2010}}}}
• {{Cite journal| last1 = D'Souza | first1 = G.| last2 = Kreimer | first2 = A.| last3 = Viscidi | first3 = R.| last4 = Pawlita | first4 = M.| last5 = Fakhry | first5 = C.| last6 = Koch | first6 = W.| last7 = Westra | first7 = W.| last8 = Gillison | first8 = M.| title = Case-control study of human papillomavirus and oropharyngeal cancer| journal = The New England Journal of Medicine| volume = 356| issue = 19| pages = 1944–1956| date=May 2007 | issn = 0028-4793| pmid = 17494927| doi = 10.1056/NEJMoa065497|ref={{harvid|D'Souza et al|2007}}}}
• {{cite journal|last1=de Martel|first1=Catherine|last2=Ferlay|first2=Jacques|last3=Franceschi|first3=Silvia|last4=Vignat|first4=Jérôme|last5=Bray|first5=Freddie|last6=Forman|first6=David|last7=Plummer|first7=Martyn|title=Global burden of cancers attributable to infections in 2008: a review and synthetic analysis|journal=The Lancet Oncology|date=June 2012|volume=13|issue=6|pages=607–615|doi=10.1016/S1470-2045(12)70137-7|pmid=22575588|ref={{harvid|de Martel et al|2012}}}}
• {{cite journal|last1=de Martel|first1=Catherine|last2=Plummer|first2=Martyn|last3=Vignat|first3=Jerome|last4=Franceschi|first4=Silvia|title=Worldwide burden of cancer attributable to HPV by site, country and HPV type|journal=International Journal of Cancer|date=15 August 2017|volume=141|issue=4|pages=664–670|doi=10.1002/ijc.30716|pmid=28369882|pmc=5520228|ref={{harvid|de Martel et al|2017}}}}
• {{Cite journal| last1 = Ernster | first1 = J.| last2 = Sciotto | first2 = C.| last3 = O'Brien | first3 = M.| last4 = Finch | first4 = J.| last5 = Robinson | first5 = L.| last6 = Willson | first6 = T.| last7 = Mathews | first7 = M.| title = Rising incidence of oropharyngeal cancer and the role of oncogenic human papilloma virus| journal = The Laryngoscope| volume = 117| issue = 12| pages = 2115–2128| date=Dec 2007 | issn = 0023-852X| pmid = 17891052| doi = 10.1097/MLG.0b013e31813e5fbb|ref={{harvid|Ernster et al|2007}} }}
• {{cite journal|last1=Forman|first1=David|last2=de Martel|first2=Catherine|last3=Lacey|first3=Charles J.|last4=Soerjomataram|first4=Isabelle|last5=Lortet-Tieulent|first5=Joannie|last6=Bruni|first6=Laia|last7=Vignat|first7=Jerome|last8=Ferlay|first8=Jacques|last9=Bray|first9=Freddie|last10=Plummer|first10=Martyn|last11=Franceschi|first11=Silvia|display-authors=3|title=Global Burden of Human Papillomavirus and Related Diseases|url=https://www.researchgate.net/publication/233836601|journal=Vaccine|date=November 2012|volume=30|pages=F12–F23|doi=10.1016/j.vaccine.2012.07.055|pmid=23199955|ref={{harvid|Forman et al|2012}}}}
• {{cite journal|last1=Gillison|first1=Maura L.|last2=Chaturvedi|first2=Anil K.|last3=Anderson|first3=William F.|last4=Fakhry|first4=Carole|title=Epidemiology of Human Papillomavirus–Positive Head and Neck Squamous Cell Carcinoma|journal=Journal of Clinical Oncology|date=10 October 2015|volume=33|issue=29|pages=3235–3242|doi=10.1200/JCO.2015.61.6995|pmc=4979086|ref={{harvid|Gillison et al|2015}}|pmid=26351338}}
• {{cite journal|last1=Habbous|first1=Steven|last2=Chu|first2=Karen P.|last3=Lau|first3=Harold|last4=Schorr|first4=Melissa|last5=Belayneh|first5=Mathieos|last6=Ha|first6=Michael N.|last7=Murray|first7=Scott|last8=O’Sullivan|first8=Brian|last9=Huang|first9=Shao Hui|last10=Snow|first10=Stephanie|last11=Parliament|first11=Matthew|last12=Hao|first12=Desiree|last13=Cheung|first13=Winson Y.|last14=Xu|first14=Wei|last15=Liu|first15=Geoffrey|display-authors=3|title=Human papillomavirus in oropharyngeal cancer in Canada: analysis of 5 comprehensive cancer centres using multiple imputation|journal=Canadian Medical Association Journal|date=13 August 2017|volume=189|issue=32|pages=E1030–E1040|doi=10.1503/cmaj.161379|pmid=28808115|pmc=5555753|ref={{harvid|Habbous et al|2017}}}}
• {{Cite journal| last1 = Hammarstedt | first1 = L.| last2 = Lindquist | first2 = D.| last3 = Dahlstrand | first3 = H.| last4 = Romanitan | first4 = M.| last5 = Dahlgren | first5 = L.| last6 = Joneberg | first6 = J.| last7 = Creson | first7 = N.| last8 = Lindholm | first8 = J.| last9 = Ye | first9 = W.| last10 = Dalianis | first10 = T.| last11 = Munck-Wikland | first11 = E.|display-authors=3| title = Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer|journal = International Journal of Cancer |volume = 119| issue = 11|pages = 2620–2623|date=Dec 2006 | issn = 0020-7136| pmid = 16991119 | doi = 10.1002/ijc.22177| ref={{harvid| Hammarstedt et al|2006}} }}
• {{cite journal|last1=Heck|first1=Julia E|last2=Berthiller|first2=Julien|last3=Vaccarella|first3=Salvatore|last4=Winn|first4=Deborah M|last5=Smith|first5=Elaine M|last6=Shan'gina|first6=Oxana|last7=Schwartz|first7=Stephen M|last8=Purdue|first8=Mark P|last9=Pilarska|first9=Agnieszka|last10=Eluf-Neto|first10=Jose|last11=Menezes|first11=Ana|last12=McClean|first12=Michael D|last13=Matos|first13=Elena|last14=Koifman|first14=Sergio|last15=Kelsey|first15=Karl T|last16=Herrero|first16=Rolando|last17=Hayes|first17=Richard B|last18=Franceschi|first18=Silvia|last19=Wünsch-Filho|first19=Victor|last20=Fernández|first20=Leticia|last21=Daudt|first21=Alexander W|last22=Curado|first22=Maria Paula|last23=Chen|first23=Chu|last24=Castellsagué|first24=Xavier|last25=Ferro|first25=Gilles|last26=Brennan|first26=Paul|last27=Boffetta|first27=Paolo|last28=Hashibe|first28=Mia|display-authors=3|title=Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium|journal=International Journal of Epidemiology|date=February 2010|volume=39|issue=1|pages=166–181|doi=10.1093/ije/dyp350|pmid = 20022926 |ref={{harvid|Heck et al|2010}}|pmc=2817092}}
• {{cite journal|last1=Hemminki|first1=K|last2=Dong|first2=C|last3=Frisch|first3=M|title=Tonsillar and other upper aerodigestive tract cancers among cervical cancer patients and their husbands|journal=European Journal of Cancer Prevention|date=December 2000|volume=9|issue=6|pages=433–437|doi=10.1097/00008469-200012000-00010|pmid = 11201683|ref={{harvid|Hemminki et al|2000}}}}
• {{cite journal|last1=Hong|first1=Angela M.|last2=Grulich|first2=Andrew E.|last3=Jones|first3=Deanna|last4=Lee|first4=C. Soon|last5=Garland|first5=Suzanne M.|last6=Dobbins|first6=Timothy A.|last7=Clark|first7=Jonathan R.|last8=Harnett|first8=Gerald B.|last9=Milross|first9=Christopher G.|last10=O’Brien|first10=Christopher J.|last11=Rose|first11=Barbara R.|title=Squamous cell carcinoma of the oropharynx in Australian males induced by human papillomavirus vaccine targets|journal=Vaccine|date=April 2010|volume=28|issue=19|pages=3269–3272|doi=10.1016/j.vaccine.2010.02.098|pmid = 20226244 |ref={{harvid|Hong et al|2010}}}}
• {{cite journal|last1=Hong|first1=Angela|last2=Lee|first2=C. Soon|last3=Jones|first3=Deanna|last4=Veillard|first4=Anne-Sophie|last5=Zhang|first5=Mei|last6=Zhang|first6=Xiaoying|last7=Smee|first7=Robert|last8=Corry|first8=June|last9=Porceddu|first9=Sandro|last10=Milross|first10=Christopher|last11=Elliott|first11=Michael|last12=Clark|first12=Jonathan|last13=Rose|first13=Barbara|display-authors=3|title=Rising prevalence of human papillomavirus-related oropharyngeal cancer in Australia over the last 2 decades|journal=Head & Neck|date=May 2016|volume=38|issue=5|pages=743–750|doi=10.1002/hed.23942|pmid=25521312|ref={{harvid|Hong et al|2016}}}}
• {{cite journal|last1=Hwang|first1=Tzer-Zen|last2=Hsiao|first2=Jenn-Ren|last3=Tsai|first3=Chia-Rung|last4=Chang|first4=Jeffrey S.|title=Incidence trends of human papillomavirus-related head and neck cancer in Taiwan, 1995-2009|journal=International Journal of Cancer|date=15 July 2015|volume=137|issue=2|pages=395–408|doi=10.1002/ijc.29330|pmid=25395239|ref={{harvid|Hwang et al|2015}}}}
• {{cite journal|last1=Jemal|first1=A.|last2=Siegel|first2=R.|last3=Ward|first3=E.|last4=Hao|first4=Y.|last5=Xu|first5=J.|last6=Murray|first6=T.|last7=Thun|first7=M. J.|title=Cancer Statistics, 2008|journal=CA: A Cancer Journal for Clinicians|date=28 January 2008|volume=58|issue=2|pages=71–96|doi=10.3322/CA.2007.0010|pmid=18287387|ref={{harvid|Jemal et al|2008}}}}
• {{Cite journal| last1 = Marur | first1 = S.| last2 = D'souza|first2 = G.| last3 = Westra | first3 = W. H.| last4 = Forastiere | first4 = A. A.|title = HPV-associated head and neck cancer: a virus-related cancer epidemic|

journal = The Lancet Oncology|year = 2010|volume = 11| issue = 8 | pages = 781–789|doi = 10.1016/S1470-2045(10)70017-6| pmid = 20451455| pmc = 5242182|ref={{harvid|Marur et al|2010}} }}* {{Cite journal| last1 = Näsman | first1 = A.| last2 = Attner | first2 = P.| last3 = Hammarstedt | first3 = L.| last4 = Du | first4 = J.| last5 = Eriksson | first5 = M.| last6 = Giraud | first6 = G.| last7 = Ahrlund-Richter | first7 = S.| last8 = Marklund | first8 = L.| last9 = Romanitan | first9 = M.| last10 = Lindquist| issue = 2| first10 = D. | last11 = Ramqvist | first11 = T. R.| last12 = Lindholm | first12 = J.| last13 = Sparén | first13 = P. R.| last14 = Ye | first14 = W.| last15 = Dahlstrand | first15 = H.| last16 = Munck-Wikland | first16 = E.| last17 = Dalianis | first17 = T.|display-authors=3| title = Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?|journal = International Journal of Cancer | volume = 125| pages = 362–366|date=July 2009|pmid = 19330833 |doi = 10.1002/ijc.24339|ref={{harvid|Nasman et al|2009}}}}

• {{Cite journal|last1 = Salem | first1 = A.|title = Dismissing links between HPV and aggressive tongue cancer in young patients| journal = Annals of Oncology|year = 2010|volume = 21| issue = 1| pages = 13–17| doi = 10.1093/annonc/mdp380| pmid = 19825879|ref=harv }}
• {{cite journal|last1=Schwartz|first1=S. M.|last2=Daling|first2=J. R.|last3=Madeleine|first3=M. M.|last4=Doody|first4=D. R.|last5=Fitzgibbons|first5=E. D.|last6=Wipf|first6=G. C.|last7=Carter|first7=J. J.|last8=Mao|first8=E.-J.|last9=Huang|first9=S.|last10=Beckmann|first10=A. M.|last11=McDougall|first11=J. K.|last12=Galloway|first12=D. A.|display-authors=3|title=Oral Cancer Risk in Relation to Sexual History and Evidence of Human Papillomavirus Infection|journal=JNCI Journal of the National Cancer Institute|date=4 November 1998|volume=90|issue=21|pages=1626–1636|doi=10.1093/jnci/90.21.1626|ref={{harvid|Schwartz et al|1998}}}}
• {{cite journal|last1=Siegel|first1=Rebecca|last2=Naishadham|first2=Deepa|last3=Jemal|first3=Ahmedin|title=Cancer statistics, 2013|journal=CA: A Cancer Journal for Clinicians|date=January 2013|volume=63|issue=1|pages=11–30|doi=10.3322/caac.21166|pmid=23335087|ref={{harvid|Siegel et al|2013}}}}
• {{cite journal|last1=Siegel|first1=Rebecca L.|last2=Miller|first2=Kimberly D.|last3=Jemal|first3=Ahmedin|title=Cancer statistics, 2015|journal=CA: A Cancer Journal for Clinicians|date=January 2015|volume=65|issue=1|pages=5–29|doi=10.3322/caac.21254|pmid=25559415|ref={{harvid|Siegel et al|2015}}}}
• {{cite journal|last1=Siegel|first1=Rebecca L.|last2=Miller|first2=Kimberly D.|last3=Jemal|first3=Ahmedin|title=Cancer statistics, 2017|journal=CA: A Cancer Journal for Clinicians|date=January 2017|volume=67|issue=1|pages=7–30|doi=10.3322/caac.21387|pmid=28055103|ref={{harvid|Siegel et al|2017}}}}
• {{Cite journal| last1 = Smith | first1 = E.| last2 = Ritchie | first2 = J.| last3 = Summersgill | first3 = K.| last4 = Klussmann | first4 = J.| last5 = Lee | first5 = J.| last6 = Wang | first6 = D.| last7 = Haugen | first7 = T.| last8 = Turek | first8 = L.| title = Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers| journal = International Journal of Cancer| volume = 108| issue = 5| pages = 766–772| date=Feb 2004 | issn = 0020-7136| pmid = 14696105| doi = 10.1002/ijc.11633 |ref={{harvid|Smith et al|2004}}}}
• {{Cite journal| last1 = Sturgis | first1 = E.| last2 = Cinciripini | first2 = P.| title = Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers?| journal = Cancer| volume = 110| issue = 7| pages = 1429–1435| date=Oct 2007 | issn = 0008-543X| pmid = 17724670 | doi = 10.1002/cncr.22963 |ref=harv}}
• {{cite journal|last1=Sturgis|first1=EM|last2=Ang|first2=KK|title=The epidemic of HPV-associated oropharyngeal cancer is here: is it time to change our treatment paradigms?|journal=Journal of the National Comprehensive Cancer Network : JNCCN|date=1 June 2011|volume=9|issue=6|pages=665–73|doi=10.6004/jnccn.2011.0055|pmid=21636538|ref=harv}}
• {{cite journal|last=Tachezy|first=R|title=HPV and other risk factors of oral cavity/oropharyngeal cancer in the Czech Republic|journal=Oral Diseases|volume=11|issue=3|pages=181–185|pmid=15888110|doi=10.1111/j.1601-0825.2005.01112.x|date=May 2005|ref=harv}}
• {{cite journal|last1=Tezal|first1=Mine|last2=Sullivan Nasca|first2=Maureen|last3=Stoler|first3=Daniel L.|last4=Melendy|first4=Thomas|last5=Hyland|first5=Andrew|last6=Smaldino|first6=Philip J.|last7=Rigual|first7=Nestor R.|last8=Loree|first8=Thom R.|title=Chronic Periodontitis−Human Papillomavirus Synergy in Base of Tongue Cancers|journal=Archives of Otolaryngology–Head & Neck Surgery|date=1 April 2009|volume=135|issue=4|pages=391–6|doi=10.1001/archoto.2009.6|pmid = 19380363|ref={{harvid|Tezal et al|2009}}}}
• {{cite journal|last1=Tezal|first1=M.|last2=Sullivan|first2=M. A.|last3=Hyland|first3=A.|last4=Marshall|first4=J. R.|last5=Stoler|first5=D.|last6=Reid|first6=M. E.|last7=Loree|first7=T. R.|last8=Rigual|first8=N. R.|last9=Merzianu|first9=M.|last10=Hauck|first10=L.|last11=Lillis|first11=C.|last12=Wactawski-Wende|first12=J.|last13=Scannapieco|first13=F. A.|display-authors=3|title=Chronic Periodontitis and the Incidence of Head and Neck Squamous Cell Carcinoma|journal=Cancer Epidemiology, Biomarkers & Prevention|date=10 September 2009|volume=18|issue=9|pages=2406–2412|doi=10.1158/1055-9965.EPI-09-0334| pmid = 19745222|ref={{harvid|Tezal et al|2009a}}}}
• {{cite journal|last1=Viens|first1=Laura J.|last2=Henley|first2=S. Jane|last3=Watson|first3=Meg|last4=Markowitz|first4=Lauri E.|last5=Thomas|first5=Cheryll C.|last6=Thompson|first6=Trevor D.|last7=Razzaghi|first7=Hilda|last8=Saraiya|first8=Mona|title=Human Papillomavirus–Associated Cancers — United States, 2008–2012|journal=MMWR. Morbidity and Mortality Weekly Report|date=8 July 2016|volume=65|issue=26|pages=661–666|doi=10.15585/mmwr.mm6526a1|pmid=27387669|ref={{harvid|Viens et al|2016}}}}

Books and conference proceedings

• {{cite book|editor-last=Bernier|editor-first=Jacques|title=Head and Neck Cancer: Multimodality Management|url=https://books.google.com/books?id=BCLkDAAAQBAJ|date= 2016|publisher=Springer International Publishing|isbn=978-3-319-27601-4}}
• {{cite book|editor-last1=Brierley |editor-first1= J.D.|editor-last2=Gospodarowicz|editor-first2=M.K.|editor-last3=Wittekind|editor-first3=Ch.|title=TNM classification of malignant tumours|url=https://books.google.ca/books?id=642GDQAAQBAJ|date=2017|publisher=Wiley-Blackwell|location=Chichester, West Sussex, UK|isbn=978-1-4443-3241-4|edition=8th|ref={{harvid|TNM 8|2017}}}}
• {{cite book|editor-last1=Cardesa|editor-first1=Antonio|editor-last2=Slootweg|editor-first2=Pieter J.|editor-last3=Gale|editor-first3=Nina|editor-last4=Franchi|editor-first4=Alessandro|title=Pathology of the Head and Neck|url=https://books.google.com/books?id=ag4bDgAAQBAJ|date=2017|publisher=Springer|isbn=978-3-662-49672-5|edition=2nd}}
• {{cite book|editor-last1=Golusiński|editor-first1=Wojciech|editor-last2=Leemans|editor-first2=C René|editor-last3=Dietz|editor-first3=Andreas|title=HPV Infection in Head and Neck Cancer|url=https://books.google.com/books?id=T8kwDQAAQBAJ|date= 2016|publisher=Springer|isbn=978-3-319-43580-0|ref={{harvid|Golusiński et al|2016}}}}
• {{cite book|editor-last1=DeVita|editor-first1=Vincent T.|editor-last2=Lawrence|editor-first2=Theodore S.|editor-last3=Rosenberg|editor-first3=Steven A.|editorlink1=Vincent DeVita|title=DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology|url=https://books.google.com/books?id=yrBI5zx69X8C|year=2008|origyear=1982|edition=8th|publisher=Lippincott Williams & Wilkins|location=Philadelphia|isbn=978-0-7817-7207-5|ref={{harvid|deVita et al|2008}}}}
• {{cite book|editor-last=Hayat|editor-first=M. A.|title=Methods of Cancer Diagnosis, Therapy, and Prognosis: Volume 7 - General Overviews, Head and Neck Cancer and Thyroid Cancer|url=https://books.google.com/books?id=saE1RuGXbgYC|date= 2010|publisher=Springer Science & Business Media|isbn=978-90-481-3186-0|ref=harv}}
• {{cite book|editor-last1=Kerr|editor-first1=David J.|editor-last2=Haller|editor-first2=Daniel G.|editor-last3=van de Velde|editor-first3=Cornelis J.H.|editor-last4=Baumann|editor-first4=Michael|editorlink1=David Kerr (oncologist)|

title=Oxford Textbook of Oncology|url=https://books.google.com/books?id=nbgoCwAAQBAJ|year=2016|origyear=1995|publisher=Oxford University Press|edition=3rd|isbn=978-0-19-965610-3|ref={{harvid|Kerr et al|2016}}}}

• {{cite book|editor-last1=Myers|editor-first1=Jeffrey N.|editor-last2=Sturgis|editor-first2=Erich M.|title=Oral Cavity and Oropharyngeal Cancer, An Issue of Otolaryngologic Clinics, E-Book|url=https://books.google.com/books?id=XYRRAAAAQBAJ|date= 2013|publisher=Elsevier Health Sciences|isbn=978-0-323-18632-2|ref=harv}}
• {{cite book|editor-last=Olshan|editor-first=Andrew F.|title=Epidemiology, Pathogenesis, and Prevention of Head and Neck Cancer|url=https://books.google.com/books?id=EKIFGVDeDPEC|date= 2010|publisher=Springer Science & Business Media|isbn=978-1-4419-1471-2|ref=harv}}
• {{cite book|editor-last1=Sobin|editor-first1= L.H.|editor-last2=Gospodarowicz|editor-first2=M.K.|editor-last3=Wittekind|editor-first3=Ch.|title=TNM classification of malignant tumours|url=https://books.google.ca/books?id=sUaevQ0I_8kC|date=2010|publisher=Wiley-Blackwell|location=Chichester, West Sussex, UK|isbn=978-1-4443-3241-4|edition=7th|ref={{harvid|TNM 7|2010}}}}
• {{cite book|editor-last=Standring|editor-first=Susan|editor-link=Susan Standring|title=Gray's Anatomy: The Anatomical Basis of Clinical Practice|url=https://books.google.com/books?id=b7FVCgAAQBAJ|date= 2015|edition=41st|publisher=Elsevier Health Sciences|isbn=978-0-7020-6851-5|ref=harv}}, see also Gray's Anatomy
• {{cite journal|title=Annual Meeting of the American Academy of Otolaryngology, Chicago, September 10-13, 2017: Oral presentations|journal=Otolaryngology–Head and Neck Surgery|date=30 August 2017|volume=157|issue=1 suppl|pages=P40–P173|doi=10.1177/0194599817717251|pmid=28854028|ref={{harvid|AAO|2017}}}}

Chapters, monographs, reports and theses

• {{cite book|last1=Bruni|first1=L|last2=Barrionuevo-Rosas|first2=L|last3=Albero|first3=G|last4=Serrano|first4=B|last5=Mena|first5=M|last6=Gómez|first6=D|last7=Muñoz|first7=J|last8=Bosch|first8=FX|last9=de Sanjosé|first9=S|title=Human Papillomavirus and Related Diseases in the World|date=7 July 2017|publisher=HPVIC|url=http://www.hpvcentre.net/statistics/reports/XWX.pdf|accessdate=11 August 2017}}, in {{harvtxt|HPVIC|2017}}
• {{cite book|last=Chaturvedi|first=Anil|last2=Gillison|first2=Maura L.| title=Human Papillomavirus and Head and Neck Cancer|pages=87–116| url=https://books.google.com/books?id=EKIFGVDeDPEC&pg=PA87|isbn=978-1-4419-1471-2|ref={{harvid|Chaturvedi|Gillison|2010}}|date=2010-03-04}}, in {{harvtxt|Olshan|2010}}
• {{cite book|last1=Chung|first1=Christine H|last2=Dietz|first2=Andreas|last3=Gregoire|first3=Vincent|display-authors=etal |title=Head and neck cancer|pages=329–364|url=https://books.google.ca/books?id=nbgoCwAAQBAJ&pg=PA329|ref={{harvid|Chung et al|2016}}|isbn=9780199656103|year=2016}}, in {{harvtxt|Kerr et al|2016}}
• {{citation |last=Hammarstedt|first=Lalle|title=Tonsillar Cancer - Incidence, Prevalence of HPV and Survival|url=https://openarchive.ki.se/xmlui/handle/10616/39379|date=25 April 2008|accessdate=3 June 2017|publisher=Department of Clinical Neuroscience, Karolinska Institutet|location=Stockholm|type=PhD thesis|isbn=978-91-7357-587-4}}
• {{cite book|last=McHanwell|first=Stephen|title=Pharynx|url=https://books.google.com/books?id=b7FVCgAAQBAJ&pg=PA571|pages=571–585|ref={{harvid|McHanwell|2015}}|isbn=9780702068515|date=2015-08-07}}, in {{harvtxt|Standring|2015}}
• {{cite book|last1=Helliwell|first1=T|last2=Woolgar|first2=JA|title=Standards and minimum datasets for reporting common cancers. Minimum dataset for head and neck histopathology reports|date=1998|publisher=The Royal College of Pathologists|location=London|ref=harv}}
• {{cite book|last1=Johnson|first1=Newell|last2=Chaturvedi|first2=Anil|title=Global burden of oral cavity and pharyngeal cancers|date=2016|url=http://www.globaloralcancerforum.org/img/White-Paper-Group-1.pdf|type=Conference white paper|accessdate=12 August 2017|ref=harv}}, in {{harvtxt|GOCF|2016}}
• {{Cite book|last1=Mehanna|first1=H|title=Update on De-intensification and Intensification Studies in HPV|journal=Recent Results in Cancer Research. Fortschritte der Krebsforschung. Progres dans les Recherches Sur le Cancer|volume=206|pages=251–256|doi=10.1007/978-3-319-43580-0_20|pmid=27699545|ref={{harvid|Mehanna|2016}}|series=Recent Results in Cancer Research|isbn=978-3-319-43578-7|year=2017}}, in {{harvtxt|Golusiński et al|2016}} excerpt [https://link.springer.com/chapter/10.1007%2F978-3-319-43580-0_20 here]
• {{cite book|last1=Munck-Wikland|first1=Eva|last2=Hammarstedt|first2=Lalle |last3=Dahlstrand|first3=Hanna|title=Role of Human Papillomavirus in Tonsillar Cancer|url=https://books.google.com/books?id=saE1RuGXbgYC&pg=PA272|pages=271–283|ref={{harvid|Munck-Wikland|2010}}|isbn=9789048131860|date=2010-04-07}}, in {{harvtxt|Hayat|2010}} (additional extract here)
• {{cite journal|last1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|title=Human papillomaviruses|url=https://www.ncbi.nlm.nih.gov/books/NBK424408/|journal=IARC Monographs on the Evaluation of Carcinogenic Risks to Humans|date=1995|volume=64|pages=1–378|pmid=16755705|ref={{harvid|IARC| 1995}}|pmc=5366848}}
• {{cite journal|last1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|title=Human papillomaviruses|url=https://www.ncbi.nlm.nih.gov/books/NBK321760/|journal=IARC Monographs on the Evaluation of Carcinogenic Risks to Humans|date=2007|volume=90|pages=1–636|pmid=18354839|ref={{harvid|IARC| 2007}}|pmc=4781057}}
• {{cite book|last1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|title=Biological Agents|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK304348/|journal=IARC Monographs on the Evaluation of Carcinogenic Risks to Humans|date=2012|volume=100B|pages=255–314|chapter=Human Papilloviruses|isbn=978-9283213192|publisher=International Agency for Research on Cancer|location=Lyon|ref={{harvid|IARC| 2012}}}}

Websites

• {{cite web|last1=Bath|first1=Charlotte|title=Deintensifiying Treatment of HPV-Positive Oropharyngeal Cancer Could Reduce Toxicity While Maintaining Function and Survival|url=http://www.ascopost.com/issues/april-25-2017/deintensifiying-treatment-of-hpv-positive-oropharyngeal-cancer-could-reduce-toxicity-while-maintaining-function-and-survival/|website=ASCO Post|publisher=ASCO|accessdate=3 August 2017|date=25 April 2017|type=Report of 2016 Multidisciplinary Head & Neck Symposium |ref={{harvid|Bath|2017}}}}
• {{cite web|last1=Hunt|first1=Jennifer L|title=Molecular Assessment of HPV in Patients with Head and Neck Tumors|url=https://www.uscap.org/site~/99th/pdf/companion04h03.pdf|website=Association for Molecular Pathology|publisher=United States and Canadian Academy of Pathology|accessdate=30 May 2017|archiveurl=https://web.archive.org/web/20110716080255/https://www.uscap.org/site~/99th/pdf/companion04h03.pdf|archivedate=16 July 2011|date=21 March 2010|ref=harv|deadurl=yes}}
• {{cite web|title=Cancer of the Oral Cavity and Pharynx by Subsite|url=http://seer.cancer.gov/csr/1975_2007/results_single/sect_20_table.09.pdf|date=15 April 2010|work=SEER Cancer Statistics Review 1975-2007|publisher=Surveillance, Epidemiology, and End Results (SEER) Program|accessdate=3 June 2017|ref={{harvid|SEER|2010}}}}
• {{cite web|title=The Pharynx|url=http://teachmeanatomy.info/neck/viscera/pharynx/|website=TeachMeAnatomy|publisher=TeachMe|accessdate=20 June 2017|date=29 April 2017|ref={{harvid|Teach Me|2017}}}}
• {{anchor|Levels}}{{Cite journal|last1=Dubner|first1=Sanford|title=Head and Neck Cancer - Resection and Neck Dissection: Relevant Anatomy|url=http://emedicine.medscape.com/article/1289474-overview#a9|website=Medscape|publisher=WebMD|accessdate=17 July 2017|date=19 June 2017}}
• {{Cite journal|last1=Joshi|first1=Arjun S|last2=Vashishta|first2=Rishi|last3=George|first3=Philip E|title=Pharynx Anatomy|url=http://emedicine.medscape.com/article/1949347-overview|website=Medscape|publisher=WebMD|accessdate=20 June 2017|date=18 November 2013|ref={{harvid|Joshi et al|2013}}}}
• {{cite web|title=Oropharyngeal Cancer Treatment|url=https://www.cancer.gov/types/head-and-neck/patient/oropharyngeal-treatment-pdq#section/_22|website=Head and neck Cancer - Patient version|publisher=National Institutes of Health - National Cancer Institute|accessdate=12 June 2017|date=December 2016|ref={{harvid|NCI|2016}}}}
• {{Cite book|title=Oropharyngeal Cancer Treatment (Adult) (PDQ®)|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK65723/#CDR0000062924__16|website= Head and Neck Cancer. Health professional version|publisher=National Institutes of Health - National Cancer Institute|accessdate=1 July 2018|date=28 March 2018|ref={{harvid|NCI|2016a}}|chapter=Oropharyngeal Cancer Treatment (Adult) (PDQ®): Health Professional Version}}
• {{cite web|title=Oropharyngeal Cancer Treatment|url=http://www.emedicinehealth.com/oropharyngeal_cancer_treatment/article_em.htm|website=emedicinehealth|publisher=WebMD|accessdate=6 August 2017|date=1 August 2017}}
• {{Cite video | title = Is Oral Sex Safe? | url = http://www.bbc.co.uk/programmes/b00xhdzl | medium = Television production | publisher = BBC Three | location = England | date = 10 January 2011 }}
• {{cite web|title=HPV Information Centre|url=http://www.hpvcentre.net/|publisher=International Agency for Research on Cancer & Catalan Institute of Oncology|accessdate=11 August 2017|location=Lyon|ref={{harvid|HPVIC|2017}}}}
• {{cite web|title=The Global Oral Cancer Forum 2016|url=http://www.globaloralcancerforum.org/|publisher=Henry Schein Cares Foundation|type=Conference proceedings|accessdate=12 August 2017|date=2017|ref={{harvid|GOCF|2016}}}}
• {{cite web |title=Cetuximab with radiation found to be inferior to standard treatment in HPV-positive oropharyngeal cancer |url=https://www.nih.gov/news-events/news-releases/cetuximab-radiation-found-be-inferior-standard-treatment-hpv-positive-oropharyngeal-cancer |website=News releases |publisher=National Institutes of Health |accessdate=15 August 2018 |date=14 August 2018|ref={{harvid|NIH|2018}}}}

Treatment guidelines

• {{cite web|title=Head and Neck Cancer Evidence-based Series (EBS) and Practice Guidelines (PG)|url=https://www.cancercare.on.ca/toolbox/qualityguidelines/diseasesite/head-neck-ebs/|website=Evidence Based Guidelines|publisher=Cancer Care Ontario|accessdate=22 May 2017|date=31 March 2017|ref={{harvid|CCO|2017}}}}
• {{cite web|title=The Management of Head and Neck Cancer in Ontario. EBS 5-3|url=https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=279838|accessdate=22 May 2017|date=December 2009|ref={{harvid|EBS|2009}}}}, in {{harvtxt|CCO|2017}}
• {{cite web|title=Routine HPV Testing in Head and Neck Squamous Cell Carcinoma. EBS 5-9|url=https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=279838|accessdate=22 May 2017|date=May 2013|ref={{harvid|EBS|2013}}}}, in {{harvtxt|CCO|2017}}
• {{cite web|title=Head and Neck Cancers|url=https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf|website=NCCN Guidelines 2.2018|publisher=National Comprehensive Cancer Network|accessdate=22 June 2018|date=20 June 2018|ref={{harvid|NCCN|2018}}}}
• {{cite web|title=Head & Neck|url=http://www.bccancer.bc.ca/health-professionals/clinical-resources/cancer-management-guidelines/head-neck|website=Cancer Management Guidelines|publisher=BC Cancer Agency|accessdate=30 June 2017|location=British Columbia|date=2017}}

External links

• {{cite web|title=Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03)|url=https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf|website=CTCAE|publisher=National Cancer Institute|accessdate=3 August 2017|date=14 June 2010|ref={{harvid|CTCAE|2010}}}}

• Recursion
• Recursion definition
• Recursionism
• Recursion novel
• Recursion (novel)
• Recursion relation
• Recursive
• Recursive Acronym
• Recursive acronym
• Recursive acronyms
• Recursive advertising
• Recursive algorithm
• Recursive Bayesian estimation
• Recursive categorical syntax
• Recursive data type
• Recursive definition
• Recursive descent parser
• Recursive filter
• Recursive functions
• Recursive Least Squares
• Recursive least squares algorithm
• Recursive least squares filter
• Recursively
• Recursively definable
• Recursively enumerable