{"entity":{"id":"hpv-positive-oropharyngeal-cancer","kind":"cancer","name":"HPV-positive oropharyngeal cancer","aka":["p16-positive oropharyngeal cancer","HPV-associated oropharyngeal squamous cell carcinoma","HPV-driven throat cancer"],"tldr":"Throat cancers caused by HPV are usually cured with chemoradiation or robotic surgery, so trials now ask how much treatment can be taken away: swapping cisplatin for cetuximab failed, cutting the radiation dose has worked only after surgery so far, and blood tests for HPV DNA may pick out the patients who can safely have less.","summary":"HPV-positive oropharyngeal squamous cell carcinoma arises in the tonsils and base of tongue when high-risk human papillomavirus, almost always type 16, integrates into the crypt epithelium and its E6 and E7 proteins disable p53 and Rb. Tumours are recognised by strong p16 staining, confirmed by HPV DNA or RNA testing where available, and they present with a neck node and a small primary. The RTOG 0129 analysis by Ang and colleagues in 2010 showed three-year overall survival of 82.4 percent for HPV-positive against 57.1 percent for HPV-negative disease, with smoking history worsening the outlook, and the eighth edition of the staging system gave HPV-positive disease a staging system of its own.\n\nStandard treatment is cisplatin chemoradiation to 70 Gy, or transoral robotic surgery with neck dissection followed by pathology-guided adjuvant treatment for smaller tumours. Two trials that replaced cisplatin with cetuximab to spare toxicity both failed: RTOG 1016 found five-year overall survival of 84.6 percent with cisplatin against 77.9 percent with cetuximab, and De-ESCALaTE found two-year survival of 97.5 against 89.4 percent, so cetuximab is reserved for patients who cannot have cisplatin. The Canadian ORATOR trial found swallowing scores slightly better after radiotherapy than after surgery, so neither route is superior for every patient.\n\nDe-escalation has worked only where selection was tight. NRG-HN002 found that 60 Gy with weekly cisplatin met its two-year progression-free survival threshold while 60 Gy alone did not; NRG-HN005 then closed early because the reduced-dose arms had worse progression-free survival than the 70 Gy control. After transoral surgery, however, ECOG-ACRIN E3311 reported two-year progression-free survival of about 95 percent with 50 Gy in intermediate-risk patients, and PATHOS is testing the same approach with swallowing and survival endpoints. Circulating tumour HPV DNA, shown by Chera and colleagues in 2020 to detect recurrence before scans, is now being used to adapt treatment, and HPV vaccination of boys and girls is expected to prevent most future cases.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/HPV-positive_oropharyngeal_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/HPV-positive_oropharyngeal_cancer"}],"tags":["subtype-page","head-and-neck"],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-ang-hpv-oropharyngeal-nejm-2010","paper-rtog-1016-lancet-2019","paper-de-escalate-lancet-2019","paper-e3311-transoral-surgery-ferris-jco-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"Now the majority of oropharyngeal cancers in North America and Western Europe, typically in men in their fifties and sixties who never smoked heavily; in the RTOG 0129 analysis three-year survival was 82 percent against 57 percent for HPV-negative disease.","subtypes":["HPV-positive tonsil cancer","HPV-positive base of tongue cancer","Low-risk (small primary, limited nodes, light or never smoker) disease eligible for de-escalation trials","High-risk HPV-positive disease (heavy smokers, bulky or low neck nodes)","p16-positive but HPV DNA-negative discordant tumours (behave more like HPV-negative disease)"],"biomarkers":["p16 immunohistochemistry (strong nuclear and cytoplasmic staining in at least 70 percent of cells)","HPV DNA or E6/E7 RNA in situ hybridisation (confirms p16)","Smoking pack-years (modifies risk group)","Circulating tumour HPV DNA (surveillance and adaptive de-escalation)","PD-L1 combined positive score (recurrent disease)"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Fine-needle biopsy of the neck node with p16 staining, HPV confirmation where p16 is equivocal, examination and imaging of the tonsils and tongue base, and PET-CT; staged with the HPV-positive system.","refs":["hpv-p16","pet-ct"],"guideline":{"version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Early disease (small primary, limited nodes)","approach":"Transoral robotic surgery with neck dissection and pathology-guided adjuvant radiotherapy (E3311), or radiotherapy alone; choice by expected swallowing and voice.","refs":["tors","imrt-igrt","ecog-e3311"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Locally advanced disease","approach":"Cisplatin chemoradiation to 70 Gy; cetuximab only for patients who cannot have cisplatin, since RTOG 1016 and De-ESCALaTE showed it inferior.","refs":["cisplatin","chemoradiation","imrt-igrt","cetuximab","rtog-1016","de-escalate"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"De-escalation","approach":"Reduced-dose or chemotherapy-free treatment only within a trial; NRG-HN005 showed that lowering the dose in definitive chemoradiation on HPV status alone loses control.","refs":["nrg-hn002-hn005","pathos","cthpv-dna","hpv-deescalation-caution"]},{"setting":"Surveillance","approach":"Examination and PET-CT at about three months; circulating tumour HPV DNA is emerging as a blood test for recurrence.","refs":["pet-ct","cthpv-dna"]},{"setting":"Recurrent or metastatic","approach":"Pembrolizumab alone or with platinum-fluorouracil (KEYNOTE-048); HPV-positive tumours respond at least as well as HPV-negative ones.","refs":["pembrolizumab","keynote-048","recurrent-metastatic-hnscc"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Prevention","approach":"HPV vaccination of girls and boys before exposure; catch-up vaccination of men is being argued for.","refs":["hpv-vaccine","gardasil-9","idea-prev-hpv-male-catchup-oropharynx"]}],"stateOfArt":["Cure rates above 80 percent with standard chemoradiation make toxicity, not survival, the main problem, which is why every major trial of the last decade has tried to remove treatment.","Surgery-first de-escalation (E3311, PATHOS) has held up; radiotherapy-dose de-escalation in the definitive setting (NRG-HN005) has not.","Circulating tumour HPV DNA is the most promising selector for who can have less and who is relapsing."],"history":[{"year":2000,"title":"Gillison links HPV16 to a distinct subset of oropharyngeal cancers","refs":[]},{"year":2010,"title":"RTOG 0129 analysis: HPV status is the strongest prognostic factor","refs":["rtog-0129"]},{"year":2017,"title":"Separate staging system for HPV-positive disease (AJCC 8th edition)","refs":[]},{"year":2019,"title":"RTOG 1016 and De-ESCALaTE: cetuximab inferior to cisplatin","refs":["rtog-1016","de-escalate"]},{"year":2020,"title":"Circulating tumour HPV DNA detects recurrence before imaging","refs":["cthpv-dna"]},{"year":2021,"title":"NRG-HN002: 60 Gy with cisplatin acceptable, 60 Gy alone not","refs":["nrg-hn002-hn005"]},{"year":2022,"title":"E3311: reduced-dose radiotherapy after transoral surgery","refs":["ecog-e3311"]},{"year":2025,"title":"NRG-HN005 closed: de-escalated chemoradiation arms worse","refs":["nrg-hn002-hn005"]}],"pipeline":["cthpv-dna","pathos","nrg-hn002-hn005","idea-cthpv-adapted-deescalation","bnt113","nct04534205","hpv-vaccine"],"openProblems":["Which patients can safely have less treatment, and by what test.","Long-term dry mouth, swallowing difficulty and fibrosis in people cured in their fifties.","Whether therapeutic HPV vaccines add to immunotherapy in recurrent disease.","HPV vaccination uptake in boys and in countries where the epidemic is beginning."],"parent":"oropharyngeal-cancer"},"route":"/cancers/hpv-positive-oropharyngeal-cancer/","neighbours":{"paper":[{"id":"paper-de-escalate-lancet-2019","kind":"paper","name":"De-ESCALaTE HPV: radiotherapy plus cisplatin or cetuximab in low-risk HPV-positive oropharyngeal cancer","route":"/key-papers/paper-de-escalate-lancet-2019/"},{"id":"paper-e3311-transoral-surgery-ferris-jco-2022","kind":"paper","name":"ECOG-ACRIN E3311: transoral surgery followed by reduced-dose radiotherapy for HPV-positive oropharyngeal cancer","route":"/key-papers/paper-e3311-transoral-surgery-ferris-jco-2022/"},{"id":"paper-ang-hpv-oropharyngeal-nejm-2010","kind":"paper","name":"Human papillomavirus and survival of patients with oropharyngeal cancer (RTOG 0129)","route":"/key-papers/paper-ang-hpv-oropharyngeal-nejm-2010/"},{"id":"paper-rtog-1016-lancet-2019","kind":"paper","name":"NRG Oncology RTOG 1016: radiotherapy plus cetuximab versus cisplatin in HPV-positive oropharyngeal cancer","route":"/key-papers/paper-rtog-1016-lancet-2019/"}],"trial":[{"id":"nct04534205","kind":"trial","name":"A Clinical Trial Investigating the Safety, Tolerability, and Therapeutic Effects of BNT113 in Combination With Pembrolizumab Versus Pembrolizumab Alone for Patients With a Form of Head and Neck Cancer Positive for Human Papilloma Virus 16 and Expressing the Protein PD-L1","route":"/trials/nct04534205/"},{"id":"nct06797986","kind":"trial","name":"A Phase I/IIa Clinical Trial to Investigate BVAC-E6E7 in Subjects With HPV Positive HNSCC.","route":"/trials/nct06797986/"},{"id":"nct06319963","kind":"trial","name":"A Study to Evaluate Lenti-HPV-07 Immunotherapy Against HPV+ Cervical or Oropharyngeal Cancer","route":"/trials/nct06319963/"},{"id":"de-escalate","kind":"trial","name":"De-ESCALaTE HPV","route":"/trials/de-escalate/"},{"id":"ecog-e3311","kind":"trial","name":"ECOG-ACRIN E3311","route":"/trials/ecog-e3311/"},{"id":"keynote-048","kind":"trial","name":"KEYNOTE-048","route":"/trials/keynote-048/"},{"id":"nrg-hn002-hn005","kind":"trial","name":"NRG-HN002 & NRG-HN005 (HPV+ de-escalation)","route":"/trials/nrg-hn002-hn005/"},{"id":"pathos","kind":"trial","name":"PATHOS","route":"/trials/pathos/"},{"id":"rtog-0129","kind":"trial","name":"RTOG 0129 (HPV analysis)","route":"/trials/rtog-0129/"},{"id":"rtog-1016","kind":"trial","name":"RTOG 1016","route":"/trials/rtog-1016/"}],"technology":[{"id":"cthpv-dna","kind":"technology","name":"Circulating tumour HPV DNA (ctHPV-DNA)","route":"/technologies/cthpv-dna/"},{"id":"hpv-vaccine","kind":"technology","name":"HPV & HBV vaccination","route":"/technologies/hpv-vaccine/"},{"id":"imrt-igrt","kind":"technology","name":"IMRT / IGRT (modern external beam)","route":"/technologies/imrt-igrt/"},{"id":"pet-ct","kind":"technology","name":"PET/CT","route":"/technologies/pet-ct/"},{"id":"tors","kind":"technology","name":"Transoral robotic surgery (TORS)","route":"/technologies/tors/"}],"idea":[{"id":"idea-prev-hpv-male-catchup-oropharynx","kind":"idea","name":"Catch-up HPV vaccination for men to prevent throat cancer","route":"/ideas/idea-prev-hpv-male-catchup-oropharynx/"},{"id":"idea-cthpv-adapted-deescalation","kind":"idea","name":"ctHPV-DNA-adapted de-escalation of chemoradiation","route":"/ideas/idea-cthpv-adapted-deescalation/"}],"drug":[{"id":"bnt113","kind":"drug","name":"BNT113","route":"/drugs/bnt113/"},{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/"},{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/"},{"id":"gardasil-9","kind":"drug","name":"Nonavalent HPV vaccine","route":"/drugs/gardasil-9/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"term":[{"id":"chemoradiation","kind":"term","name":"Chemoradiation (chemoradiotherapy, CRT)","route":"/terms/chemoradiation/"},{"id":"extranodal-extension","kind":"term","name":"Extranodal extension (ENE)","route":"/terms/extranodal-extension/"},{"id":"hpv-p16","kind":"term","name":"HPV-positive (p16) head and neck cancer","route":"/terms/hpv-p16/"}],"pairing":[{"id":"hpv-deescalation-caution","kind":"pairing","name":"Caution: de-escalating radiation on HPV status alone","route":"/pairings/hpv-deescalation-caution/"}],"cancer":[{"id":"oropharyngeal-cancer","kind":"cancer","name":"Oropharyngeal cancer (tonsil and base of tongue)","route":"/cancers/oropharyngeal-cancer/"},{"id":"recurrent-metastatic-hnscc","kind":"cancer","name":"Recurrent or metastatic head and neck squamous cell carcinoma","route":"/cancers/recurrent-metastatic-hnscc/"}]}}