# HPV-negative head and neck squamous cell carcinoma (including HPV-negative oropharyngeal cancer)

Source: https://onco.cc/cancers/hpv-negative-head-and-neck-cancer/  
OnCo record `hpv-negative-head-and-neck-cancer` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Head and neck cancers caused by tobacco and alcohol rather than HPV are harder to cure: surgery or cisplatin chemoradiation is the mainstay, immunotherapy given around surgery (KEYNOTE-689) or after it (NIVOPOSTOP) has begun to help, and pembrolizumab is the first treatment once the disease has spread.

## Summary

HPV-negative head and neck squamous cell carcinoma is the classical, tobacco and alcohol driven disease of the oral cavity, larynx, hypopharynx and oropharynx, with areca nut and chewed tobacco the cause in South Asia. Tumours almost always carry TP53 mutation and CDKN2A loss, often EGFR overexpression, and arise from a field of damaged mucosa that produces second primaries; HPV-negative oropharyngeal cancer had three-year survival of 57.1 percent in the RTOG 0129 analysis against 82.4 percent for HPV-positive disease, and it is staged and treated with the other HPV-negative sites rather than with HPV-positive oropharyngeal cancer.

Curative treatment is surgery followed by radiotherapy, with cisplatin added when there is extranodal extension or a positive margin (the Bernier and Cooper trials of 2004), or definitive cisplatin chemoradiation, which the MACH-NC meta-analysis showed adds about 6.5 percentage points to five-year survival over radiotherapy alone; cetuximab with radiotherapy (Bonner) is the option for patients who cannot have cisplatin. Adding PD-1 or PD-L1 antibodies during chemoradiation failed in JAVELIN Head and Neck 100 and KEYNOTE-412, and the radiosensitiser xevinapant made outcomes worse in TrilynX, but immunotherapy around surgery has succeeded: KEYNOTE-689 gave median event-free survival of 59.7 against 29.6 months with perioperative pembrolizumab in tumours with a PD-L1 combined positive score of 1 or more, and NIVOPOSTOP raised three-year disease-free survival from 52.5 to 63.1 percent with nivolumab added to postoperative chemoradiation.

Recurrent or metastatic disease is treated as for all head and neck squamous cell carcinoma: pembrolizumab alone or with platinum and fluorouracil (KEYNOTE-048) replaced the cetuximab-based EXTREME regimen, though HPV-negative tumours respond less often to PD-1 blockade than HPV-positive ones. Trials now target this group specifically: FORTIFI-HN01 tests the EGFR and TGF-beta antibody ficerafusp alfa with pembrolizumab only in HPV-negative disease, and a phase 3 of ficlatuzumab with cetuximab is restricted to HPV-negative tumours. In India, oral metronomic methotrexate-celecoxib and low-dose nivolumab from Tata Memorial have set low-cost standards, and smoking cessation and alcohol reduction remain the interventions with the largest effect.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Tobacco-related head and neck cancer; HPV-negative oropharyngeal cancer; p16-negative head and neck cancer
- Tags: subtype-page; head-and-neck
- Group: head and neck
- Burden: Most of the close to 900,000 head and neck cancers diagnosed each year worldwide are HPV-negative: oral cavity, laryngeal and hypopharyngeal cancers in smokers and drinkers, and areca-nut related oral cancer in South Asia; in the RTOG 0129 analysis three-year survival for HPV-negative oropharyngeal cancer was 57 percent.
- Subtypes: HPV-negative oropharyngeal cancer; Oral cavity squamous cell carcinoma (almost always HPV-negative); Laryngeal and hypopharyngeal squamous cell carcinoma; TP53-mutant, CDKN2A-deleted tumours (the commonest genotype); Tobacco and alcohol related, and areca-nut related, disease
- Biomarkers: p16 negative and HPV DNA negative; PD-L1 combined positive score (perioperative and recurrent treatment); TP53 mutation and CDKN2A loss; EGFR expression (a target, not a predictive marker); Extranodal extension and margin status (postoperative treatment); Smoking and alcohol exposure

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/hpv-negative-head-and-neck-cancer/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/hpv-negative-head-and-neck-cancer/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/hpv-negative-head-and-neck-cancer/#what-it-is [5 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/hpv-negative-head-and-neck-cancer/#finding-it [6 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/hpv-negative-head-and-neck-cancer/#treating-it [7 settings, 5 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/hpv-negative-head-and-neck-cancer/#evidence [14 trials, 5 key papers, 8 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/hpv-negative-head-and-neck-cancer/#science [3 targets]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/hpv-negative-head-and-neck-cancer/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/hpv-negative-head-and-neck-cancer/#living-with-it [26 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/hpv-negative-head-and-neck-cancer/coming/ [11 medicines, 10 trials, 5 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/hpv-negative-head-and-neck-cancer/data/ [63 connected records]

## Standard of care

- Diagnosis and staging: Biopsy with p16 (and HPV testing for oropharyngeal primaries), PD-L1 combined positive score, panendoscopy for second primaries, CT or MRI and PET-CT for stage III to IV. ([HPV-positive (p16) head and neck cancer](https://onco.cc/terms/hpv-p16/), [PD-L1 expression testing (22C3, SP142, SP263)](https://onco.cc/terms/pd-l1-testing/), [PET/CT](https://onco.cc/technologies/pet-ct/))
- Resectable stage III to IVA: Surgery with neck dissection; perioperative pembrolizumab for tumours with a combined positive score of 1 or more (KEYNOTE-689), then radiotherapy or chemoradiation by pathology. ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [KEYNOTE-689](https://onco.cc/trials/keynote-689/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/))
- After surgery, high risk: Postoperative cisplatin chemoradiation for extranodal extension or positive margins; nivolumab added on the basis of NIVOPOSTOP. ([Cisplatin](https://onco.cc/drugs/cisplatin/), [Chemoradiation (chemoradiotherapy, CRT)](https://onco.cc/terms/chemoradiation/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [NIVOPOSTOP (GORTEC 2018-01)](https://onco.cc/trials/nivopostop/))
- Unresectable or organ-preserving: Definitive cisplatin chemoradiation to 70 Gy; cetuximab with radiotherapy for patients who cannot have cisplatin (Bonner). ([Cisplatin](https://onco.cc/drugs/cisplatin/), [Chemoradiation (chemoradiotherapy, CRT)](https://onco.cc/terms/chemoradiation/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [Bonner trial (cetuximab plus radiotherapy)](https://onco.cc/trials/bonner-cetuximab-rt/))
- Recurrent or metastatic: Pembrolizumab alone (combined positive score 1 or more) or with platinum-fluorouracil (KEYNOTE-048); cetuximab-based EXTREME for rapid disease or PD-1 failure. ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [KEYNOTE-048](https://onco.cc/trials/keynote-048/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [EXTREME](https://onco.cc/trials/extreme/), [Recurrent or metastatic head and neck squamous cell carcinoma](https://onco.cc/cancers/recurrent-metastatic-hnscc/))
- Resource-limited settings: Oral metronomic methotrexate with celecoxib, with or without low-dose nivolumab (Tata Memorial trials). ([Methotrexate](https://onco.cc/drugs/methotrexate/), [Oral metronomic chemotherapy vs intravenous cisplatin (Tata Memorial)](https://onco.cc/trials/metronomic-vs-cisplatin-tmh/), [Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial)](https://onco.cc/trials/low-dose-nivolumab-tmh/))
- Prevention: Smoking cessation, alcohol reduction and betel quid cessation; second primaries make cessation after diagnosis worthwhile. ([Smoking cessation in cancer patients](https://onco.cc/technologies/smoking-cessation-after-diagnosis/), [Alcohol reduction, pricing and cancer warning labels](https://onco.cc/technologies/alcohol-reduction-labelling/))

## State of the art

- Cisplatin chemoradiation and surgery with postoperative treatment remain the curative backbone, essentially unchanged since 2004 until KEYNOTE-689 and NIVOPOSTOP.
- Immunotherapy helps when given around surgery, not during radiotherapy, a lesson from JAVELIN Head and Neck 100 and KEYNOTE-412.
- Two decades of radiosensitisers and EGFR inhibitors added to chemoradiation have not improved on cisplatin.

## Open problems

- Cure rates for locally advanced HPV-negative disease have barely moved in twenty years.
- No predictive biomarker beyond PD-L1, which is imperfect.
- Function after laryngectomy, glossectomy and high-dose radiotherapy.
- Second primaries and continued smoking after treatment.
- Incidence still rising where tobacco and areca nut use are common.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Head_and_neck_cancer
- Wikipedia: https://en.wikipedia.org/wiki/Head_and_neck_cancer

## Connected records

- cancers: [Head and neck squamous cell carcinoma](https://onco.cc/cancers/head-and-neck/), [HPV-positive oropharyngeal cancer](https://onco.cc/cancers/hpv-positive-oropharyngeal-cancer/), [Hypopharyngeal cancer](https://onco.cc/cancers/hypopharyngeal-cancer/), [Laryngeal and hypopharyngeal cancer](https://onco.cc/cancers/laryngeal-cancer/), [Oral cavity cancer (mouth and tongue)](https://onco.cc/cancers/oral-cavity-cancer/), [Oropharyngeal cancer (tonsil and base of tongue)](https://onco.cc/cancers/oropharyngeal-cancer/), [Recurrent or metastatic head and neck squamous cell carcinoma](https://onco.cc/cancers/recurrent-metastatic-hnscc/)
- drugs: [Celecoxib](https://onco.cc/drugs/celecoxib/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [Cetuximab sarotalocan](https://onco.cc/drugs/cetuximab-sarotalocan/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Ficerafusp alfa](https://onco.cc/drugs/ficerafusp-alfa/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [MRG003](https://onco.cc/drugs/mrg003/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Petosemtamab](https://onco.cc/drugs/petosemtamab/), [Xevinapant](https://onco.cc/drugs/xevinapant/)
- trials: [A Study of Dostarlimab vs Placebo After Chemoradiation in Adult Participants With Locally Advanced Unresected Head and Neck Squamous Cell Carcinoma](https://onco.cc/trials/nct06256588/), [A Study of Ficlatuzumab in Combination With Cetuximab in Participants With Recurrent or Metastatic (R/M) HPV Negative Head and Neck Squamous Cell Carcinoma](https://onco.cc/trials/nct06064877/), [Bonner trial (cetuximab plus radiotherapy)](https://onco.cc/trials/bonner-cetuximab-rt/), [EXTREME](https://onco.cc/trials/extreme/), [FORTIFI-HN01](https://onco.cc/trials/fortifi-hn01/), [JAVELIN Head and Neck 100](https://onco.cc/trials/javelin-hn-100/), [KEYNOTE-048](https://onco.cc/trials/keynote-048/), [KEYNOTE-412](https://onco.cc/trials/keynote-412/), [KEYNOTE-689](https://onco.cc/trials/keynote-689/), [Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial)](https://onco.cc/trials/low-dose-nivolumab-tmh/), [NIVOPOSTOP (GORTEC 2018-01)](https://onco.cc/trials/nivopostop/), [Oral metronomic chemotherapy vs intravenous cisplatin (Tata Memorial)](https://onco.cc/trials/metronomic-vs-cisplatin-tmh/), [Response Adaptive Radiotherapy Following Immunotherapy-based Induction for Non-HPV Related HNSCC](https://onco.cc/trials/nct06345287/), [TrilynX](https://onco.cc/trials/trilynx/)
- key papers: [EORTC 22931: postoperative irradiation with or without concomitant cisplatin for locally advanced head and neck cancer](https://onco.cc/key-papers/paper-bernier-eortc-22931-nejm-2004/), [Human papillomavirus and survival of patients with oropharyngeal cancer (RTOG 0129)](https://onco.cc/key-papers/paper-ang-hpv-oropharyngeal-nejm-2010/), [KEYNOTE-689: neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck cancer](https://onco.cc/key-papers/paper-keynote-689-nejm-2025/), [Radiotherapy plus cetuximab for locoregionally advanced squamous cell carcinoma of the head and neck](https://onco.cc/key-papers/paper-bonner-cetuximab-radiotherapy-nejm-2006/), [RTOG 9501: postoperative concurrent radiotherapy and chemotherapy for high-risk head and neck squamous cell carcinoma](https://onco.cc/key-papers/paper-cooper-rtog-9501-nejm-2004/)
- terms: [CDKN2A/B homozygous deletion](https://onco.cc/terms/cdkn2a-homozygous-deletion/), [Chemoradiation (chemoradiotherapy, CRT)](https://onco.cc/terms/chemoradiation/), [Extranodal extension (ENE)](https://onco.cc/terms/extranodal-extension/), [HPV-positive (p16) head and neck cancer](https://onco.cc/terms/hpv-p16/), [PD-L1 expression testing (22C3, SP142, SP263)](https://onco.cc/terms/pd-l1-testing/)
- technologies: [Alcohol reduction, pricing and cancer warning labels](https://onco.cc/technologies/alcohol-reduction-labelling/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [PET/CT](https://onco.cc/technologies/pet-ct/), [Smoking cessation in cancer patients](https://onco.cc/technologies/smoking-cessation-after-diagnosis/)
- people: [Jean-Pascal Machiels](https://onco.cc/people/jean-pascal-machiels/)
- companies: [GORTEC](https://onco.cc/companies/gortec/)

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JSON: https://onco.cc/api/v1/entities/hpv-negative-head-and-neck-cancer.json