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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.
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.
Averages across everyone diagnosed, often years ago. A median is the middle of a group: half the people counted lived longer than the figure shown, and some lived far longer. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
Site decides cause and behaviour: HPV drives oropharyngeal cancer, EBV drives nasopharyngeal cancer, tobacco drives oral and laryngeal cancer; all drain into the neck node levels that surgeons and radiotherapists map.
Same organ: Acinic cell carcinoma of the salivary glands, Carcinoma ex pleomorphic adenoma, Multiple endocrine neoplasia type 1 (MEN1), Multiple endocrine neoplasia type 2 (MEN2A and MEN2B), Hyperparathyroidism-jaw tumour syndrome (CDC73-related parathyroid carcinoma), Oropharyngeal cancer (tonsil and base of tongue), Laryngeal and hypopharyngeal cancer, Oral cavity cancer (mouth and tongue), Head and neck squamous cell carcinoma, Nasopharyngeal carcinoma, Salivary gland cancers, Papillary thyroid cancer, Follicular thyroid cancer, Medullary thyroid cancer, Anaplastic thyroid cancer, Thyroid cancer, Nasal cavity and paranasal sinus cancers (including esthesioneuroblastoma), NUT carcinoma (midline carcinoma with NUTM1 rearrangement), Parathyroid carcinoma, Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4), HPV-positive oropharyngeal cancer, Recurrent or metastatic head and neck squamous cell carcinoma, Hypopharyngeal cancer, Adenoid cystic carcinoma, Salivary duct carcinoma, Mucoepidermoid carcinoma, Oral tongue and floor of mouth cancer, Buccal mucosa and gingivobuccal cancer (oral cancer in India), Lip cancer, Locoregionally advanced nasopharyngeal carcinoma (stage III to IVA), Recurrent and metastatic nasopharyngeal carcinoma, Esthesioneuroblastoma (olfactory neuroblastoma), Sinonasal undifferentiated carcinoma (SNUC) and SWI/SNF-deficient sinonasal carcinoma
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.
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.
Postoperative cisplatin chemoradiation for extranodal extension or positive margins; nivolumab added on the basis of NIVOPOSTOP.
Definitive cisplatin chemoradiation to 70 Gy; cetuximab with radiotherapy for patients who cannot have cisplatin (Bonner).
Pembrolizumab alone (combined positive score 1 or more) or with platinum-fluorouracil (KEYNOTE-048); cetuximab-based EXTREME for rapid disease or PD-1 failure.
Oral metronomic methotrexate with celecoxib, with or without low-dose nivolumab (Tata Memorial trials).
Smoking cessation, alcohol reduction and betel quid cessation; second primaries make cessation after diagnosis worthwhile.
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Perioperative pembrolizumab is a new standard for resectable head and neck cancer with PD-L1 expression, adding immunotherapy to a treatment pathway that had not changed since postoperative chemoradiation was defined.
HPV-positive oropharyngeal cancer is now staged and studied separately, and this risk model underlies de-escalation trials and the eighth-edition staging system.
Cetuximab-radiotherapy is the standard for patients who cannot receive cisplatin; head-to-head trials in HPV-positive disease (RTOG 1016, De-ESCALaTE) later showed it inferior to cisplatin where cisplatin is possible.
Cisplatin chemoradiation after surgery is standard for extranodal extension or involved margins; radiotherapy alone suffices for other adverse features.
With EORTC 22931, this trial defines who receives postoperative chemoradiation: patients with extranodal extension or positive margins, not those whose only risk factor is multiple nodes.
Query for this cancer: (TITLE:"HPV-negative head and neck squamous cell carcinoma" OR ABSTRACT:"HPV-negative head and neck squamous cell carcinoma" OR TITLE:"including HPV-negative oropharyngeal cancer" OR ABSTRACT:"including HPV-negative oropharyngeal cancer" OR TITLE:"Tobacco-related head and neck cancer" OR ABSTRACT:"Tobacco-related head and neck cancer" OR TITLE:"HPV-negative oropharyngeal cancer" OR ABSTRACT:"HPV-negative oropharyngeal cancer" OR TITLE:"p16-negative head and neck cancer" OR ABSTRACT:"p16-negative head and neck cancer") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about HPV-negative head and neck squamous cell carcinoma (including HPV-negative oropharyngeal cancer), not a curated reading list.
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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.
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Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
Dose reduce or avoid for CrCl below 60 (carboplatin is the alternative).
High-dose methotrexate requires normal renal function, hydration, urine alkalinisation and leucovorin rescue with level monitoring.
Immunotherapy can attack hormone-producing glands: most often the thyroid (usually ending in an under-active thyroid needing lifelong tablets), and less often the pituitary (hypophysitis) or adrenal glands, which can be life-threatening if missed.
See all on the product pages:CisplatinMethotrexateNivolumabPembrolizumab·Printable cards in the navigator
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