Head and Neck Cancer: A Review (JAMA, 2026)

This is a comprehensive clinical review1 published in JAMA (February 2026) by Dunn, Ho, and Pfister from Memorial Sloan Kettering Cancer Center. It covers the epidemiology, pathophysiology, diagnosis, and treatment of head and neck squamous cell carcinomas (HNSCCs) of the upper aerodigestive tract — including the oral cavity, oropharynx, hypopharynx, larynx, and paranasal sinuses (excluding nasopharynx cancers). The review is based on 89 studies selected from nearly 14,000 articles published between 2010 and 2025, prioritizing RCTs, meta-analyses, and systematic reviews alongside the most recent NCCN guidelines.

Epidemiology of HNSCC

Head and neck cancer is the seventh most common cancer worldwide, with approximately 90% being squamous cell carcinomas. In 2024, around 71,110 individuals in the US were diagnosed, accounting for 16,110 deaths.

Non-HPV-Associated HNSCC:

  • Median age at diagnosis is 66 years, with a male-to-female ratio of 2:1 to 4:1
  • Tobacco and alcohol are the dominant global risk factors. Smoking risk scales progressively with pack-years (>50 pack-years: OR 6.81), and cessation significantly reduces risk (>20 years cessation: OR 0.12)
  • Smokeless tobacco carries a relative risk of 1.8 for oral cavity cancer; betel quid use without tobacco still confers an OR of ~9.9
  • Alcohol consumption of ≥3 drinks/day raises risk (OR 2.04); cessation for >20 years reduces risk by ~40%
  • Patients with Fanconi anemia carry germline DNA repair defects and face elevated HNSCC risk (19% over 20 years)

HPV-Associated HNSCC:

  • HPV accounts for 60–70% of oropharynx squamous cell carcinomas in the US and Europe, with HPV-16 being the dominant serotype (present in ~87% of HPV-associated cases)
  • Incidence of HPV-positive oropharynx cancer rose from 0.8 to 4.62 per 100,000 between 1988 and 2014, while HPV-negative cases declined
  • Affected patients tend to be younger (median age 54 vs. 66), White, non-smokers, with higher socioeconomic status and more sexual partners
  • Predominantly affects males (8.5 vs. 1.8 per 100,000 person-years)

Treatment by Disease Stage

Stage Prevalence at Presentation Treatment
Localized (I–II) ~30% Surgery or radiotherapy
Locoregionally advanced (III–IV, M0) ~50–60% Surgery + postop RT ± chemo, or concurrent chemoradiation
Recurrent/Metastatic ~10–20% Immunotherapy ± chemotherapy; salvage surgery/RT if feasible

Localized Disease:

  • Surgery and radiation have equivalent 5-year overall survival (70–90%)
  • Surgery is preferred for oral cavity and paranasal sinus cancers (radiation risks osteoradionecrosis, occurring in ~8.3% of irradiated patients)
  • Radiation is generally preferred for oropharynx, larynx, and hypopharynx to preserve speech and swallowing
  • Intensity-modulated radiation therapy (IMRT) is the standard technique; parotid-sparing IMRT markedly reduces xerostomia (29% vs. 83%)
  • Prophylactic neck dissection improves survival in early-stage oral cavity cancer (80% vs. 67% 3-year OS)

Locoregionally Advanced Disease:

  • Cisplatin-based concurrent chemoradiation is the cornerstone of non-surgical treatment (70 Gy in 35 fractions); high-dose cisplatin (100 mg/m²) every 3 weeks is recommended
  • A meta-analysis of 107 RCTs (19,805 patients) showed concurrent chemoradiation improved survival by 6.5% at 5 years over surgery/radiation alone
  • Carboplatin + fluorouracil is an alternative when cisplatin is contraindicated
  • For oral cavity cancers, surgery is preferred over chemoradiation given higher risks of bone exposure and osteoradionecrosis with high-dose RT
  • Total laryngectomy showed improved survival over chemoradiation for T4a larynx cancer with thyroid cartilage invasion (median OS 61 vs. 39 months)
  • Cetuximab is now reserved only for patients with contraindications to cisplatin, as three RCTs demonstrated its inferiority to cisplatin + RT in HPV-positive oropharyngeal cancer
  • PET/CT-guided neck dissection (obtained ≥12 weeks post-chemoradiation) reduces unnecessary surgeries without compromising survival

Recurrent/Metastatic Disease:

  • First-line treatment is pembrolizumab (anti-PD-1) monotherapy (for PD-L1 CPS ≥1) or pembrolizumab + platinum-doublet chemotherapy (for all patients)
  • In the KEYNOTE-048 trial, pembrolizumab monotherapy improved median OS to 12.3–14.9 months vs. 10.3–10.7 months with cetuximab + chemotherapy in PD-L1-positive patients
  • Platinum + fluorouracil + cetuximab remains an alternative first-line option
  • For platinum-refractory disease, nivolumab and pembrolizumab are FDA-approved, with nivolumab showing 1-year OS of 36% vs. 16.6% for standard agents

Postoperative Radiation, Induction Chemotherapy, and Immunotherapy

Postoperative Radiation:

  • NCCN guidelines recommend adding cisplatin to postoperative radiotherapy for patients with positive surgical margins and/or extranodal extension
  • A pooled analysis of 2 RCTs (793 patients) showed cisplatin + radiation improved 10-year disease-free survival compared to radiation alone (18.4% vs. 12.3%)

Induction Chemotherapy:

  • Three phase 3 RCTs (869 patients total) showed no survival benefit from induction chemotherapy prior to concurrent chemoradiotherapy
  • However, induction chemo may still be used for rapid tumor debulking in cases with life-threatening complications (e.g., airway obstruction)
  • Standard induction regimen: docetaxel + cisplatin + fluorouracil (TPF)

Induction/Adjuvant Immunotherapy:

  • The 2025 KEYNOTE-689 phase 3 trial (363 patients) demonstrated that neoadjuvant pembrolizumab (2 cycles) followed by adjuvant pembrolizumab (15 cycles) added to standard surgical care improved event-free survival at 36 months (57.6% vs. 46.4%; HR 0.73)
  • This represents an emerging shift toward perioperative immunotherapy in locally advanced, surgically resectable HNSCC

Prognosis

Stage 5-Year Overall Survival
Early-stage (I–II) 70–90%
Locally advanced (III–IV) 25–60%
HPV-positive oropharynx (locally advanced) >80%
Recurrent/metastatic <20% (median OS 12–15 months)

Key prognostic factors include:

  • HPV status: HPV-positive oropharynx cancers have significantly better outcomes — 3-year OS of 82.4% vs. 57.1% for locally advanced disease, and median OS of 2.6 vs. 0.8 years for recurrent/metastatic disease
  • p16/HPV concordance: Tumors positive for both p16 and HPV DNA have a 5-year OS of 81.1%, compared to ~54% for discordant cases
  • Smoking cessation: Quitting at or within 12 months of diagnosis improves overall survival (HR 0.80)
  • Recurrences typically occur within the first 3 years, though late recurrences (>5 years) can occur in HPV-positive cases

Surveillance Recommendations

Per NCCN guidelines, post-treatment follow-up consists of:

  • Year 1: Complete history and physical examination every 1–3 months
  • Year 2: Every 2–6 months
  • Years 3–5: Every 4–8 months
  • Beyond 5 years: Every 12 months

Additional monitoring:

  • Thyroid-stimulating hormone should be checked every 6–12 months after radiation to detect radiation-induced hypothyroidism
  • Routine surveillance imaging is not supported in asymptomatic patients with no evidence of disease on initial post-treatment imaging (obtained no sooner than 12 weeks after radiation completion)
  • A 10-year retrospective study (1,114 patients) found no survival difference between recurrences detected on surveillance PET/CT vs. those presenting symptomatically (3-year OS 60% vs. 54%)
  • Validated questionnaires for anxiety and depression are recommended, given that suicide rates among head and neck cancer survivors are significantly elevated compared to both the general population and other cancer types

  1. Dunn LA, Ho AL, Pfister DG. Head and Neck Cancer: A Review. JAMA. 2026 Feb 10;335(6):531-541. doi: 10.1001/jama.2025.21733. PMID: 41396597. ↩