Key points
- Most head and neck cancers arise from the mucosal lining of the mouth, throat and larynx and are called “head and neck squamous cell carcinoma” [1].
- Tobacco and alcohol are the most important risk factors, and their combined effect is greater than the product of their individual effects [2].
- Oropharyngeal cancer (of the tonsils and base of the tongue) linked to human papillomavirus (HPV) is increasing and has a better prognosis [3, 4].
- Treatment is usually multidisciplinary: surgery, radiation therapy and concurrent chemotherapy with cisplatin [1, 7].
- Immunotherapy now improves survival in recurrent or metastatic disease [14, 22], and in resectable locally advanced disease, pembrolizumab before and after surgery, or nivolumab with postoperative chemoradiation, has also reduced the risk of recurrence [13, 23].
- Nasopharyngeal cancer (behind the nose) is a different disease that is linked to the Epstein–Barr virus and has its own specific treatment [6, 20].
What are head and neck cancers?
“Head and neck cancers” is the name for a group of cancers that arise in the oral cavity (tongue, floor of the mouth, gums and inner lining of the cheeks), the pharynx (nasopharynx, oropharynx and hypopharynx) and the larynx. Most of them develop from the mucosal lining (epithelium) of these areas and are called head and neck squamous cell carcinoma (HNSCC) [1].
This group is the sixth most common cancer worldwide; in 2018 it accounted for about 890,000 new cases and 450,000 deaths [1]. Cancers of the mouth and larynx are mostly linked to tobacco and alcohol use, whereas cancers of the pharynx, especially the oropharynx, are increasingly attributed to HPV infection (mainly type 16) [1]. Nasopharyngeal cancer has a distinct geographic distribution: it is more common in East and Southeast Asia and is closely associated with the Epstein–Barr virus (EBV) [6].
Signs and symptoms
Symptoms depend on where the tumor is [1]:
- Oral cavity: a sore or ulcer that does not heal, pain when chewing or difficulty speaking.
- Oropharynx and hypopharynx: difficulty swallowing, pain when swallowing or ear pain; because of their hidden location, these tumors often cause symptoms later.
- Larynx: a change in the voice or persistent hoarseness (which often leads to early diagnosis); in advanced cases, shortness of breath.
- HPV-positive oropharynx: a new, painless lump in the neck.
- Nasopharynx: a neck lump, nosebleeds and one-sided nasal blockage.
In any adult, a new neck lump should be considered malignant until proven otherwise [1].
When should I contact my doctor?
If you have a mouth sore that does not heal, your voice has been hoarse for a while, you have trouble swallowing, or you can feel a lump in your neck, see a doctor (preferably an ear, nose and throat specialist). Most of these symptoms have benign causes, but early evaluation is important [1].
Risk factors and prevention
Tobacco
Cigarettes, water pipes (hookah), pipes and chewing tobacco are the most important risk factor for cancers of the mouth, throat and larynx. In a large pooled analysis, about 72% of head and neck cancers were attributable to tobacco and/or alcohol, and this proportion reached 89% for laryngeal cancer [2].
Alcohol
Human papillomavirus (HPV)
The main driver of the rise in oropharyngeal cancer in high-income countries; in the United States, the proportion of HPV-positive oropharyngeal tumors rose from 16.3% (1984 to 1989) to 71.7% (2000 to 2004) [3].
Chewing tobacco and areca nut (betel)
Chewing areca nut products and “betel quid” is associated with very high rates of oral cavity cancer in some Asian populations, including in India and Taiwan [1].
Epstein–Barr virus (EBV)
Linked to nasopharyngeal cancer; the virus’s DNA in plasma is used for population screening, prognosis and follow-up of this cancer [6].
Quitting tobacco (including hookah) and alcohol completely is the most effective step [1, 2]. With HPV vaccines, preventing the head and neck cancers linked to this virus through broad vaccination programs appears possible [1]. Pay attention to persistent sores or white (leukoplakia) or red (erythroplakia) patches in your mouth; some of these lesions are precancerous [1].
Diagnosis and staging
Diagnostic pathway for head and neck cancer
- 1
Examination and endoscopy
A complete examination of the mouth, throat and neck, and head and neck endoscopy by a specialist [19].
- 2
Biopsy
The diagnosis is confirmed by a biopsy of the lesion or neck lump; for a neck lump of unknown origin, diagnostic transoral surgery (removal of the tonsils and base-of-tongue tissue) has found the primary tumor in about 70% of cases [1].
- 3
p16/HPV and EBV testing
In oropharyngeal cancer, p16 staining is strongly recommended, and in cancer of unknown primary, p16 and EBER are tested [19]. In nasopharyngeal cancer, plasma EBV DNA is used for prognosis and follow-up [6].
- 4
Imaging
Contrast-enhanced CT and/or MRI of the head and neck, and chest imaging with CT and/or PET [19].
- 5
TNM staging
The eighth edition of AJCC/UICC (2017) added depth of invasion to the staging of oral cavity tumors and extranodal extension to the staging of non-viral tumors, and defined a separate staging system for p16-positive oropharyngeal cancer [1].
Treatment by stage
| Situation | Main treatment | Notes |
|---|---|---|
| Early stage | Surgery or radiation therapy alone [1] | The choice depends on side effects and function, because conservative surgery and radiation therapy give similar local control [19]. |
| Resectable locally advanced (especially oral cavity) | Surgery followed by adjuvant radiation therapy or chemoradiation [19] | Adding cisplatin to postoperative radiation therapy in high-risk patients improved survival [8]. Pembrolizumab before and after surgery improved event-free survival [13], and adding nivolumab to postoperative chemoradiation in high-risk patients improved disease-free survival [23]. |
| Locally advanced (non-surgical treatment) | Concurrent chemoradiation with cisplatin [7, 19] | For patients who cannot receive cisplatin: cetuximab or carboplatin/5-FU with radiation therapy, or accelerated radiation therapy [19]. |
| Larynx preservation | Concurrent chemoradiation, or induction chemotherapy followed by radiation therapy [9, 19] | Concurrent chemoradiation achieved the highest rate of larynx preservation [9]. |
| Recurrent or metastatic | Pembrolizumab alone (PD-L1 positive) or with chemotherapy [14, 19, 22] | After platinum failure: nivolumab [15]; for tumors without PD-L1 expression: platinum/5-FU/cetuximab [19]. |
Treatment decisions should be made by a multidisciplinary head and neck team (surgeon, radiation oncologist, medical oncologist, dentist, dietitian and speech therapist) [1].
Treatment options
Surgery
The main treatment for most oral cavity cancers and some laryngeal and pharyngeal tumors, often together with neck lymph node dissection [1].
Radiation therapy
Used alone in early stages, with chemotherapy in advanced stages, or as adjuvant treatment after surgery; postoperative radiation therapy should start within 6 weeks [19].
Chemotherapy
Cisplatin given concurrently with radiation therapy is standard; adding concurrent chemotherapy increases 5-year survival by about 6.5 percentage points, whereas induction or adjuvant chemotherapy generally has no such effect [7].
HPV-related oropharyngeal cancer
HPV-positive oropharyngeal cancer has one of the fastest-rising incidence trends of all cancers in high-income countries [5]. In the United States, the population incidence of this cancer increased by about 225% from 1988 to 2004, while the incidence of the HPV-negative type fell by 50% [3]. The disease is more common in younger people [5]; the classic risk factors (tobacco and alcohol) are often absent, and its most common presentation is a new painless lump in the neck [1].
HPV status is a strong, independent prognostic factor, and HPV-positive patients have a better prognosis [4]. For this reason, the eighth edition of the AJCC/UICC staging system stages these tumors separately [5].
However, attempts to “de-escalate” treatment by replacing cisplatin with cetuximab in two large trials (RTOG 1016 and De-ESCALaTE) led to lower survival and more recurrences, without reducing side effects [11, 12]; guidelines therefore recommend the same treatment for HPV-positive and HPV-negative tumors, and treatment de-escalation is done only within clinical trials [19].
Nasopharyngeal cancer
Nasopharyngeal cancer is more common in East and Southeast Asia, and its incidence and mortality have fallen over the past decade; widespread use of intensity-modulated radiation therapy (IMRT) and optimized chemotherapy have improved survival and reduced side effects [6].
- Very early stage (T1N0): radiation therapy alone [20].
- Locoregionally advanced disease: induction chemotherapy followed by chemoradiation with cisplatin is the preferred approach [20]. In a phase 3 trial, three cycles of gemcitabine–cisplatin before chemoradiation both reduced the likelihood of recurrence and improved overall survival [16, 17].
- Recurrent or metastatic disease: gemcitabine–cisplatin chemotherapy is the backbone of first-line treatment; in a phase 3 trial, this regimen improved progression-free survival compared with fluorouracil–cisplatin [21]. The newer regimen adds immunotherapy to this chemotherapy: in the JUPITER-02 trial, adding toripalimab to gemcitabine–cisplatin prolonged progression-free survival and reduced the risk of death [18].
What should I do after diagnosis?
Frequently asked questions
Is head and neck cancer contagious?
No, the cancer itself is not contagious. HPV, which plays a role in some oropharyngeal cancers, is transmitted through sexual contact, but the interval between oral infection and the development of cancer is usually 10 to 30 years [1].
How is HPV-positive cancer different?
Does the larynx always have to be removed?
Who can benefit from immunotherapy?
In recurrent or metastatic disease, pembrolizumab (alone or with chemotherapy) is the first-line treatment [14, 22], and nivolumab is effective after platinum-based chemotherapy has failed [15]. In resectable locally advanced disease, pembrolizumab before and after surgery [13] and nivolumab with postoperative chemoradiation in high-risk patients [23] have also reduced the risk of recurrence.
How is nasopharyngeal cancer treated?
The main treatment is radiation therapy; in more advanced stages, chemotherapy is usually given first, followed by radiation therapy with cisplatin [16, 20], and in recurrent or metastatic disease, gemcitabine–cisplatin chemotherapy is the backbone of treatment [21]; adding immunotherapy to it has also improved survival in trials [18].
Evidence and recent advances (for physicians)
For physicians
Chemoradiotherapy and postoperative treatment
The updated individual patient data meta-analysis MACH-NC (107 trials, 19,805 patients) showed that the survival benefit is limited to concurrent chemotherapy (HR 0.83; absolute benefit at 5 and 10 years 6.5% and 3.6%; induction HR 0.96 and adjuvant HR 1.02), that it decreases with increasing age, and that concurrent chemotherapy is superior to induction (HR 0.84) [7]. In EORTC 22931, adding three-weekly cisplatin to 66 Gy postoperative radiotherapy improved progression-free survival (HR 0.75) and overall survival (HR 0.70) and reduced 5-year locoregional recurrence from 31% to 18%, at the cost of more severe toxicity (41% vs 21%) [8].
In patients with advanced nodal disease (N2 or N3), PET-CT surveillance twelve weeks after chemoradiotherapy, with neck dissection only for an incomplete response, gave survival similar to planned neck dissection and reduced the number of operations from 221 to 54 [10]. Guidelines do not recommend neck dissection when PET is negative and the nodes are of normal size at week 12 [19].
Larynx preservation
At 10-year follow-up of RTOG 91-11, both strategies (induction PF chemotherapy followed by radiotherapy, and cisplatin concurrent with radiotherapy) improved laryngectomy-free survival compared with radiotherapy alone; larynx preservation was higher with concurrent treatment (HR 0.58 vs induction), but deaths unrelated to laryngeal cancer were more frequent in this group (30.8% vs 20.8% and 16.9%) [9]. The EHNS–ESMO–ESTRO guideline considers induction TPF chemotherapy followed by radiotherapy a valid larynx-preservation option and, apart from this, does not recommend induction routinely [19].
Treatment de-escalation in HPV-positive oropharyngeal cancer
HPV status is a strong, independent prognostic factor: in a large trial, 3-year survival was 82.4% in HPV-positive patients vs 57.1% in HPV-negative patients, and the risk of death was 58% lower after adjustment for other factors; each additional pack-year of smoking increased the risk of death [4].
In RTOG 1016, cetuximab vs cisplatin did not meet the non-inferiority criterion for overall survival (5-year OS 77.9% vs 84.6%; HR 1.45) and almost doubled locoregional failure (HR 2.05) [11]; in De-ESCALaTE HPV, in low-risk patients, severe toxicity was not reduced, but 2-year survival was lower (89.4% vs 97.5%) and recurrence was higher (16.1% vs 6.0%) [12].
Immunotherapy: from metastatic disease to the preoperative setting
For physicians
Recurrent or metastatic disease: the first evidence of benefit from immunotherapy came from the CheckMate 141 trial: in platinum-refractory patients, nivolumab increased one-year survival from 16.6% to 36.0% and caused fewer severe adverse events than chemotherapy [15]. Subsequently, in the KEYNOTE-048 trial, pembrolizumab plus platinum and 5-fluorouracil in all patients (13.0 vs 10.7 months; HR 0.77) and pembrolizumab monotherapy in PD-L1–positive tumors improved overall survival compared with the cetuximab–chemotherapy regimen and became standard first-line treatments; pembrolizumab monotherapy was non-inferior in the total population, progression-free survival was not improved with either regimen, and grade 3 or higher adverse events occurred in 55% with monotherapy vs 83% with cetuximab–chemotherapy [14]. At 5-year follow-up, pembrolizumab monotherapy in CPS ≥20 (HR 0.61) and CPS ≥1 (HR 0.74) and pembrolizumab–chemotherapy in the total population (HR 0.72) maintained their survival advantage; 5-year survival in the total population was 14.4% with monotherapy vs 6.5% [22]. PD-L1 expression is measured by the “combined positive score” (CPS) [14, 19].
Resectable locally advanced disease: in the phase 3 KEYNOTE-689 trial, two cycles of pembrolizumab before surgery and 15 cycles afterward (together with standard therapy) increased 36-month event-free survival in tumors with CPS ≥10 from 45.9% to 59.8% (HR 0.66); the benefit was also significant in the total population (HR 0.73), and preoperative treatment did not reduce the likelihood of undergoing surgery; grade 3 or higher treatment-related adverse events occurred in 44.6% vs 42.9%, and grade 3 or higher immune-mediated adverse events in 10.0% of the pembrolizumab group [13]. In the phase 3 NIVOPOST-OP trial (680 patients), adding nivolumab to postoperative cisplatin-based chemoradiotherapy in high-risk patients improved disease-free survival regardless of PD-L1 expression (HR 0.76; 95% CI 0.60 to 0.98); grade 4 treatment-related adverse events occurred in 10% vs 5%, and there were 2 treatment-related deaths in each group [23]. Overall survival data from neither trial are conclusive yet.
Nasopharyngeal cancer
In a Chinese phase 3 trial, three cycles of gemcitabine–cisplatin before chemoradiotherapy increased 3-year recurrence-free survival from 76.5% to 85.3% [16], and in the final analysis improved 5-year overall survival to 87.9% vs 78.8% [17]. In the JUPITER-02 trial, adding toripalimab to gemcitabine–cisplatin increased median progression-free survival from 8.2 to 21.4 months and reduced the risk of death (HR 0.63) [18]; the NCCN guideline considers this combination the preferred first-line option [20].
Treatment regimens and dosing (for physicians)
Treatment regimens and doses: index13 regimens
- Cisplatin: prehydration and maintenance of hydration and urine output for 24 hours afterward, highly effective antiemetic premedication, monitoring of renal function and electrolytes, and consideration of audiometry; for reduced creatinine clearance, myelosuppression or neuropathy, consider dose reduction or alternative therapy [29].
- 5-Fluorouracil (TPF, KEYNOTE-048 and EXTREME): DPD deficiency can cause fatal fluoropyrimidine toxicity [19].
- Cetuximab (Bonner and EXTREME): premedicate with an IV H1 antihistamine 30 to 60 minutes before the first dose [26]. For grade 1 to 2 infusion reactions, reduce the infusion rate by 50%; for grade 3 to 4, stop immediately and permanently; for grade 3 to 4 skin rash, delay 1 to 2 weeks and resume at 250, then 200, then 150 mg/m² [26]. Monitor serum magnesium, potassium and calcium during and after treatment; cardiopulmonary arrest or sudden death was reported in 2% of patients in Bonner [26].
- Pembrolizumab, nivolumab and toripalimab: monitor liver enzymes, creatinine and thyroid function at baseline and periodically; immune-mediated adverse reactions are managed by withholding or permanently discontinuing the drug, and dose reduction is not recommended [24, 25, 28].
For physicians
Locally advanced (excluding nasopharynx): definitive chemoradiotherapy and larynx preservation
Definitive chemoradiotherapy with three-weekly cisplatin
Locally advanced disease treated non-surgically (including larynx preservation), cisplatin-eligible patient
Locally advanced disease treated non-surgically (including larynx preservation), cisplatin-eligible patient [12, 19]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Cisplatin | 100 mg/m² | IV | Days 1, 22 and 43 of radiotherapy |
| Radiotherapy | 70 Gy in 35 fractions | External beam | 35 fractions (2 Gy per fraction) |
This regimen is the standard of care in the EHNS–ESMO–ESTRO guideline [II, A] [19]. In RTOG 1016 (HPV-positive oropharynx), accelerated radiotherapy of 70 Gy in 35 fractions over 6 weeks (6 fractions per week) was used with cisplatin 100 mg/m² on days 1 and 22 only [11].
For cisplatin-ineligible patients: carboplatin + 5-FU or cetuximab concurrent with radiotherapy, or altered-fractionation radiotherapy without chemotherapy [II, A] [19].
Evidence: De-ESCALaTE HPV (2019), NRG Oncology RTOG 1016 (2019)
Cetuximab + radiotherapy (Bonner)
Locally advanced disease, only in cisplatin-ineligible patientsCycle length: Weekly
Locally advanced disease, only in cisplatin-ineligible patients [19, 26]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Loading dose | |||
| Cetuximab | 400 mg/m² | IV, 120-minute infusion | One week before the start of radiotherapy |
| Subsequent doses | |||
| Cetuximab | 250 mg/m² | IV, 60-minute infusion | Weekly during radiotherapy, 1 hour before the radiation session |
| Radiotherapy | 6 to 7 weeks | External beam | Daily |
In HPV-positive oropharyngeal cancer, cetuximab resulted in lower survival than cisplatin and is not a substitute for it [11, 12].
Evidence: NRG Oncology RTOG 1016 (2019), De-ESCALaTE HPV (2019), Bonner (2006)
TPF induction chemotherapy
Larynx preservation (followed by radiotherapy) or selected locally advanced disease; outside larynx preservation, induction is not routinely recommendedCycle length: Every 21 days
Larynx preservation (followed by radiotherapy) or selected locally advanced disease; outside larynx preservation, induction is not routinely recommended [19, 27]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| TAX323: 4 cycles (larynx preservation per ESMO: up to 3 cycles) | |||
| Docetaxel | 75 mg/m² | IV, 1-hour infusion | Day 1 |
| TAX323 | |||
| Cisplatin | 75 mg/m² | IV, 1-hour infusion | Day 1, after docetaxel |
| 5-Fluorouracil | 750 mg/m² per day | Continuous IV infusion | Days 1 to 5 |
| TAX324: 3 cycles | |||
| Docetaxel / cisplatin / 5-fluorouracil | 75 / 100 mg/m² / 1000 mg/m² per day | IV; 5-FU as a continuous infusion | Day 1 / day 1 / days 1 to 4 |
Premedication and prophylaxis: oral dexamethasone 16 mg per day (8 mg twice daily) for 3 days, starting the day before docetaxel; prophylaxis against neutropenic infection (in TAX323/324 all patients received prophylactic antibiotics) [27].
Modifications: G-CSF from the second cycle for febrile neutropenia, infection with neutropenia, or neutropenia lasting more than 7 days; if it recurs despite G-CSF, reduce docetaxel from 75 to 60, then 45 mg/m²; give the next cycle only with neutrophils above 1500/µL and platelets above 100,000/µL [27].
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Resectable locally advanced (excluding nasopharynx): treatment before and after surgery
Postoperative chemoradiotherapy (EORTC 22931)
After surgery in high-risk patients; recommended by ESMO for microscopically positive margins (R1) and extranodal extension
After surgery in high-risk patients; recommended by ESMO for microscopically positive margins (R1) and extranodal extension [8, 19]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Cisplatin | 100 mg/m² (alternative: 40 mg/m² weekly) | IV | Days 1, 22 and 43 of radiotherapy |
| Radiotherapy | 66 Gy | External beam | Over 6.5 weeks |
Postoperative radiotherapy or chemoradiotherapy should start within 6 weeks after surgery [II, A] [19]. Weekly cisplatin 40 mg/m² is a valid alternative in the postoperative setting [II, A] [19].
Evidence: EORTC 22931 (2004)
Pembrolizumab before and after surgery (KEYNOTE-689)
Resectable locally advanced head and neck cancer (stage III to IVA) with PD-L1 CPS ≥1Cycle length: Every 21 days
Resectable locally advanced head and neck cancer (stage III to IVA) with PD-L1 CPS ≥1 [13, 24]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Neoadjuvant: 2 cycles (6 weeks) | |||
| Pembrolizumab | 200 mg every 3 weeks (or 400 mg every 6 weeks) | IV | Day 1 |
| Adjuvant: 3 cycles concurrent with radiotherapy | |||
| Pembrolizumab | 200 mg | IV | Every 3 weeks, before cisplatin on the same day |
| Adjuvant: 3 cycles (only with high-risk features) | |||
| Cisplatin | 100 mg/m² | IV | Every 3 weeks, concurrent with radiotherapy |
| Maintenance: up to 12 cycles | |||
| Pembrolizumab | 200 mg | IV | Every 3 weeks |
Adjuvant therapy was started within 6 weeks after surgery; in both groups, cisplatin was given only for positive margins (less than 1 mm) or extranodal extension [24].
Evidence: KEYNOTE-689 (2025), KEYNOTE-689 / NIVOPOSTOP (2025)
Nivolumab + postoperative chemoradiotherapy (NIVOPOST-OP; not approved)
After complete resection of oral cavity, oropharyngeal, laryngeal or hypopharyngeal cancer with at least one high-risk feature (extracapsular extension, microscopically positive margins, 4 or more involved nodes, multiple perineural invasion); age 19 to 74 years, ECOG 0 to 1
After complete resection of oral cavity, oropharyngeal, laryngeal or hypopharyngeal cancer with at least one high-risk feature (extracapsular extension, microscopically positive margins, 4 or more involved nodes, multiple perineural invasion); age 19 to 74 years, ECOG 0 to 1 [23]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Before chemoradiotherapy | |||
| Nivolumab | 240 mg | IV | One dose |
| Concurrent: 3 cycles | |||
| Nivolumab | 360 mg | IV | Every 3 weeks |
| Cisplatin | 100 mg/m² | IV | Every 3 weeks |
| Concurrent | |||
| Radiotherapy | 66 Gy | External beam | |
| Adjuvant: 6 cycles | |||
| Nivolumab | 480 mg | IV | Every 4 weeks |
Overall survival data are not yet conclusive, and this use of nivolumab is not approved [23].
Evidence: NIVOPOST-OP (GORTEC 2018-01) (2026), KEYNOTE-689 / NIVOPOSTOP (2025)
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Recurrent or metastatic (excluding nasopharynx): first line and after platinum
Pembrolizumab + platinum + 5-FU (KEYNOTE-048)
First line for unresectable recurrent or metastatic disease; per the FDA label, regardless of PD-L1; ESMO recommends it for CPS ≥1 and considers it an alternative option in tumors without PD-L1 expressionCycle length: Every 21 days
First line for unresectable recurrent or metastatic disease; per the FDA label, regardless of PD-L1; ESMO recommends it for CPS ≥1 and considers it an alternative option in tumors without PD-L1 expression [14, 19, 24]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Pembrolizumab | 200 mg every 3 weeks (or 400 mg every 6 weeks) | IV | Day 1, before chemotherapy |
| Up to 6 cycles | |||
| Cisplatin or carboplatin | Cisplatin 100 mg/m² or carboplatin AUC 5 | IV | Day 1 |
| 5-Fluorouracil | 1000 mg/m² per day | Continuous IV infusion over 96 hours | Days 1 to 4 |
Patients with autoimmune disease requiring systemic treatment within the past 2 years were excluded [24].
Evidence: KEYNOTE-048 (2025), KEYNOTE-048 (2019)
Pembrolizumab monotherapy (KEYNOTE-048)
First line for unresectable recurrent or metastatic disease with PD-L1 CPS ≥1 (greater benefit with CPS ≥20); also after progression on platinumCycle length: Every 21 or 42 days
First line for unresectable recurrent or metastatic disease with PD-L1 CPS ≥1 (greater benefit with CPS ≥20); also after progression on platinum [14, 22, 24]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Pembrolizumab | 200 mg every 3 weeks or 400 mg every 6 weeks | IV | Day 1 |
The choice between monotherapy and combination with chemotherapy is based on CPS, tumor burden and symptoms [V, C] [19].
Evidence: KEYNOTE-048 (2025), KEYNOTE-048 (2019)
Cetuximab + platinum + 5-FU (EXTREME)
First line for recurrent or metastatic disease; standard in tumors without PD-L1 expression
First line for recurrent or metastatic disease; standard in tumors without PD-L1 expression [19, 26]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Cetuximab | First dose 400 mg/m² (120 minutes), then 250 mg/m² (60 minutes); or 500 mg/m² every 2 weeks | IV | Weekly, 1 hour before chemotherapy |
| Up to 6 cycles | |||
| Cisplatin or carboplatin | Cisplatin 100 mg/m² or carboplatin AUC 5 | IV | Day 1 |
| 5-Fluorouracil | 1000 mg/m² per day | Continuous IV infusion | Days 1 to 4 |
| Maintenance | |||
| Cetuximab | 250 mg/m² | IV | Weekly |
Evidence: EXTREME (2008)
Nivolumab (CheckMate 141)
Recurrent or metastatic disease progressing on or within 6 months after platinum-based therapyCycle length: Every 14 or 28 days
Recurrent or metastatic disease progressing on or within 6 months after platinum-based therapy [15, 25]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Nivolumab | 240 mg every 2 weeks or 480 mg every 4 weeks (in the trial: 3 mg/kg every 2 weeks) | IV, 30-minute infusion | Day 1 |
The trial excluded nasopharyngeal carcinoma, autoimmune disease and untreated brain metastases [25].
Evidence: CheckMate 141 (2016)
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Nasopharyngeal cancer: locoregionally advanced and recurrent or metastatic
Gemcitabine + cisplatin induction, then chemoradiotherapy
Locoregionally advanced non-keratinizing nasopharyngeal cancer; in the trial: T3–4N1 or N2–3 (AJCC 7th edition), M0, KPS ≥70, creatinine clearance ≥60 mL/min, age 18 to 65 yearsCycle length: Every 21 days
Locoregionally advanced non-keratinizing nasopharyngeal cancer; in the trial: T3–4N1 or N2–3 (AJCC 7th edition), M0, KPS ≥70, creatinine clearance ≥60 mL/min, age 18 to 65 years [16, 20, 30]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Induction: 3 cycles | |||
| Gemcitabine | 1000 mg/m² | IV | Days 1 and 8 |
| Cisplatin | 80 mg/m² | IV | Day 1 |
| Chemoradiotherapy: 3 cycles | |||
| Cisplatin | 100 mg/m² | IV | Every 3 weeks, concurrent with IMRT |
| Chemoradiotherapy | |||
| Intensity-modulated radiotherapy (IMRT) | Per protocol | External beam | |
Evidence: GP induction NPC (Zhang 2019) (2019)
Gemcitabine + cisplatin (GP)
First line for recurrent or metastatic nasopharyngeal cancer, ECOG 0 to 1Cycle length: Every 21 days
First line for recurrent or metastatic nasopharyngeal cancer, ECOG 0 to 1 [21]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Gemcitabine | 1000 mg/m² | IV | Days 1 and 8 |
| Cisplatin | 80 mg/m² | IV | Day 1 |
Improved progression-free survival compared with fluorouracil + cisplatin [21].
Toripalimab + gemcitabine + cisplatin (JUPITER-02)
First line for metastatic or locally advanced recurrent nasopharyngeal cancer (at least 6 months after the end of definitive treatment)Cycle length: Every 21 days
First line for metastatic or locally advanced recurrent nasopharyngeal cancer (at least 6 months after the end of definitive treatment) [18, 28]
Before prescribing: Common safety considerations| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Toripalimab | 240 mg | IV; first infusion over 60 minutes, subsequent infusions over 30 minutes if tolerated | Day 1, every 3 weeks |
| Up to 6 cycles | |||
| Gemcitabine | 1000 mg/m² | IV | Days 1 and 8 |
| Cisplatin | 80 mg/m² | IV | Day 1 |
| Maintenance | |||
| Toripalimab | 240 mg | IV | Every 3 weeks |
Patients with autoimmune disease (except stable hypothyroidism or type 1 diabetes) or requiring immunosuppression were excluded [28]. Toripalimab monotherapy after progression on platinum: 3 mg/kg every 2 weeks [28].
Evidence: JUPITER-02 (2023)
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Scientific evidence
Key studies
10 itemsNeoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer
Nivolumab added to cisplatin and radiotherapy versus cisplatin and radiotherapy alone after surgery for people with squamous cell carcinoma of the head and neck at a high risk of relapse (GORTEC 2018-01 NIVOPOST-OP): a randomised, open-label, phase 3 trial
Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: 5-year follow-up from the randomized phase III KEYNOTE-048 study
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck
Postoperative Irradiation with or without Concomitant Chemotherapy for Locally Advanced Head and Neck Cancer
Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group
Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial
Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 Randomized Clinical Trial
Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma
Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study
Clinical guidelines
2 itemsPan-Asian adaptation of the EHNS-ESMO-ESTRO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with squamous cell carcinoma of the head and neck
NCCN Guidelines® Insights: Head and Neck Cancers, Version 2.2025
References
30 referencesShow all references, 22 with a study cardClose the reference list
Numbers in the text, such as [1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.
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- 10PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer
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- 17Final Overall Survival Analysis of Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma: A Multicenter, Randomized Phase III Trial
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- 23Nivolumab added to cisplatin and radiotherapy versus cisplatin and radiotherapy alone after surgery for people with squamous cell carcinoma of the head and neck at a high risk of relapse (GORTEC 2018-01 NIVOPOST-OP): a randomised, open-label, phase 3 trial
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- 29Cisplatin for injection, for intravenous use: Prescribing Information
- 30Induction Gemcitabine and Cisplatin in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma (NCT01872962) — ClinicalTrials.gov record
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