Head and Neck Cancers

Background:

• Types:

  • ~90% of head & neck cancers are squamous cell carcinoma (HNSCC).

  • ~10% are salivary gland tumors, lymphomas, sarcomas, mucosal melanomas

• Risk factors:

  • HPV infection (16, 18, 33, 35)

    • HPV 16 is by far the dominant subtype (>80% of HPV-positive HNSCC)

    • HPV 18 is the second most common but plays a much smaller role than in cervical cancer (~2.5% of all HNSCC)

  • Smoking

  • Alcohol use (synergistic with smoking)

  • EBV esp in nasopharyngeal carcinoma

  • Betel nut chewing

  • Genetic factors such as Fanconi Anemia (avoid alkylating agents and radiation due to increased toxicity in these patients)

• Sites of tumors:

  • Nasal cavity and paranasal sinuses

  • Oral cavity cancers:

    • Mucosal lip, Buccal mucosa, anterior tongue, hard palate

  • Oropharyngeal cancers:

    • Upper throat, tonsil, base of tongue (posterior 1/3), soft palate, pharyngeal wall

    • Most primary H&N tumors are located in the oropharynx

    • ~70% are HPV-positive

  • Nasopharyngeal cancers (NPC):

    • Pharyngeal recess (fossa of Rosenmüller), posterior/lateral/superior walls

    • NPC is often discussed separately from other HNSCC because it is a distinct entity in terms of atiology and biology and treatment.

  • Hypopharyngeal cancer (lower throat)

  • Laryngeal cancers:

    • Supraglottis, glottis, subglottis

Treatment:

• Concurrent chemo-RT is the standard curative-intent treatment for locoregionally advanced HNSCC

  • Chemo is not curative single modality in H&N cancer

  • RT is typically over 6-7 weeks

• Regimens: 

  • Non-nasopharyngeal cancers:

    • High-dose cisplatin 100 mg/m² q3 weeks

    • Carboplatin/5FU

    • Other recommended:

      • Weekly cisplatin 40 mg/m²

      • Carboplatin/paclitaxel

    • If cisplatin-ineligible:

      • Carboplatin/paclitaxel

      • Carboplatin/5-FU 

  • Nasopharyngeal cancers:

    • Concurrent cisplatin + RT is the backbone.

      • Induction gemcitabine/cisplatin → concurrent cisplatin + RT 

      • Concurrent cisplatin + RT → adjuvant cisplatin/5-FU

• Follow up:

  • Clinical assessment about 4-8 weeks after completion of chemo/RT or RT alone.

  • PET-CT at a minimum of 12 weeks after completion of chemoRT

• If recurrent/residual disease after chemo-RT:

  • Salvage surgery (if feasible)

    • Re-radiating is typically not an option. 

• Post surgery:

  • Adjuvant RT if:

    • Adverse pathologic features

      • Lymphovascular invasion

      • T3/4, N2/N2

      • Perineural invasion

  • Adjuvant chemo-RT if:

    • Extranodal extension

    • Extracapsular extension

    • Positive margins

Oral Cavity Cancer

• Presents with mass, weight loss, loose teeth, submental nodes, bleeding, dysphagia/odynophagia

• More classically tobacco-associated.

Treatment:

• Resection + neck LN dissection → postoperative therapy (based on pathologic risk factors)

  • Observation if:

    • T1-2

    • Resectable T3-4a

  • Adjuvant RT if:

    • Adverse pathologic features present:

      • pT3-4

      • pN2-3

      • PNI

      • LVI

      • Close margins

      • Multiple involved LNs

  • Adjuvant concurrent cisplatin + RT if:

    • Classic high-risk features present:

      • Positive margin

      • Extranodal extension

Oropharyngeal cancers

• Associated with HPV 16 and less frequently HPV 18, 31 and 33.

  • High-risk HPV infection → E6 + E7 expression

    • E6 promotes p53 degradation and E7 inhibits RB → increased p16 expression → uncontrolled cell-cycle progression

  • Patients with HPV-associated oropharyngeal SCC tend to present at a younger age than patients with HPV-negative disease.

  • Patients with HPV-positive oropharyngeal SCC without a significant smoking history have a better prognosis than patients with HPV-negative, tobacco-associated disease.

• Staging:

  • First check HPV/p16 status:

    • T4 N0 M0 p16 negative oropharyngeal cancer → Stage IVA

    • T4 N0 M0 p16 positive oropharyngeal cancer → Stage III

      • p16+ patients can have substantial nodal disease while remaining Stage I/II.

      • Stage IV p16+ disease requires distant metastasis (M1)

• Treatment:

  • If early stage (T1-2, N0-1):

    • Resection + neck LN dissection

    • Definitive RT

  • If locally advanced (T3-4, N0-3):

    • Definitive concurrent chemo-RT (curative-intent)

    • Resection + neck LN dissection → postoperative therapy (based on pathologic risk factors)

      • Observation if:

        • Low risk pathology

      • Adjuvant RT if:

        • Adverse pathologic features present:

        • pT3-4

        • pN2-3

        • PNI

        • LVI

        • Close margins

        • Multiple involved LNs

      •  Adjuvant concurrent chemo-RT if:

        • Classic high-risk features present:

        • Positive margin

        • Extranodal extension

  • If recurrent/persistent disease:

    • Salvage surgical resection ± neck dissection

    • Systemic therapy (if unresectable)

Hypopharyngeal Cancer

Treatment:

• T1N+ or T2/T3 N0-3 (locally advanced disease):

  • Treatment options:

    • Induction chemotherapy (TPF: Docetaxel, Cisplatin, Fluorouracil)

    • Chemo-RT

    • Partial or total laryngopharyngectomy + neck LN dissection + thyroidectomy + pretracheal and ipsilateral paratracheal LN dissection

    • Clinical trial

  • Induction chemotherapy → definitive therapy depending on response

    • Partial response → surgery → adjuvant RT

    • Complete response → adjuvant RT

• T4:

  • T4aN0: Surgery with neck dissection → adjuvant RT

  • T4bN0:

    • Concurrent chemo-RT

    • Induction chemo → RT or chemo-RT

• Treatment for recurrent/unresectable/metastatic disease:

  • Consider regimen based on tumor burden and performance status:

    • If high tumor burden and good PS: consider chemo + pembrolizumab. 

    • If high tumor burden and poor PS: consider single agent IO.

    • If no rapidly progressive disease:

      • CPS >20: Single agent pembrolizumab

      • CPS 1-20: pembro + platinum chemo (or pembro alone if poor PS)

      • CPS<1: platinum chemo +/- pembro

  • First Line: 

    • Pembrolizumab + platinum + 5FU 

      • Keynote-048: proved this regimen is superior to EXTREME regimen

    • Single agent IO (Pembrolizumab or Nivo)

    • Cetuximab + 5FU + Platinum (EXTREME trial)

      • Consider if IO is contraindicated

    • Locoregional treatment (surgery, RT, ablative therapies) for oligometastatic disease 

  • Subsequent Lines: 

    • IO (nivolumab or pembro) if IO not previously used.

      • Category 1 option for patients with recurrent and/or metastatic SCC of the head and neck who progressed on platinum based chemo. 

    • Platinum/cetuximab/5FU: combination or single agents (if not previously used)

    • Taxanes

    • Methotrexate

    • Capecitabine

    • Afatinib: if progressed on platinum therapy

    • Erdaftinib: for FGFR mutation/fusion

    • Fam-trastuzumab deruxtecan (Enhertu): for HER2+ (if no other options)

Supraglottic Laryngeal Cancer

• Presents with hoarseness, dysphagia, hemoptysis

• Treatment:

  • T1-T2, N0 (or select T3, N0):

    • If patient prefers larynx-preserving surgery: can undergo either RT or partial laryngectomy (endoscopic or open resection) and neck dissection.

    • If surgery is pursued: consider adjuvant RT if any high risk features present

  • T3:

    • Induction chemotherapy, surgery or concurrent chemo-RT

    • If induction chemotherapy given subsequent steps depend on response:

      • CR → definitive RT

      • PR → RT or chemoRT

      • Less than PR → laryngectomy

  • T4:

    • Surgery preferred

    • If surgery declined or not feasible in T4b: chemo-RT or induction chemo

  • Locoregional recurrence, persistent disease, second primary, prior RT:

    • If resectable: Surgery +/- postoperative reirradiation, chemo-RT, clinical trial

    • If unresectable: chemo-RT, chemotherapy, clinical trial

Nasopharyngeal Cancer

• Presents with hearing loss, tinnitus, nasal obstruction/pain, posterior neck nodes

• Associated with EBV

  • High levels of EBV DNA are associated with poor disease outcomes following RT or chemoRT

• Treatment:

  • T1N0M0 (EBV negative):

    • Definitive RT to nasopharynx and elective RT to neck

  • T2N0M0:

    • If EBV negative: definitive RT

    • If EBV positive: definitive RT + chemo

  • T3N0M0:

    • Chemo-RT

  • T4 or any N+, M0 (locally advanced):

    • Chemo-RT

    • Chemo-RT followed by chemo

    • Induction chemo (cisplatin/gemcitabine) followed by chemo-RT

    • Clinical trial

  • Recurrent/unresectable/metastatic disease

    • Cisplatin + 5-FU

    • Platinum + Taxane

    • Carboplatin + Cetuximab

    • Gemcitabine + Carboplatin

    • Cisplatin + Gemcitabine + toripalimab (or any other PD-1 inhibitor)

    • Subsequent line: Can use nivolumab or pembrolizumab (needs to be PDL1 positive) or Tislelizumab

Salivary Gland Tumor

• < 2% of all head and neck cancers

• They have positive androgen receptors

• Initial Treatment: surgical resection + LN dissection

• Consider adjuvant RT if:

  • T3/T4 disease

  • Intermediate or high grade

  • Close or positive margins

  • Perineural invasion

  • Lymphovascular invasion

  • LN metastases

• Systemic therapy for metastatic disease: 

  • Combination regimens: cisplatin, doxorubicin, and cyclophosphamide

  • Single agents: vinorelbine or mitoxantrone

  • If adenoid cystic carcinoma histology:

    • Taxanes are normally avoided due to lack of effectiveness.

    • If patient progress on initial therapy and remain candidates for treatment, one can offer therapy with VEGF tyrosine kinase inhibitors (Lenvatinib, Sorafenib, or Axitinib)

Thymoma/ Thymic Cancer

• Causes anterior mediastinal mass

• Associated with myasthenia gravis and pure red cell aplasia

• Treatment:

  • If localized disease: Surgical resection (leads to improvement of associated paraneoplastic syndrome)

    • If R0 resection: Surveillance

    • If R1/R2: Consider adjuvant RT (might consider chemo-RT for R2)

  • Preferred chemo regimen for thymoma: CAP (Cisplatin, Doxorubicin, Cyclophosphamide) 

    • If chemotherapy is given with RT: Cisplatin + Etoposide

    • Subsequent line for thymoma: Pemetrexed

  • Preferred chemo regimen for patients with thymic cancer: Carboplatin/Paclitaxel

    • Subsequent line for thymic cancer: Lenvatinib/Sunitib

NUT Carcinoma

• Highly aggressive subset of SCC, found in head and neck or mediastinum

• Hallmark is the rearrangement of NUT gene: located on chromosome 15

• Initial treatment: surgery followed by chemo-RT