Head and Neck Cancers

Risk factors:

• HPV infection (16, 18, 33, 35)

• Smoking

• Alcohol use (synergistic with smoking)

• Betelnut chewing

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

  
  

Sites of tumor:

• Oral Cavity: mucosal lip, Buccal mucosa, anterior tongue, hard palate

• Oropharyngeal Cancer: upper throat, tonsil, base of tongue, soft palate, pharyngeal wall

• Hypopharyngeal Cancer (lower throat)

• Laryngeal Cancer

Treatment:

• Principles of concurrent chemo-RT:

  • RT is typically over 6-7 weeks

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

  • Concurrent chemotherapy options: 

    • Cisplatin 40 mg/m2 weekly (preferred)

    • High dose cisplatin 100 mg/m2 q3 weeks (may have more side effects)

    • Carboplatin/5FU

    • Consider cetuximab if cisplatin contraindicated though it is inferior

      • Consider against cetuximab in HPV+ disease

• Follow up:

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

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

• Recurrent/Residual Disease after chemo-RT:

  • Indication for salvage surgery (if feasible)

  • Re-radiating is typically not an option. 

• Post surgery:

  • If adverse pathologic features (lymphovascular invasion, T3/4, N2/N2, perineural invasion, etc): adjuvant RT

  • If extranodal/extracapsular extension or positive margins: adjuvant chemo-RT

Oropharyngeal Cancer

• Presents with oral mass, weight loss, loose teeth, ill fitting dentures, submental nodes, neck mass, dysphagia, odynophagia, bleeding

• Most primary tumors identified with head and neck SCC are located in the oropharynx, with 70% being HPV-positive.

• Associated with HPV 16 and 18. HPV 31 and 33 are responsible for the vast majority of the remaining fraction. Encodes for E6 and E7 protein. E6 attaches to p53 (tumor suppressor) and E7 attaches to RB protein. Together they inhibit p53 and RB allowing for tumor formation.

• Patients with HPV-associated H&N cancers tend to be younger. HPV positive tend to have a better prognosis (compared to smokers).

• Localized p16+ tumors can only go up to stage 3

  • Example: Patient with a T4 N0 HPV+ Oropharyngeal cancer will be considered to have Clinical Stage III disease, while a T4a N0 Non-HPV Oropharyngeal cancer will be considered to have Stage IVA disease

• Base of tongue tumors:

  • No surgical options for these patients. Automatically requires chemo-RT even if early stage

Treatment:

• Treatment of cancers in oral cavity:

  • For T1 and T2: Resection is preferred + elective neck LN dissection, can consider adjuvant RT if adverse features (positive/close margins, extranodal extension, LVI, PNI, upstaged to pT3/T4 or pN2/N3)

• Treatment of cancers of the oropharynx:

  • If T1-2, N0-1 tumor: Resection + LN dissection is preferred (if surgical candidate)

    • Can offer definitive RT

    • If adverse features seen: adjuvant chemo-RT

  • If locally advanced disease (N+): Treated with concurrent chemoRT

  • If recurrence: Consider surgical resection, neck dissection

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

Hypopharyngeal Cancer

Treatment:

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

  • Treatment options:

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

    • Chemo-RT

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

    • Clinical trial

  • Induction chemotherapy typically followed by 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)

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