Alexander N. Shoushtari, Shrujal S. Baxi, and David G. Pfister
Epidemiology
• H&N CA: US∼50K cases/y, 11K D/y. >90% = H&N squamous cell ca (SCCHN). M:F 3:1
• RF: Tobacco, EtOH, HPV, EBV betel quid
• Genetic syndromes: Overall, rare; Fanconi most common. Others: Lynch-2, Bloom, Li–Fraumeni, Xeroderma Pigmentosa
• Special populations: Nasopharyngeal endemic in southern China and Hong Kong
• Risk of 2nd 1º CA:∼3%/y for aerodigestive tracts due to “field cancerization” by tobacco/EtOH (not HPV); → consider selective use of “triple endoscopy” = EGD, bronchoscopy, laryngoscopy
Anatomic Divisions of H&N Cancer
• Oral cavity: Buccal mucosa, alveolar ridges, floor of mouth, hard palate, tongue (ant 2/3)
• Oropharynx: Tongue (base), tonsils, soft palate, post pharyngeal wall to level of hyoid
• Nasopharynx: Superior to soft palate
• Hypopharynx: Hyoid bone to cricoid cartilage
• Larynx: Divided into supraglottic, glottic; subglottic (rare)
Molecular Pathogenesis
• p16 inactivation: Frequent alteration in SCCHN
• EGFR: Alterations in >90% of all SCCHN; overexpression correlates w/poorer prognosis (JNCI 1998;90:824)
• CCND1 overexpression affects: ↑ cell cycle progression
• HPV: E6, E7 viral protein → inhibit p53, Rb, other tumor suppressors
• EBV: → LMP1, other viral proteins → ↑ cell replication; a/w nasopharyngeal carcinoma (esp. endemic subtype)
• Others: p53 Mt, PI3K/AKT/mTOR & PTEN inactivation
Pathology
• Precursor lesions: Hyperplasia → Dysplasia → Carcinoma in situ → Invasive CA
Leukoplakia – fixed white plaques; hyperparakeratosis w/hyperplasia
Erythroplakia – red patches; often a/w epithelial dysplasia
• Key pathologic findings
1° tumor – size, differentiation, depth of invasion, LVI or PNI, precursor lesions, surgical margins
Nodes – laterality, size, extracapsular extension
• Molecular studies
p16 (+) by IHC in HPV-associated tumors due to inactivated Rb
p53 Mt more common in tobacco/EtOH-associated tumors
HPV-Associated SCCHN
• Serotypes: -16 (>90%), -18 (NEJM 2001;344:1125)
• Dx: p16 IHC (more sensitive), HPV in-situ hybridization (more specific), HPV DNA PCR
• Location: Most commonly oropharyngeal
• Demographics: Younger pt w/min. smoking/EtOH hx, p/w extensive nodal disease → w/u locates small oropharyngeal 1° tumor
• Prognosis: Better than stage-matched HPV-negative tumors (NEJM 2010;363:24)
Initial Workup of SCCHN
• Hx – dysphagia, nutrition/wt loss, trismus/pain; EtOH, tobacco, sexual hx
• Physical – Detailed H&N exam w/mirror exam or direct visualization. Consider triple endoscopy if unknown 1° or diffuse mucosal abnormalities
• Imaging – CT/MRI of neck, chest imaging = CXR at minimum. Consider CT chest or PET/CT if N2 or N3 disease
• Bx – after imaging if possible to avoid false (+), esp PET/CT; FNA of involved neck node well-tolerated, convenient; tissue HPV testing if oropharynx
• Multidisciplinary care – rad onc, surgery, med onc; nutrition (PEG if malnutrition at baseline), dental, speech path, smoking/EtOH cessation
Staging (TNM)
• T stage is variable by site; N & M stages are more uniform
• Stage I = T1; Stage II = T2; Stage III = T3 or N1 (single ipsilateral LN ≤ 3 cm)
• Stage IV = still potentially curable
IVA = “moderately advanced local disease,” T4 or N2 (single LN 3–6 cm; or 2+ LNs)
IVB = “very advanced local disease,” T4b or N3 (any LN > 6 cm)
IVC = distant mets = likely incurable
• Nasopharyngeal staging system differs from other upper aerodigestive ca
Prognosis
• HPV-associated more favorable than nonHPV; EGFR overexpression → worse
Treatment – Curative Intent
• Surgery & RT alone (early stage) or together (more advanced stage) are mainstays; chemotherapy has ↑ role in latter
• Surgical margins – clear = 5 mm or more; close margins <5 mm; (+) = CIS or invasive at margin; close/(+) may dictate changes to RT or chemo plan. No OS benefit to adjuvant chemo alone (MACH-NC, Radiother Oncol 2009;92:4)
• RT – when surgery is not technically feasible or undesirable (eg, larynx preservation). SEs of RT – both short and long term- fatigue, xerostomia, 2° malignancies (sarcomas). EBRT standard 66–70 Gy, 2 Gy fractions to 1° tumor and/or high-risk LNs. “Hyperfractionation” = potential higher cumulative doses in smaller fractions. Increasingly, IMRT used to minimize xerostomia (Lancet Oncol 2011;12:127) and optimize targeting but longer planning, more expertise required.
Role of Chemoradiation (CRT)
• Standard is concurrent CRT; used as alternative to surgery for organ preservation or improve outcomes for unresectable or high-risk, resected disease
• Larynx preservation improved w/concurrent cisplatin + RT (RTOG 91-11, JCO 2013;epub)
• Adjuvant cisplatin added during post-op RT ↑ DFS (NEJM 2004;350:1937) & OS (NEJM 2004;350:1945) if (+) margins or extracapsular extension in LN (Head Neck 2005;27:843)
• Advanced disease: Cisplatin CRT ↑ OS but also ↑ tox (cytopenias, renal, N/V) (JCO 2003;21:92). Carbo + 5-FU CRT ↑ OS in oropharyngeal (JCO 2004;22:69); Cetuximab CRT ↑ OS (NEJM 2006;354:567)
Role of Induction Chemotherapy
• Rationale – ↓ 1° tumor size, organ preservation, ↓ risk of distant mets; controversial as ↑ duration of tx, potential ↑ tox risk, no trials have yet shown OS advantage of induction + CRT vs. CRT alone
• If induction chosen, docetaxel, cisplatin, 5-FU preferred (NEJM 2007;357:1695)
Treatment – Palliative Intent
• For distant mets or recurrent disease s/p RT that is unresectable or ineligible for more RT
• Historically, platinum doublet (eg, cisplatin + 5-FU) vs. single agent used; other combos ↑ RR but also ↑ SEs w/no clear OS benefit.
• Cetuximab improves OS by ∼2–3 mo when added to platinum doublet (EXTREME, NEJM 2008;359:1116) – SEs = acneiform rash (correlates w/response), GI complaints, rare sev. HSR
Post-therapy Surveillance
• H&P q1–3 mo × 1 y, then gradually lengthen interval until yearly >5 y
• New baseline imaging w/in 6 mos of tx
• Consider trending EBV titers for nasopharyngeal ca
• Surveillance for 2° CA, complications of RT (eg, thyroid function)