1. Nasopharyngeal Carcinoma – Biology and Management
Erin Alesi, MD
Medical Oncology and Palliative Medicine

2. Objectives Review anatomy of the nasopharynx
Discuss epidemiology of nasopharyngeal (NP) carcinoma
Discuss etiology and risk factors
Review histology
Review staging
Discuss treatment of early and locally advanced NP carcinoma
Discuss treatment of recurrent and metastatic NP carcinoma

3. Nasopharynx - anatomy

4. Nasopharynx - Anatomy
Continuation of nasal cavity, superior to oropharynx
Boundaries:
Anterior: Posterior nasal choanae
Posterior: Prevertebral muscle and anterior margins of C1-C2
Superior: Clivus (basiocciput) and basisphenoid
Inferior: Hard and soft palate

5. Nasopharynx - Anatomy Contains
Torus tubarius – cartilaginous opening of Eustachian tube
Eustachian tube = communication between NP and middle ear through sinus of Morgagni
Sinus of Morgagni may allow NP carcinoma to reach skull base
Fossa of Rosenmüller – lateral NP recess posterior to torus tubarius
Common site of NP carcinoma
Adenoids – NP tonsils
Midline roof of NP

6. Nasopharynx - Anatomy

7. NP Carcinoma - Epidemiology
Incidence = 86,000 cases worldwide annually
Deaths = 50,000 annually
Distinct racial and geographic distribution
Endemic in Southern China (Hong Kong, Singapore, Taiwan)
Incidence 25 cases per 100,000 per year
Intermediate risk areas – SE Asia, Middle East, N Africa, Arctic
Rare in US and Western Europe
Incidence cases per 100,000 per year

8. NP Carcinoma - Epidemiology
2-3x more common in males vs. females
Age
High-risk areas: incidence peaks at years
Minor peak in AYA population
Lower-risk areas: incidence increases with age
Also minor peak in AYA population in US
Overall incidence declining in endemic areas over past 30 years
Unclear cause - ?Lifestyle changes due to rapid economic development

9. NP Carcinoma – Etiology/Risk factors
Endemic areas
EBV infection
High intake of preserved foods
Smoking
Genetic predispositions
United States and Europe
Tobacco Use
Alcohol Use

10. NP Carcinoma – Etiology/Risk factors
EBV
Primary etiologic agent in pathogenesis of NP carcinoma
EBV DNA and EBV gene expression detected in precursor lesions and tumor cells
Tumor cell expression of EBV-latent proteins:
EBNA-1, LMP-1 and 2, BamHI-A fragment of EBV genome
Serology
IgA antibodies to EBV viral capsid antigen (VCA)
Smoking may cause EBV reactivation

11. NP Carcinoma – Etiology/Risk factors
Dietary practices in endemic areas
Cooking of salt-cured food
Releases volatile nitrosamines in steam  distributed over NP mucosa
Early childhood exposure to salted fish (used for weaning)
High consumption of preserved and fermented foods
High levels of nitrosamines, bacterial mutagens, direct genotoxins, EBV-reactivating substances
Chinese medicinal herbs
EBV reactivation, promotion effect on EBV-transformed cells
Maghrebian population of Tunisia, Algeria, Morocco
Consumption of rancid butter and sheep’s fat = butyric acid  EBV reactivation, other mutagenic properties

12. NP Carcinoma – Etiology/Risk factors
Heredity
Clustering noted within families
1st degree relative with NP carcinoma increases risk 7-fold
Association with HLA haplotypes
Association with genetic polymorphisms
CYP2A6 – nitrosamine-metabolizing gene polymorphism
HPV
Detected in small subset of white pts in nonendemic, low-incidence regions
Unclear significance

13. NP Carcinoma – Etiology/Risk factors
Molecular pathogenesis
Virologic, genetic, environmental factors
Genetic
Chromosomal abnormalities
Copy number changes on 3p, 9p, 11q, 12p, 14q
Gene alterations
Deletion p16, LTBR amplification
Epigenetic changes
Methylation of RASSF1A and TSLC1

14. NP Carcinoma - Histology
Arises from epithelial lining of NP
WHO 3 Histopathologic types
Keratinizing SCCa (WHO Type 1) – most common sporadic form
Non-keratinizing Carcinoma
Differentiated (WHO Type II)
Undifferentiated (WHO Type III) – most common endemic form
Strongly associated with EBV, more favorable prognosis
Basaloid SCCa
Rare
Aggressive clinical course, poor survival

15. NP Carcinoma - Histology
North America
Keratinizing SCCa – 25%
Nonkeratinizing Differentiated – 12%
Nonkeratinizing Undifferentiated – 63%
Southern China
Keratinizing SCCa – 2%
Nonkeratinizing Differentiated – 3%
Nonkeratinizing Undifferentiated – 95%

16. NP Carcinoma – Clinical Presentation
Headache, diplopia, facial numbness – cranial nerve involvement
Neck mass – cervical LN involvement
Clinical Triad (but often do not occur together)
Neck mass
Nasal obstruction with epistaxis
Serous otitis media

17. NP Carcinoma – Clinical Presentation
Frequently originates from NP recess (Fossa of Rosenmüller)
Clinically occult site, often asymptomatic for prolonged period
Locally advanced at presentation
Appearance: smooth bulge in mucosa, discrete nodule +/- ulceration, infiltrative fungating mass
Frequent erosion into skull base +/- cranial nerve involvement
CN III, V, VI, VII are most common due to paracavernous sinus tumor invasion

18. NP Carcinoma – Clinical Presentation
Tendency toward early metastatic spread
Cervical LN involvement at diagnosis – 75-90% cases, >50% bilateral
Distant mets at diagnosis – 5-11% of cases
Bone (75%), lung, liver, distant LN
Paraneoplastic syndromes
Neutrophilia, FUO, Hypertrophic osteoarthropathy, dermatomyositis

19. NP Carcinoma – Prognosis
5 year OS
Stage I – 100%
Stage II – 94.3%
Stage III – 83.6%
Stage IVA/B – 70.5%
Pre- and post-treatment DNA levels may have prognostic significance
Stage I, II disease, low pre-therapy DNA (<4000 copies/mL) – 91 percent
Stage I, II disease, high pre-therapy DNA (≥4000 copies/mL) – 64 percent
Stage III, IVA/IVB disease, low pre-therapy DNA – 66 percent
Stage III, IVA/IVB disease, high pre-therapy DNA – 54 percent
Post-RT EBV DNA validated as most significant prognostic biomarker in evaluating response to treatment and detecting recurrence
Still not routinely used, being evaluated in clinical trials

20. NP Carcinoma – Diagnostic evaluation
Definitive diagnosis with endoscope-guided biopsy of primary tumor
Routine Evaluation
H and P (include cranial nerves)
CBC, BMP, Hepatic panel
CXR (usually chest CT)
Nasopharyngoscopy
CT or MRI of nasopharynx, skull base, and neck
PET scan if N3 disease, signs/sx of distant mets, EBV DNA load ≥4,000 copies/mL
Pre-treatment plasma EBV DNA levels (not currently routine, may correlate with outcome)

21. NP Carcinoma - Staging AJCC TNM Staging System

22. NP Carcinoma - Staging

23. NP Carcinoma - Staging

24. NP Carcinoma - Staging

25. NP Carcinoma Treatment of early and locoregionally advanced disease
General principles
Surgery is generally not 1st line treatment due to deep anatomical location of NP and close proximity to neurovascular structures
Salvage neck dissection may be performed for residual nodal disease or isolated neck recurrence
Not common: nasopharyngectomy for small local recurrence
Primary treatment is with RT +/- chemotherapy

26. NP Carcinoma – Early Stage Disease
Stage I – T1N0M0
Confined to nasopharynx (or adjacent oropharynx or nasal cavity) without posterolateral (parapharyngeal) infiltration or nodal involvement
RT alone
Good locoregional control
5y OS 90%

27. NP Carcinoma – Intermediate Stage Disease
Stage II – T1 or 2, N0 or1, M0
Parapharyngeal extension without bony involvement
Up to 1 ipsilateral cervical LN ≤ 6cm diameter
Combined modality therapy (concurrent CRT) recommended
Higher distant failure rates

28. NP Carcinoma – Intermediate Stage Disease

29. NP Carcinoma – Intermediate Stage Disease
Phase III RCT, 230 Chinese pts with previously untreated stage II NP carcinoma, WHO types II-III
RT alone – Gy
RT + weekly cisplatin 30mg/m2 x 6 cycles (concurrent CRT)
Concurrent CRT significantly better than RT alone
5y OS 94.5 vs. 85.8%, HR 0.30 (95% CI )
Primarily due to improved distant metastasis-free survival (no difference in locoregional control between groups)
Number of chemo cycles was only independent variable associated with survival, progression, distant control

30. NP Carcinoma – Intermediate Stage Disease
Phase III RCT, 230 Chinese pts with previously untreated stage II NP carcinoma
Concurrent CRT significantly better than RT alone
Increased incidence of severe (grade 3-4) side effects (statistically significant)
Neutropenia (12 vs 0%)
Nausea/Vomiting (8.6 vs 0%)
Mucositis (46 vs 33%)
No increased risk of late toxicities

31. NP Carcinoma – Locally Advanced Disease
Stage III – T3 N0-2 or T1-2, N2
Bony involvement (T3) or bilateral cervical LN ≤ 6cm diameter (N2)
Stage IVA –T4 N0-2
Intracranial extension and/or involvement of CN, hypopharynx, orbit
Stage IVB – T1-4 N3
Cervical LN ≥ 6cm diameter or extension into supraclavicular fossa (N3)
Combined modality therapy
Concurrent CRT
+/- Adjuvant or Induction chemotherapy

32. NP Carcinoma – Locally Advanced Disease
Concurrent CRT
Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC)
1834 pts, 7 trials, Lancet Oncology 2015
Concurrent CRT (+/- induction or adjuvant chemo) vs. RT alone
Concurrent CRT +/- Adjuvant chemo significantly improved OS
10y OS 58.7 vs. 50.5%, HR 0.79 (95% CI )
Also significantly improved PFS, locoregional control, distant control and cancer mortality
No statistically significant differences between groups with/without adjuvant therapy

33. NP Carcinoma – Locally Advanced Disease
Adjuvant therapy after concurrent CRT
The Regimen – United States Intergroup 0099 Trial, 1998
Cisplatin 100mg/m2 concurrent with RT every 3 weeks on days 1, 22, and 43, followed by
Cisplatin 80mg/m2 + 5FU 1000mg/m2/d x 4d every 4 weeks starting days 71, 99, and 127 (3 cycles)
55% of patients completed all 3 cycles

34. NP Carcinoma – Locally Advanced Disease
Adjuvant therapy after concurrent CRT
Unclear benefit on survival

35. NP Carcinoma – Locally Advanced Disease

36. NP Carcinoma – Locally Advanced Disease
Phase III RCT, 508 Chinese patients, stage III-IVB, WHO Types II and III
Concurrent CRT +/- Adjuvant chemotherapy
Modified regimen:
Concurrent CRT with weekly cisplatin 40mg/m2 x 6-7 cycles
Adjuvant chemo with cisplatin 80mg/m2 + 5FU 800mg/m2/d x 5d every 28 d for 3 cycles
63% completed all 3 cycles
2y failure-free survival rate not statistically significant with CRT + adjuvant vs. CRT without adjuvant
86 vs 84%, HR 0.74 (95% CI )

37. NP Carcinoma – Locally Advanced Disease

38. NP Carcinoma – Locally Advanced Disease
Meta-analysis, 20 trials, 5144 pts with locally advanced NP carcinoma, all treatment types
Concurrent CRT + Adjuvant chemotherapy = highest probability of benefit on OS compared to RT alone
HR 0.65 (95% CI )
CRT alone HR 0.77 (95% CI 0.64 to 0.92)
CRT + adjuvant vs. CRT alone
OS: HR 0.85 (0.68 to 1.05)
PFS: HR 0.81 (0.66 to 0.98)*
Loco-regional control: HR 0.70 (0.48 to 1.02)
Distant control: HR 0.87 (0.61 to 1.25)
More chemo = more toxicity

39. NP Carcinoma – Locally Advanced Disease
More chemo = more toxicity
Concurrent CRT + Adjuvant chemo significantly reduced deaths due to disease progression, though increased deaths due to acute toxicity, infection, 2nd malignancy, suicide
Similar 5y OS in both groups (68 vs. 64%, HR 0.81, 95% CI )

40. NP Carcinoma – Locally Advanced Disease
Current bottom line on adjuvant chemo
May improve disease control but with increased toxicity and unclear benefit on OS
Need more trials designed specifically to answer this question
Other treatment combinations are even less well-defined
Sequential therapy: Induction chemotherapy + RT or concurrent CRT
Ongoing trials

41. NP Carcinoma – Metastatic Disease
Preferred Regimen
Gemcitabine + Cisplatin
Gem 1000mg/m2/d on D1 and 8 + Cis 80mg/m2 on D1 every 21 D x 6 cycles
Better PFS compared to Cis + 5FU
7.0 vs 5.6 months, HR 0.55, 95% CI
Improved prelim OS data
29.1 vs 20.9 months, HR 0.62, 95% CI