Nasopharyngeal cancer

Question 1

What is the incidence of nasopharyngeal cancer (NPC) in the United States vs. in Asian countries?

Answer 1

NPC is rare in the United States (0.2–0.5 in 100,000) but endemic in Asia (25–50 in 100,000).

Question 2

What are the environmental risk factors associated with NPC?

Answer 2

Consumption of salted fish and preserved meats, EBV infection, and smoking for keratinizing squamous cell type (no alcohol association)

Question 3

What is the median age at Dx for NPC?

Answer 3

∼50 yrs

Question 4

Is there a sex predilection for NPC?

Answer 4

Yes. Males > Females (3:1)

Question 5

What are the anatomic boundaries that make up the nasopharynx (NPX)?

Answer 5

Superior: sphenoid bone
Inferior: soft palate
Posterior: clivus/C1–2
Anterior: post edge of choanae

Question 6

From what anatomic location do most NPCs arise?

Answer 6

Fossa of Rosenmuller (pharyngeal recess)

Question 7

What is the local pattern of spread for NPC superiorly, inferiorly, posteriorly, laterally, and anteriorly?

Answer 7

Superiorly: invades (via the foramen lacerum) the cavernous sinus with initial CN VI involvement
Inferiorly/posteriorly: OPX
Laterally: parapharyngeal space
Anteriorly: nasal cavity

Question 8

What 2 CN syndromes are commonly associated with NPC, and what CNs are involved in each?

Answer 8

Petrosphenoidal syndrome: CNs III–IV and VI involvement (oculomotor signs/Sx)
Retroparotidian syndrome: CN IX–XII involvement

Question 9

What CNs or structures traverse through the base of skull sinuses/foramina (e.g., cavernous sinus, foramen rotundum, ovale, lacerum, jugular, hypoglossal)?

Answer 9

Cavernous sinus: CNs III–IV, V1 and V2, and VI
Foramen rotundum: V2
Foramen ovale: V3
Foramen lacerum: cartilage of the eustachian tube
Jugular foramen: CNs IX–XI
Hypoglossal canal: CN XII

Question 10

What are the histologic subtypes of NPC and corresponding WHO classifications?

Answer 10

Keratinizing SCC (WHO type I, 25%). Sporadic form
Nonkeratinizing carcinoma: Differentiated (WHO type II, 12%).
Undifferentiated (WHO type III 63% vs. 95% in Asia)

Question 11

Which type of NPC is endemic and prone to distant recurrence?

Answer 11

Nonkeratinizing undifferentiated (WHO type III) is endemic (better LC but higher metastatic risk).

Question 12

Which type of NPC is associated with smoking and has poor LC but a lower propensity for DM?

Answer 12

Keratinizing SCC (WHO type I) is associated with smoking, poorer LC, and less distant spread.

Question 13

Which type of NPC is most strongly associated with EBV exposure?

Answer 13

Nonkeratinizing undifferentiated (WHO type III)

Question 14

With what autoimmune condition can NPC be associated?

Answer 14

Dermatomyositis

Question 15

What histologic feature of NPC is an adverse prognostic factor in terms of LC and OS?

Answer 15

Presence of keratin (WHO type I)

Question 16

What role does p53 play in the pathogenesis of NPC?

Answer 16

Little. p53 alteration is seen in the minority of cases (unlike other H&N cancers).

Question 17

What is a commonality b/t NPX and OPX cancers?

Answer 17

Viral-associated tumors (EBV-NPX: HPV-OPX) have better LC but higher propensity for distant spread compared to nonviral-associated tumors in these
regions.

Question 18

What are some common presenting Sx in pts with NPC?

Answer 18

Neck mass (>60%); epistaxis, headache, diplopia, facial numbness, otalgia, and nasal congestion. Trismus and/or CN deficits are seen with more advanced Dz.

Question 19

What is the workup for a pt who presents with a neck node and a suspicious mass in the NPX according to the NCCN guidelines?

Answer 19

H&P, nasopharyngolaryngoscopy and Bx of the lesion, MRI with gadolinium of base of skull, NPX, and neck to clavicles, CT of skull base/neck with contrast as indicated; dental, speech and swallow, and audiology evaluations
as indicated, and PET scan or other imaging to evaluate for DM

Question 20

What is the DDx for a pt with a nasopharyngeal mass?

Answer 20

Carcinoma, lymphoma, melanoma, plasmacytoma, angiofibroma, RMS (children), and mets

Question 21

What % of NPC pts present with palpable LAD?

Answer 21

60%–90%

Question 22

What % of NPC pts present with bilat LAD?

Answer 22

Up to 50%

Question 23

Adenopathy near the mastoid tip is indicative of involvement of which nodal group?

Answer 23

Retropharyngeal nodes (node of Rouviere)

Question 24

Pts with upper-level V LAD are most likely to have what kind of H&N primary?

Answer 24

NPC

Question 25

What factors predict for DM in pts with NPC?

Answer 25

Lower neck nodal involvement, advanced nodal stage, and nonkeratinizing undifferentiated (WHO type III) histology

Question 26

What are the common DM sites for NPC?

Answer 26

Bones, lungs, and liver

Question 27

What correlates better with DM spread in NPC: N stage or T stage?

Answer 27

N stage

Question 28

T staging for NPC

Answer 28

T0 No primary identified with EBV+ cervical node(s)
T1 NPX ± OPX ± nasal cavity without parapharyngeal involvement
T2 Parapharyngeal extension ± adjacent ST involvement (medial or lat pterygoid, prevertebral muscles)
T3 Base of skull bones ± PNS ± cervical vertebra, pterygoid structures
T4 intracranial extension, CNs, hypopharynx, orbit, parotid, beyond lat pterygoid muscle

Question 29

N staging for NPC

Answer 29

N1 Unilat cervical ≤6 cm ± retropharyngeal LN ≤6 cm (unilat or bilat), above caudal border of cricoid
N2 Bilat cervical ≤6 cm above the caudal border of the cricoid
N3 >6 cm and/or extension or involvement below the caudal border of the cricoid

Question 30

What is the typical Tx paradigm for pts with NPC?

Answer 30

RT alone for stage I, CRT for stages II–IVA, chemo (with RT reserved for focal palliation) for stage IVB

Question 31

What must be done before planning the NPC pt for RT?

Answer 31

Nutrition consult, dental evaluation are recommended before RT.

Question 32

When is Sg indicated in the management of NPC?

Answer 32

To Bx the lesion and in cases of selective neck dissection for persistent Dz after CRT.

Question 33

For early-stage NPC, what are the typical survival and control rates with RT alone?

Answer 33

With RT alone, the 3-yr OS is 70%–100% for stage I–II NPC and LC rates are 70%–80% for T1–T2 lesions.

Question 34

What stages of NPC should be treated with concurrent chemoradiotherapy (CRT)?

Answer 34

Per the Intergroup 0099 study (Al Sarraf M et al., JCO 1998), all T3–T4 or N+ pts should be considered for CRT. Per RTOG 0225 (Lee N et al., JCO 2009), pts with T2 and N+ Dz should be considered (AJCC 8th edition
staging).

Question 35

What was the CRT regimen used for locally advanced NPC in the Intergroup 0099 (Al-Sarraf et al.) study?

Answer 35

Concurrent chemo with cisplatin (100 mg/m2) q3 wks and RT to 70 Gy → adj chemo with cisplatin/5-FU × 3 cycles

Question 36

What were the PFS and OS outcomes in the Intergroup 0099 (Al-Sarraf et al.) trial?

Answer 36

In Intergroup 0099, 3-yr PFS was 24% vs. 69%, and 3-yr OS was 46% vs. 76% in favor of CRT over RT alone. B/c of this striking difference, the study was closed early. This was 1 of the 1st studies to demonstrate a survival
benefit with CRT.

Question 37

What are the main criticisms of the Intergroup 0099 (Al-Sarraf et al.) study?

Answer 37

Major criticisms of Intergroup 0099 include the large number of pts (25%) with WHO type I NPC (not typically seen in endemic areas) and the poor results of the RT-alone arm. Single-institution studies with RT alone (PMH:
Chow E et al., Radiother Oncol 2002) for locally advanced NPC had better 5-yr DFS (48%) and OS (62%). Other groups (NYU: Cooper JS et al., IJROBP
2000) also demonstrated better outcomes with RT alone (3-yr DFS was 43%, and 3-yr OS was 61%).

Question 38

What are the 3 key confirmatory randomized trials from Asia that demonstrated a benefit with CRT vs. RT alone for locoregionally advanced NPC?

Answer 38

1. Hong Kong (NPC-9901: Lee AWM et al., Cancer 2017): 348 pts, RCT, median f/u 10.7 yrs; concurrent cisplatin + RT + adj chemo vs. RT alone, no adj chemo; CRT improved PFS (56% vs. 42%), LRC (87% vs. 74%),
and OS (62% vs. 49%, p = .047) but not DM rate; toxicities similar @10 yrs (52% vs. 47%)

2. Singapore (SQNP01: Wee J et al., JCO 2005): 221 pts, RCT, median f/u 3.2 yrs; used Al-Sarraf regimen: better DFS (72% vs. 53%), OS (80% vs. 65%), and DM rate (13% vs. 30%); greater toxicity with CRT; confirmed results of Intergroup 0099 for endemic NPC
3. Taiwan (Lin JC et al., JCO 2003): 284 pts, median f/u 5.4 yrs; cisplatin/5-FU + RT vs. RT alone: better PFS (72% vs. 53%) and OS (72% vs. 54%). The subgroup reanalysis (Lin JC et al., IJROBP 2004) showed that CRT
   benefited low-risk “advanced” NPC (LN <6 cm, no SCV) but not high-risk “advanced” pts

Question 39

Is there a benefit to the addition of induction chemo followed CRT in locally advanced NPC?

Answer 39

Yes. Sun Trial (Sun et al., Lancet Oncol 2016). 480 pts. RCT of induction TPF f/b CRT vs. CRT alone. Median follow-up 3.75 yrs. Improved 3-yr: FFS (80% vs. 72%), OS (92% vs. 86%), DMFS (90% vs. 83%). No significant
difference in LRF.

Question 40

Is there a benefit with the use of adj chemo after definitive CRT in locally advanced NPC?

Answer 40

Maybe. Network Meta-analysis (Ribassin-Majed et al., JCO 2017) found the addition of adj chemo ranked sup to CRT alone for PFS, LRC and OS. However, only PFS was statistically significant.

Question 41

Estimate the LC of NPC treated with IMRT to 70 Gy in standard fx.

Answer 41

UCSF data (Lee N, IJROBP 2004) suggests LC rates as high as 97% for NPC pts treated with IMRT.

Question 42

What is the typical IMRT dose painting technique, and what are the corresponding IMRT doses used in the Tx of NPC?

Answer 42

Many institutions (MSKCC/RTOG) employ the SIB technique: 2.12 Gy × 33 = 69.96 Gy to GTV, 1.8 Gy × 33 = 59.4 Gy to intermediate-risk areas, and 1.64 Gy × 33 = 54 Gy to low-risk areas.

Question 43

How would you support the use of IMRT in NPC?

Answer 43

Better salivary outcomes with IMRT were demonstrated in data from Queen Mary Hospital (Pow EH et al., IJROBP 2006): 51 pts, stage II NPC, 2D vs. IMRT. At 2 mos, there was no difference in xerostomia; however, over time,
QOL and objective salivary function improved for the IMRT group.

Question 44

What are the RTOG 0225 dose constraints for the chiasm/optic nerves when using IMRT for NPC?

Answer 44

Per RTOG 0225, the dose constraints for the chiasm/optic nerves are 54 Gy or 1% of the PTV not >60 Gy.

Question 45

What are the accepted RTOG 0225 dose constraints for the parotids?

Answer 45

Per RTOG 0225, the dose constraints for the parotids are as follows: mean dose <26 Gy (should be achieved in at least 1 gland) or at least 20 cc of the combined volume of both parotid glands <20 Gy or at least 50% of 1 gland <30 Gy.

Question 46

Why might sparing of the parotid glands not be sufficient to prevent xerostomia?

Answer 46

Sparing of the parotids alone may not be sufficient b/c mucus production by minor salivary glands may be necessary for subjective improvement, according to data from Prince of Wales Hospital (Kam MK et al., JCO 2007): 60 pts randomized to IMRT or 2D-RT. Objective improvement in both stimulated and unstimulated salivary flow was found, but not in the subjective improvement of xerostomia.

Question 47

What is the NCCN-recommended f/u schedule for NPC pts?

Answer 47

H&P with nasopharyngolaryngoscopy (q1–3 mos for yr 1, q2–6 mos for yr 2, q4–8 mos for yrs 3–5, and q12 mos if >5 yrs), imaging (for signs/Sx or smoking Hx/surveillance), TSH q6–12 mos (if neck irradiated), speech/hearing/dental evaluation, and smoking cessation