Radiation Oncology: A Question-Based Review

Nasopharyngeal Cancer

John P. Christodouleas and Giuseppe Sanguineti

image Background

What is the prevalence of nasopharyngeal cancer (NPC) in the U.S. vs. in Asian countries?

NPC is rare in the U.S. (0.2–0.5 in 100,000 cases) but endemic in Asia (25–50 in 100,000 cases).

What are the environ-mental risk factors associated with NPC?

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

What is the median age at Dx for NPC?

The median age at Dx is ~50 yrs for NPC.

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

1.     Superior: sphenoid bone

2.     Inferior: soft palate

3.     Posterior: clivus/C1-2

4.     Anterior: post edge of choanae

From what anatomic location does most NPC arise?

Fossa of Rossenmuller (fossa post to the torus tubarius, which is the cartilaginous prominence in the lat wall of the NPX that forms the opening of the eustachian tube)

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

1.     Superiorly: invades the cavernous sinus with predominantly CN VI involvement

2.     Inferiorly/posteriorly: oropharyngeal structures

3.     Laterally: parapharyngeal space

4.     Anteriorly: nasal cavity

How does NPC reach and invade the cavernous sinus?

NPC can track to the cavernous sinus through the foramen lacerum.

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

1.     Petrosphenoidal syndrome: CN III–IV and VI involvement (oculomotor signs/Sx)

2.     Retroparotidian syndrome: CN IX–XII involvement

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

1.     Cavernous sinus: CNs III–IV, V1-2, and VI

2.     Foramen rotundum: V2

3.     Foramen ovale: V3

4.     Foramen lacerum: cartilage of the eustachian tube

5.     Jugular foramen: CNs IX–XI

6.     Hypoglossal canal: CN XII

What are the 3 WHO histologic subtypes of NPC, and what is the prevalence of each type?

1.     WHO I: keratizing squamous cell carcinoma (SCC) (20%)

2.     WHO IIa: nonkeratinizing SCC (nondifferentiated) (30%–40%)

3.     WHO IIb: undifferentiated or lymphoepithelial (40%–50%)

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

WHO IIb (undifferentiated or lymphoepithelial) is endemic (better LC but more distant spread).

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

WHO I (keratizing SCC) is associated with smoking, poor LC, and less distant spread.

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

WHO IIb (undifferentiated or lymphoepithelial) NPC is most strongly associated with EBV.

With what autoimmune condition can NPC be associated?

NPC may be associated with dermatomyositis.

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

The presence of keratin is an adverse prognostic feature.

What role does p53 play in the pathogenesis of NPC?

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

image Workup/Staging

What are some common presenting Sx in pts with NPC?

Neck mass (>60%); epistaxis, otalgia, and nasal congestion; and trismus. CN deficits are seen with more advanced Dz.

What is the general workup for a pt who presents with a neck node and a suspicious mass in the NPX?

Neck node and suspicious mass workup: H&P, CBC/CMP, direct nasopharyngolaryngoscopy and Bx of the lesion, CT head/neck/chest, MRI head/neck, and PET scan

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

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

What % of NPC pts present with palpable LAD?

60%–90% of NPC pts present with palpable LAD.

What % of NPC pts present with bilat LAD?

Up to 50% of NPC pts present with bilat LAD.

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

Adenopathy near the mastoid tip is indicative of retropharyngeal nodal involvement (node of Rouviere).

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

Pts with upper level V LAD are very likely to have NPC.

What factors predict for DM in pts with NPC?

Predictors of DM include lower neck nodal involvement, retropharyngeal LN involvement, and WHO type IIb histology.

What are the common DM sites for NPC?

Common metastatic sites for NPC include bones > lungs, liver, and brain.

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

Mets correlate better with the N stage than the T stage in NPC.

Describe the latest T staging of NPC.

1.     T1: confined to NPX, or tumor extends to oropharynx (OPX) and/or nasal cavity without parapharyngeal extension

2.     T2: tumor with parapharyngeal extension (posterolat infiltration of tumor (i.e., beyond pharyngobasilar fascia)

3.     T3: involves bony structures and/or paranasal sinuses

4.     T4: intracranial extension and/or involvement of CNs, infratemporal fossa, hypopharynx, orbit, or masticator space

Describe the latest N staging of NPC.

1.     N1: unilat nodes ≤6 cm above supraclavicular fossa and/or retropharyngeal LNs ≤7 cm (unilat or bilat)

2.     N2: bilat nodes ≤6 cm above supraclavicular fossa

3.     N3a: LNs >6 cm

4.     N3b: extension to supraclavicular fossa (includes some level IV–V nodes)

How does the latest AJCC 7th edition (2009) staging of NPC differ from previous staging schemes?

According to the latest AJCC staging, T2a lesions are now T1; T2b lesions are now T2; old stage IIA is now stage I; and old stage IIB is now stage II. Retropharyngeal LN involvement is now considered N1 Dz.

What is the T stage of an NPC causing CN involvement?

T4 lesions may involve the CNs. They also may involve the intracranial structures, infratemporal fossa, hypopharynx, orbit, or masticator space.

What is the T stage of an NPC with soft palate involvement alone without parapharyngeal spread?

T1 designates lesions without parapharyngeal extension (may have extension to the OPX/nasal cavity). If there is extension beyond the pharyngobasilar fascia (+parapharynx), then the lesion is T2.

What is the T stage of an NPC with sphenoid sinus involvement?

T3 denotes involvement of bony structures and/or the paranasal sinuses.

What is the T stage of an NPC that is confined to the NPX?

T1 designates lesions confined to the NPX or tumor extending to the OPX and/or nasal cavity without parapharyngeal extension.

What is the NPC nodal staging if a supraclavicular node is involved?

N3b designates LAD in the supraclavicular fossa (N3a is a node >6 cm).

What is the NPC nodal staging of a single ipsi node measuring 4 cm?

N1—any # of nodes confined to the ipsi neck <6 cm

What is the NPC nodal staging of bilat nodal Dz, none >6 cm?

N2—bilat nodes, all <6 cm

What are the stage groupings for NPC?

1.     Stage I: T1N0

2.     Stage II: T1-2N1, T2N0

3.     Stage III: T3N0-2, any N2

4.     Stage IVA: T4N0-2

5.     Stage IVB: N3

6.     Stage IVC: M1

image Treatment/Prognosis

What is the typical Tx paradigm for pts with NPC?

NPC Tx paradigm: RT alone or CRT (no surgical indication except for Bx)

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

Nutrition consult, PEG tube, and dental evaluation are all recommended before RT.

When is surgery indicated in the management of NPC?

Surgery is performed to Bx the lesion and in cases of elective neck dissection for persistent Dz after CRT.

What NPC stages can be treated with definitive RT alone (without chemo)?

T1N0. RT alone is controversial for certain T2N0 pts and select pts with N1 Dz due to small retropharyngeal nodal involvement, as these pts were likely not considered N1 pts in the Al-Sarraf study.

What NPC stages should be treated with definitive CRT according to the NCCN guidelines?

T2 or N+ pts should be treated with CRT per the NCCN guidelines.

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

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.

What stages of NPC should be treated with concurrent chemoradiotherapy?

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), all pts with ≥T2b (old staging) or T2 (new staging) and N+ Dz should be considered.

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

Concurrent chemo with cisplatin IV 100 mg/m2 days 1, 22, and 43 and RT to 70 Gy → adj chemo with CDDP/5-FU × 3 cycles

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

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 these remarkable results, the study was closed early. This was one of the 1st studies to demonstrate a survival benefit with CRT.

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

Major criticisms of Intergroup 0099 include the large number (25%) of pts 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 (Princess Margaret Hospital: Chow E et al., Radiother Oncol 2002) for locally advanced NPC had better 5-yr DFS (48%) and OS (62%). Other groups (New York University: Cooper JS et al., IJROBP 2000) also demonstrated better outcomes with RT alone (3-yr DFS was 43%, and 3-yr OS was 61%).

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

1.     Hong Kong (NPC-9901Lee AW et al., JCO 2005): 348 pts, RCT, median follow-up 2.3 yrs; just concurrent cisplatin + RT, no adj chemo; better DFS (72% vs. 62%), LRC (92% vs. 82%), but not DM or OS; greater toxicity in the CRT arm (84% vs. 53%); greater otologic toxicity (28% vs. 13%)

2.     Singapore (SQNP01: Wee J et al., JCO 2005): 221 pts, RCT, median follow-up 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 follow-up 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.

Is there a benefit with the use of induction chemo followed by RT or CRT in NPC?

No. Multiple RCTs in Asia demonstrated no benefit in terms of DFS, OS, or DM with induction chemo.

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

No. Multiple RCTs in Asia and 1 Italian study did not demonstrate a benefit with adj chemo.

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

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

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

Many institutions (Memorial Sloan Kettering Cancer Center [MSKCC]/RTOG) employ the simultaneous integrated boost 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.

How would you support the use of IMRT in NPC?

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.

image Toxicity

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

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

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

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.

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

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.

What is the follow-up paradigm for NPC pts?

NPC follow-up paradigm: H&P with nasopharyngolaryngoscopy (q1–3mos for yr 1, q2–4mos for yr 2, q4–6mos for yrs 3–5, and q6–12mos if >5 yrs), imaging (for signs/Sx), TSH (if neck irradiated), speech/hearing/dental evaluation, and smoking cessation