Nasopharyngeal cancer

1. D R D E E P I K A M A L I K
J R I I I , D E P A R T M E N T O F R A D I A T I O N O N C O L O G Y
M G I M S , S E V A G R A M
Nasopharyngeal carcinoma

2. Anatomy of nasopharynx

5. Lateral wall
•Contain the eustachian
tube
•Torus tubarius- elevation
of mucous membrane of
lateral nasopharynx
formed by cartilage of
eustachian tube
•Fossa of rosenmuller-*
pharyngeal recess lying
posterior to torus

7. Posterior wall
 Superior pharyngeal
constrictor muscle,
 pharygobasillar fascia,
 buccopharyngeal fascia
 Superior constrictor extends to
base skull only in midline
 Laterally , Pharyngobasillar fascia
attaches it to base skull at
basiocciput and petrous part of
temporal bone

8.  Sinus of morgagni-
muscular deficiency
 Eustachian tube and
levator veli palatini pass
through it
 Significance ?

10. Jugular foramen
Base of skull
Foramen magnum
Foramen ovale
Foramen spinosum
Foramen lacerum
Stylomastoid foramen
Hypoglossal canal

11. Nasopharyngeal carcinoma

12. Epidemiology
 Uncommon
 Overall incidence world- 0.6/ 1 lakh population
 India – 17.2 per 1 lakh people per year
 Highest incidence- South China. ( 17.8 in Hong Kong; 26.9 in
Guangdong province)
china

13.  Age-
in low risk populations- bimodal age distribution ( 15-
25 years) (50-59 years)
In high risk populations- 4th and 5th decade
 Sex- similar age distribution
M:F =2:1 to 3:1

14. Etiological features
 Genetics-
-High incidence in southern
China and descendants of
south China
-Genome study-
- HLA haplotypes- A2, B46,
B17 – high risk
•Environment
-Salted fish in Southern China
( dimethyl nitrosamine- carcinogen)
-alcohol
-exposure to dust, fumes,
formaldehyde
-exposure to cigarette smoke
•Epstein – barr virus
•Tumorogenic potential – set of latent genes : ---
-latent membrane proteins (LMP1, LMP2A,
LMP2B)
- EBV- determined nuclear antigens (EBNA1 ,
EBNA2)
•LMP1- principal oncogene, 80-90% of NPC

15. Local extension- anteriorly
 Nasal fossae  destruction of lateral wall destruction of
pterygoid plate
 Advanced cases- infiltration of orbital apex ( through IOF)

16. Local extension- inferiorly
 Oropharynx
 Advanced disease- invasion of C1

17. Local extension- lateral
 Lateral parapharygeal space, invasion of levator
and tensor veli palatini muscle

18. Local extension- superior and posterior
 Base of skull, sphenoid sinus, clivus

19. Foramen
lacerum
Foramen
spinosum
Foramen
ovale
Foramen
rotundum

20.  Lateral to the pharyngobasilar fascia, the nasopharynx is bounded by four
spaces
 These include the masticator (infratemporal fossa), the parapharyngeal, the
carotid and the parotid space

21. Lymphatic spread
 Vast avalvular lymphatic network in
mucous membrane
 frequent involvement of regional lymph
nodes.
-85-90% cases present with ipsilateral nodes
-Approxmately 50 % present with bilateral nodes

22.  Upper jugular-94%
 Middle juular-85%
 Retropharyngeal node-
80%
 Posterior cervical -46%
 Lower jugular-19%
 Supraclavicular -17%
 Submental-17%

23. 2 major lymph collectors
1. Lateral side of NPx 
lateral pharyngeal nodes,
jugulodigstric, and 3rd, 4th ,
5th retropharyngeal group
2. Posterior collector 1st
group of RPN ( node of
rouviere)
Further metastatic spread to
midjugular, lower jugular ,
posterior cervical ,
supraclavicular nodes

24. Haematogenous spread
 3-6% cases- distant metastasis at presentation
 18-50 % cases- distant metastasis during disease
course
 bone > lungs and liver ( lung mets- better
prognosis)

25. Clinical presentation
 Neck mass
 Most common presentation ( 66
%) u/l, b/l
 Typically: mass in upper
posterior neck , beneath superior
portion of SCM close to mastoid
process
•Nasopharyngeal mass
•37%
•Epistaxis,,Nasal obstruction,
Nasal discharge
•Base of skull extension
Headache – 40 %
Cranial nerve involvement- 23 %

26. Syndromes associated with NPC
 Cranial Nerve compression II to VI ( direct
extension intracranially) as they emerge from cranial
vault at or near base of skull orifices
 M/c - cranial nerve V and VI

27. Retroparotid Syndrome of VILLARET
 Enlarged lateral retropharyngeal lymph metastasizing to
retroparotid space.
 Involves IX to XII cranial nerve & Cervical Sympathetic trunk.
 Difficulty in swallowing ( IX, X)
 Perversion of taste in posterior 3rd of tongue( IX)
 Hyper or hypoaesthesia of mucous membrane of soft palate
, pharynx, larynx (X)
 Hemiparesis of soft palate , paralysis and atrophy of
trapezius and SCM (XI)
 Unilateral paralysis and atrophy of tongue (XII)
 Horner syndrome (cervical sympathetic chain)

28. Horner syndrome

29. PETROSPHENOID SYNDROME of JACOD
 II- VI CN
Unilateral neuralgia of V nerve
Unilateral ptosis (III)
Complete ophthalmoplegia
(III,IV,V)
Amaurosis (II)

30. TROTTER’S TRIAD/ SOM syndrome
NPC
Neuralgia
I/L ( V)
Conductive
hearing
loss (VIII)
Palatal
Palsy (X)

31. Diagnosis is made by Biopsy
 Local anaesthesia (OPD)
 G.A. ( deep tumour, uncooperative patient)
 At times- tumour invisible, submucosal
 For suspicious NPC cases- random biopsies of most
commonly involved sites
 b/l fossa of rosenmuller
superior posterior wall
FNAC of suspicious neck mass- to establish metastasis in regional lymph
nodes

32. Physical examination
 Palpation of neck node (size,
laterality, lowest extent of largest
node, supraclavicular fossa inv)
 Cranial nerve exam ( vision and
hearing)
 Chest percussion and ausculation
 Abdominal palpation
 Spine and bone exam
Nasopharyngoscopy and
biopsies
Panendoscopy +/-

33. Lab studies
 CBC
 LFT
 EBV specific serological tests
- Ig A
- VCA (Ig A antiviral capsid antigen)
- antiviral capsule antigen titres
- serum EBV DNA levels (prognosis, surviellance
post treament )

34. Imaging for locoregional extent
MRI-
 study of choice
 Why?
 AJCC staging requires a search for invasion into soft
tissue ( parapharyngeal space), bony structures. MRI
is superior to CT in delineating muscle, soft tissue
and skull base.
 Thin slices (3 mm). ( thicker slices, >5mm , risk
misdiagnosis)

35.  Ng et al : compared MRI and CT in assessing disease
extent.
 Higher sensitivity of MRI for skull base inv (60% vs
40%), intracranial inv (57% vs 36%),
retropharyngeal node( 58%vs 21 %), prevertebral
muscle infiltration ( 51% vs 22%)
 MRI modified staging in 27% ( 23% upstaged, 4%
downstaged)

36. Imaging for nodal metastasis
 MRI , CT
 LN metastasis radiologically defined as ( Van den Brekel)
-presence of central necrosis
-extracapsular spread
-SAD>= 10 mm ( 11mm for jugulodigastric ,
5mm retropharyngral node)
-cluster of 3 or more LN that are borderline in
size.

37. Imaging for metastatic workup
 If clinically indicated or N3 disease
 PET-CT :study of choice
(Sensitivity-100%, specificity-90%)
 Others-
CT chest( clinical suspicion of lung met)
CT abdomen ( abnormal LFT, clinical)
Bone scan- clinical suspicion, raised Alk Ph

38. Staging systems
 AJCC identical
 UICC
 Ho system : advantage- N stage classification ( level
or location)

39. Comparison
System Staging
T1 T2 T3 T4
Fletcher
(1967)
< 1 cm
diameter
> 1 cm but confined to
nasopharynx
Beyond
nasopharynx
Involving skull base
or cranial nerves
Ho
(1978)
Confined to
nasopharynx
Extending to nasal
fossa or oropharynx
Bone/ Cranial
nerve/ orbital /
hypopharyngeal /
infratemporal fossa
involvement
NA
IUAC
(1988)
Limited to
one site in
nasopharynx
Extending to two sites
in nasopharynx
No bony
destruction
Bony destruction
including eustachian
tube
Huaqing
(1994)
Limited to
nasopharynx
Involving the nasal
cavity, oropharynx,
anterior cervical
vertebrae, PPS before
SO line
Pterygoid process /
posterior cranial
nerve / posterior
cervical vertebrae /
BOS / PPS beyond
SO line
Infratemporal fossa
/ cavernous sinus /
PNS / direct
invasion of C2 or
C1 / anterior cranial
nerves

40. AJCC 2010
 Tx
 T0
 Tis
 T1-tumor confined to NPhx or extends to nasal cavity and/or
oropharynx (soft palate, C1/C2) without parapharygeal exetension
 T2- with parapharyngeal extension (beyond Pharyngobasilar fascia)
 T3-bony structures of skull base and/or paranasal sinuses
 T4- with intracranial extension and/or involvement of cranial nerves,
hypopharynx, orbit, infratemporal fossa, masticator space
( beyond anterior surface of lateral pterygoid muscle, or lateral extension beyond posterolateral wallof maxillary antrum
and pterygomaxillary fissure)
HPx, orbit,
masticator spce

41.  Nx
 N0
 N1- U/L cervical LN above supraclavicular fossa
</= 6 cm OR U/L or B/L retropharyngeal LN </=
6 cm
 N2- B/L cervical LN above supraclavicular fossa
</= 6 cm
 N3a – LN > 6cm
 N3b- LN below SCF
U/L neck node ( above SCF) or B/L
retopharyngeal nodes <6cm

42. Pathologic classification
 80-99 % - carcinomas
 ~ 5%- lymphomas
 ( adenocarcinoma, plasmacytoma, melanoma,
sarcoma)

43. WHO 2005 classification- NPC
1.Keratinising SCC- keratin
pearls
2.Non keratinising differentiated SCC
2.Non keratiniing undiff SCC
To
4.Basaloid SCC (
palisading)

44. WHO 2005 classification- NPC
Keratinising SCC- keratin
pearls
Non keratinising differentiated SCC
Non keratiniing undiff SCC
To
Basaloid SCC
Non keratinising type-
strong association with
EBV
Lymphoepithelioma/ lymphoepithelial
carcinoma- variant of undifferentiated SCC

45. Treatment

47. Radiation therapy
 Primary treatment
 After 1950, surgical interventon rare


48.  Positioning:
 Supine position, head extended
 Immobilization
 a custom-made thermoplastic cast covering head to shoulder region

49. Dose
 70 Gray / 7 weeks , 50-60 Gray to potential risk sites
Local control significantly improved
in patients receiving > 67 Gy to
tumor target.
Marks et al, Vikram et al
Perez etal
•T1-T2 , (local control rate of 100%, >70
Gy ) Vs (80 %, 66-70 Gy)
• T3-T4 , local control <55%, even with
>70 Gy
Mesic etal –
T3-4 tumors, doses >60 Gy or larger portals,
no improvement on outcome

50. Fraction
 2 Gray/ fraction
•Lee et al
•T1 , 4 fractionation schedules
•Total dose was important factor
•Dose / fraction did not affect local control
•Dose /fraction was a signifcant risk factor for
temporal lobe necrosis

51. Time
 No interruptions
•Marcial etal
•Split course irradiation (30 Gy/10 Fr/ 2 weeks --- 3 week rest--- 30 Gy/10 Fr/
2 weeks
Vs
•66 Gy/33 Fr/6.5 to 7 weeks
• similar 5 year local control and DFS
Vikram etal
• interruption >21 days poorer local control
•Many subsequent studies show similar results

52. Volumes
 Nasopharynx , adjacent parapharyngeal tissue ( 1-2
cm margin) and cervical lymphnodes. Also include
posterior ethmoid cells, post 1/3rd maxillary
antrum and nasl cavity

53. Conventional 2 D technique ( chao, perez, brady)
 Opposing lateral portals ( tumor + upper nodes) AND
matching lower anterior cervical field for lower neck nodes
 After 45 Gy, shield spinal cord

54.  GTV- nasopharyngeal tumor , gross retropharyngeal
lymphadenopathy, gross nodal disease.
 N0 disease- prophylactic irradiation recommended ( high
incidence of occult metastasis)
 CTV: GTV +regions of microscopic disease
 Definition of margins and dose levels may be different in
different centres

55.  CTV 70
 CTV 59.4
(High risk
subclinical)
( all potential areas of
microscopic spread)
 PTV
GTV + >/= 5 mm margin ( can be reduced to
1mm for tumors close to critical structure,
brainstem, SC
CTV70 + >/= 5 mm margin
•Entire nasopharynx
•Retropharyngeal LN
•Clivus
•Base skull
•Pterygoid fossae
•Parapharyngeal space
•Sphenoid sinus
•Posterior ¼th to 1/3rd of nasal cavity
•Posterior 1/4th to 1/3rd of maxillary sinuses
•High risk nodal levels ( all bilaterally)
•{ upper deep jugular, level I, level II, level
III, level IV, level V, retropharyngeal }
•CTV + circumferential margin of 3-5 mm to
all CTV’s
( margin may be decreased to 1mm , close to
critical structures)

56.  Note-
 CTV margins- mat be limited to exclude bone not at
risk for subclinical disease or air.
 Bilateral IB LN can be spared if patient is node
negative *

57. IMRT – normal tissue dose constraints
 Brain stem <5Gy
 Optic N <54 Gy
 Optic chiasm <54 Gy
 SC <45 GY or 1 cc of PTV cannot exceed 50 Gy
 Mandible , TM Jt <70 Gy 75 Gy
 Brachial plexus <66 Gy
 Temporal lobe <60 Gy
 Oral cavity 40 Gy
 Parotid <26 Gy
 Eyes <35 Gy
 Lens <25 Gy
 Larynx <45 Gy
1 % of PTV cannot exceed 60 Gy

58. 3 D CRT
 Memmorial Sloan Kettering cancer
centre, new york----
 3D planning vs 2 D. better dose
coverage to tumor, decreasing
issues
Liebel et al-
• mean tumor dose increased by
13%
•Tumor control increased by 15 %
•Jen et al
•Significant improvement in 3
year L-FFR for T4 (86% vs 47
•Significant improvement in in
EFS for stage III and IV
•Incidence of xerostomia –
significantly less

59. IMRT
 is replacing conventional RT *
 Overstringent use of normal tissue constraints –
inadequate coverage of tumot targets**
UCSF
• First
• 70 Gy , PTV gross and inv LN ( 2.12-2.25 Gy/Fr
• 59.4 Gy, PTV high risk subclinical( 1.8 Gy/Fr
• 54 Gy , PTV low risk subclinical (1.64 Gy/Fr
• Once daily
• L-FFR- 96%, D-FFR- 72%, Nodal FFR- 98%

60.  SMART ( dose painting)
•MSKCC
•AF by concommitant boost vs SMART
•No significant improvement in 3 yr L-
FFR
•T3, T4 tumors, SMART
•Locoregional control excellent
•Serious late toxicities
•4% - carotid artery
pseudoaneurysm, haemmorhhage
•4% - temporal lobe necrosis

61.  2 IMRT approaches
 1. extended whole field IMRT
 2. split field
 Which is better? – controversial *

62. Brachytherapy
 Dose escalation
 Intracavitary or interstitial implants
 T1-T3 NPC as a boost OR recurrent disease
 Not suitable when intracranial extension* ( bone inv)
 Presently its use is declining**
 HDR

63.  Rotterdam applicator, others (Mould technique, Levendag’s
Forzhou (Chinese district),Simple catheter based
•Designed by Levendag
• can be worn by the patient comfortably
•Made up of silicone: flexible and closely
conforms to the curvature of the nasopharynx.
•A silicone bridge and flange used to fix the
applicator

65. Prescription points
 Tumor points:
 Na (Nasopharynx) – 2
 BOS (Base of Skull) - 2
 R (Node of Rouviere) - 1
 Normal Tissue points:
 OC ( Optic Chiasm) - 1
 P (Pituitary gland) - 1
 C (Cord) – 1
 Pa (Soft Palate) – 2
 Re (Retina) - 2
 No ( Nose) - 2

66. SRS
 Dose escalation
•T1-T4
•SRT boost 12 Gy following EBRT 66 Gy
•OS- 69%, distant failure rate- 32%
•12.1 % - temporal lobe necrosis
•3.6% - retinopathy

67. Chemotherapy
 NPC – highly chemosensitive
 Stage I : RT
 Stage III-IVB : CTRT +/- adjuvant chemo
 Intermediate stages- lesser evidence, CTRT

68. Concurrent Chemoradiation
 Intergroup 0099 trial
 RT vs CRT * ( cisplatin)
 Significant OS benefit for
CRT (78% vs 47%) at 3 years.
Metaanalysis of 1o trials
In favour of CRT

69.  Adjuvant chemotherapy
 US intergroup regimen -
Cisplatin and 5 FU
 Efficacy?*
 RCT’s- RT vs RT+ adj CT --
negative results
 RCT- CRT vs CRT+ adj CT-
statistically not significant
 therefore,; optional therapy **
Neoadjuvant chemotherapy
•RCT ph II- Docetaxel/cisplatin
followed by CTRT vs CTRT  OS
benefit
•
•Ph III trial, taiwan - ICT***
CRT , excellent FFLF, FFDF, OS
with acceptable toxicities (
ASTRO 2012)
•Ongoing Ph III trial ( HongKong)
, 3 arms#( cisplatin/5FU+CTRT
vs CTRT+adj cisplatin/5FU vs
cisplatin/capecitabine +CTRT
-Estimated enrolment completion
by april 2017

70. Persistent/ Recurrent NPC
 Persistent NPC- does not completely regress
following primary treatment
 Recurrent NPC- reemerge after initial complete
regression
 Persistent disease- better survival and control rates

71.  When to consider it as
persistent disease and proceed
with t/t
 Perez etal recommend :
observation period of 10 weeks
before additional t/t *
 Bx
 Positive biopsies beyond 12
weeks indicate poor prognosis.
•Early detection – crucial
•Nasopharyngoscopy – more sensitive
•Biosy – to confirm
•MRI- delineate tumor extent, ( PNI,
intracranial extension); superior to CT
•FDG PET- superior to MRI ( Sn 100%, sp
93%)
•Circulating EBV DNA- detect failure **

72. Additional RT for
persistent disease
Re –irradiation for
recurrent disease
 Brachytherapy after a full
course EBRT : 87-95% 5
year L-FFR (T1)
 SRT
 SRT 15 Gy vs HDR brachy
20 Gy ( T1-T4)
3 yr LFFR( 86% vs 71%)
 Brachytherapy
 Brachy + EBRT(better)
 2D, 3D, IMRT (100% salavge
rate, no complications)*
 SRS/SRT
- to be avoided when carotid
encasement- fatal Haemorrhage
 Concurrent chemo- Cisplatin
 Induction chemo- gemcitabine,
cisplatin

73. Surgical treatment
 Persistent / recurrent nodal disease- RND
 If extension beyond nodes- additional brachy
 Approaches- infratemporal (L), transpalatal,
transmaxillary, transcervical (I), anterolateral
 Recent- transnasal, endoscopic

74. Sequelae of treatment
•Temporal lobe necrosis- most
troublesome
•65% of irradiation induced deaths in NPC
•Larger fraction size>2 Gy
•Difficult and delayed diagnosis*
•Cranial neuropathy
•m/c XII
•( IX, X, XI, VI)
•Slurring, dysphagia, aspiration
•Oral complications
•Xerostomia
Parotid sparing IMRT, MPD- 34 Gy
only after ruling out parotis inv
•Osteoradionecrosis
Px flouride, decayed teeth removal
before RT
Hearing loss
• SNHL -More with cisplatin
CTRT
Mean cochlea dose < 48 Gy
-Otitis media- eustachian
tube damage
Carotid artery injury
Ruptured
pseudoaneurysm
Endocrine
dysfunction
Galactorrhoea,
hyperprolactinaemia
2nd malignancy
•Rare, 0.04%, after 10 yrs
•Maxillary osteosarcoma
Soft tissue sarcoma