Carcinoma nasopharynx anatomy to management

Carcinoma Nasopharynx
Anatomy to Management
By
Dr. Ayush Garg

Anatomy of Nasopharynx
• 4cm high, 4cm wide and 3cm in
length
• Anterior - continuous with the
nasal cavity via the posterior
choanae,
• Floor - communicates with the
oropharynx
• Roof and posterior wall
• Body of the sphenoid,
Basiocciput
• First two cervical vertebrae
• Lateral wall
• Eustachian Tube orifice
• Fossa of ROSSENMULLER

Fossa of Rosenmuller(FOR)
• It is situated in the corner between the lateral and
dorsal walls.
• It can measure up to 1.5 cm in adults.
• It opens into the nasopharynx at a point below
foramen lacerum.
• It is a hidden area.

Anatomical relation of FOR
• Anteriorly
• Eustachian tube and levator
palatini
• Posteriorly
• Pharyngeal wall mucosa
overlying pharyngobasilar
fascia & retropharyngeal
space
• Medially
• Nasopharyngeal cavity
• Superiorly
• Foramen lacerum & floor
of carotid canal
• Posterolateral
• Carotid canal & petrous
apex, foramen ovale and
spinosum

Space between base of
skull & sup.connstictor.
Through it enters-
 Eustachian tube
 Tensor & Levator
veli palatini muscle
 Asc. Palatine
artery(facial artery)
a-mucosa
b-pharyngobasilar fascia
c-muscular coat
d-buccopharyngeal fascia
Sinus of Morgagni

•A lateral gap sinus of Morgagni is created by indentation
of superior constrictor.
• This gap is bridged only by pharyngobasilar fascia.
• Through this opening the E.T. along with its two muscles
enter the nasopharynx.
• Tumors can easily breach this area and spread into the
parapharyngeal space.
Sinus of Morgagni

Parapharyngeal Space
• The parapharyngeal space is
located deep within the neck
lateral to the pharynx and
medial to the ramus of the
mandible.
• Shape of an inverted pyramid
with the floor at the skull base
and it’s tip at the greater cornu
of the hyoid bone
• Two compartments :
• Prestyloid
• Retrostyloid

Lymphatic Drainage
• Richest lymphatic plexus in the head and neck
region.
• Submucosal lymphatics congregate at the
pretubal region – “pretubal plexus”.
• These then pass on to the retropharyngeal nodes
as 8 -12 trunks which decussate in the midline.
• Lymphatic trunks pierce the level of the base of
the skull and run between the pharyngobasilar
fascia and the longus capitis.
• The lymphatic trunks drain in three directions:
• To the retropharyngeal nodes.
• To do the posterior cervical nodal and the
confluence of the 11th, cranial nerve and the
jugular lymph node chains, situated at the
tip of the mastoid.
• To the Jugulo-digastric nodes (Lederman )

Different radiologic levels based on magnetic resonance imaging of 202 patients with
nasopharyngeal carcinoma treated at pamela youde nethersole eastern hospital (hong kong).

Blood Supply
• External carotid artery
• Ascending pharyngeal
• Facial arteries
• Venous drainage-
• The pterygoid venous plexus (superiorly)
• The pharyngeal plexus (inferiorly)
• The trigeminal nerve
• The pharyngeal branch of the sphenopalatine ganglion
• Below passavant's ridge the nerve supply is the same as for the
rest of the pharynx by the glossopharyngeal and vagus nerves.

Epidemiology & Frequency
• Nasopharyngeal carcinoma is an uncommon cancer in most parts of
the world.
• A bimodal age distribution is observed in low-risk populations. The
first peak incidence arises between 15 to 25 years of age, with the
second peak at 50 to 59 years of age. In high-risk populations, the
peak incidence occurs in the fourth and fifth decades of life.
• Both genders have a similar age distribution; however, the male-to-
female incidence ratio is 2:1 to 3:1.7
• The high incidence of nasopharyngeal carcinoma is seen among
Southern Chinese populations.

Indian Incidence
 Incidence per lakh population: 3947
 Percentage: 0.40%
 Mortality per lakh population: 2836
 5 year prevalence per lakh population: 9967
Most common in North east states of India-Nagaland and
Meghalaya

Etiology
GENETIC
ENVIRONMENTVIRAL

Genetic Factors
• Chinese have higher genetic susceptibility for NPC .
• Genomic studies have revealed 3 HLA locus.
• These include A2, B46, and B17, which are associated with
an increased risk of developing nasopharyngeal carcinoma.

Environmental Factors
• Smoking and Alcohol consumption
• Occupational
exposure to nickel, chromium radioactive metal
inhalation of chemical fumes-formaldehyde
• Ingestions
salted fish - Nitrosamine
smoked food

• Drugs-Some herbal medicines.
• Cooking habits- Household smoke and fumes
• Religious practice-Incense stick smoke
• Socioeconomic status-Nutritional deficiencies
eg. Vitamin A & C
17

• More than 90% of patients having elevated antibody titres to
Epstein-Barr virus are those who have NPC of the
undifferentiated / poorly differentiated forms.
• Moderate to well differentiated NPC are devoid of Epstein-Barr
virus antigen.
• Thus the role of virus in NPC is still controversial.
• EBV-DNA or RNA presence in cell indicates that the virus
has entered the tumor cell before clonal expansion.
EBV’s tumerogenic potential is due to two latent genes
18
1. LATENT MEMBRANE PROTEINS (LMP)
2. EBV-NUCLEAR ANTIGEN (EBNA)
Viral Factors

Patterns of Spread in Sagittal and Coronal
view
Potential
areas of spread include
Superiorly into the
sphenoid sinus/clivus,
Anteriorly into the nasal
cavity/maxillary sinus,
Posteriorly into the
prevertebral muscles and
prepontine cistern as well
Inferiorly into the
oropharynx.

Anatomy of the cavernous sinus showing position of the cranial
nerves in relationship to the nasopharynx.
Cranial nerve V2 and V1 are in closest proximity to the skull base,
while involvement of cranial nerve III and IV indicate advanced
involvement of the cavernous sinus.

Superior Spread: Infiltration Of Orbital
Cavity Via Inferior Orbital Fissure

Large tumour extending into nasal cavity,parapharyngeal &
prevertebral space

Distant metastases
• Distant metastasis is present in 3% to 6% of the cases at
presentation and may occur in 18% to 50% of cases during
the disease course.
• The rate of distant metastasis is highest in patients with
advanced neck node metastasis, especially with low-neck
involvement.
• Bone is the most common distant metastatic site, followed
by the lungs and liver.
• Brain and skin metastases rarely occur.

Fiberoptic Endoscopic examination
nasopharyngoscopy
±pan endoscopy
• used routinely to complement the mirror examination.
• assessment of extent of primary tumor.
• critical in assessing the superficial spread of neoplasm
• superior to any imaging modality in detecting mucosal spread
• biopsy of the tumor can be done for histopathological
confirmation.

Nasopharyngeal biopsy
 Tumor visible on clinical examination:
biopsy performed with local anaesthesia in an outpatient setting.
Tumor not visible or patient cannot cooperate:
biopsy by direct visualization under general anaesthesia.
For suspicious cases of a nasopharyngeal primary tumor with
lack of visible tumor: random biopsies of the pharyngeal recess
(fossa of Rosenmüller).
FNAC of a suspicious neck mass :may be performed prior to
biopsy of the nasopharynx when primary tumor is not clinically
detectable

Radiological studies
CECT head & neck
Contrast enhanced MRI of head and neck

Contrast enhanced MRI head and neck
Includes imaging of nasopharynx ,paranasal sinus, nasal cavity,
base of skull & neck
When utilizing MRI, thin slices (3 mm) should be used
Preferred imaging technique for staging.
The AJCC T-classification requires details for tumor invasion
into the soft tissue (e.g., parapharyngeal space) and bony
structures so MRI necessary for proper staging

A:Axial T1-weighted magnetic resonance image (MRI) with 5-mm slices.
B: Axial T1 MRI with 3-mm slices; skull-base invasion (arrow) upstaged this tumor
from T1 to T3.

MRI is considered superior to CT for assessing
primary tumour invasion into
surrounding soft tissue
bony structures
pharyngobasilar fascia invasion
infiltration of prevertebral muscles
invasion into sinus of Morgagni
skull base invasion
cavernous sinus extension
perineural disease
(Liao et al., 2008; Sakata, 1999)
Liao XB, Mao YP, Liu LZ, et al: How does magnetic resonance imaging influence staging according to AJCC staging system for
nasopharyngeal carcinoma compared with computed tomography IJROBP 72:1368-1377, 2008
MRI is also more reliable for differentiating between the primary tumor
and retropharyngeal adenopathy
(Chang, 2005; Chong, 1996; Chung, 2004; King, 2000)

A: Axial T1-weighted MRI demonstrating involvement of maxillary branch of
trigeminal nerve by nasopharyngeal carcinoma (V2) (arrow).
B: Coronal contrast-enhanced MRI showing involvement of the trigeminal cave
(also known as Meckel’s cave) by nasopharyngeal carcinoma (arrow)

A: Axial T1-weighted magnetic resonance image (MRI) showing tumor
infiltration of the right parapharyngeal space (left arrow). Note the resultant
serous otitis media (right arrow).
A: Axial contrast-enhanced magnetic resonance image (MRI) demonstrating
involvement of the cavernous sinus by nasopharyngeal carcinoma

Contrast enhanced CT scan head and neck
 Acceptable alternative imaging
 Relatively inexpensive
 Rapid image acquisition

Som P.M defined lymph node metastases radiologically by following
criteria
Size: greatest nodal diameter is 1.5cm for jugulodigastric and
submandibular nodes 0.8 cm for retropharyngeal nodes &1 cm for all
other cervical nodes.
More accurate size criterion is shortest axial diameter exceeds 11
mm in the jugulodigastric, 5mm in retropharyngeal & 10 mm in all
other cervical nodes
Shape: metastatic nodes are spherical (hyperplastic node is bean
shaped)
Extracapsular spread
central necrosis
Localized nodal groupings in node-draining area (three or more
contiguous & confluent L.N each of which has maximal diameter of 8-
15 mm or minimal axial diameter of 8-1 0 mm)
Detection of occult lymph node metastasis

Metastatic Workup
• Routine: Chest X ray
• Additional: if clinically indicated or N3 disease
CT Thorax:
CT Abdomen:
Bone Scan :
PET-CT

Role Of 18FDG PET-CT
In detection of unknown /small primary tumor
In evaluating clinically occult nodal involvement
Can be used in place of conventional staging by CT, bone,
scans and ultrasound for detection of distant metastasis
In follow up to differentiate between treatment sequelae &
tumor recurrence/residual

EBV specific Serological tests:
• Association of EBV with NPC (non keratinizing type) provides basis for
serological test
May enhance early detection of the primary disease/ relapses, supplement TNM
staging & improve prognostication
• For diagnosis: anti -VCA & anti EAAb are both sensitive however IgA anti-
VCA has better specificity & may serve as screening test in high-risk patients.
• For prognosis: prognostic effects of pre & post treatment Ab titre have been
controversial due to inconsistent results in various studies
Titers remained persistently high even in patients who achieved remission.
There was no reliable cut-off value for differentiating between recurrence and
remission.
 Ig A antiviral capsule antigen ( Ig A anti –
VCA)
 Ig G anti early antigen (IgG anti EA A)

• PCR based technique makes it possible to detect EBV DNA levels
• Plasma EBV DNA is superior to serum anti-EBV Ab in prognostication
• Diagnosis: has high sensitivity (96%) & specificity (93%) for detecting NPC
• Levels correlated significantly with tumor load, TNM staging, recurrence rate,
and survival.
• Prognosis: study by Leung et al on 376 NPC pts. showed pretherapy DNA load
was an independent prognostic factor for OS
• Risk grouping: identify poor-risk among early-stage pts. & can complement
TNM staging and guide treatment decision.
Plasma Epstein Virus DNA Levels

Prognosis Multivariate analysis by Lin et al* demonstrated that
combined EBV DNA load pretreatment & 1week post-treatment was most
significant factor in prognostication compared with other clinical
parameters (including age, gender, performance status, pathologic type, T
category, N category, and stage group).
Post treatment surveillance: Wang et al* studied the value of monitoring
plasma EBV DNA every 3-6 months in 245 patients in clinical remission
after NPC treatment.
All 36 patients with detectable EBV DNA had confirmed relapses,
whereas FDG-PET was much less accurate
Salvage treatment: *Wang et al showed that for patients with
metastatic/recurrent NPC treated by chemotherapy, clearance rates of
plasma EBV DNA during the first month of salvage chemotherapy could
predict tumor response and OS & can guide oncologists in the timely
change of chemotherapy regimen for patients unlikely to respond
*Lin JC, Wang WY, Chen KY, et al: Quantification of plasma Epstein- Barr virus DNA in patients with advanced NPCN Engl J Med 350:2461-2470, 2004
*Wang WY, Twu CW, Lin WY, et al: Plasma Epstein–Barr virus DNA screening followed by (18)F-fluoro-2-deoxy-D-glucose positron emission tomography in detecting
posttreatment failures of nasopharyngeal carcinoma. Cancer 117:4452-4459, 2011

Pathological classification: WHO 2005
• WHO classes
• based on light microscopy findings
• 3 histological types
• Type I – Keratinizing SCC
• Type IIa – Nonkeratinizing Differentiated Carcinoma
• Type IIb – Nonkeratinizing Undifferentiated Carcinoma
• Type III-basaloid Squamous Cell Carcinoma
43

STAGING
Systems available:
Fletcher (1967)
Ho’s staging (1978)
IUAC (1988)
Huaqing staging (1994)
AJCC (2017)

Changes from 7th edition: T stage change
The AJCC 8th system
(T0)
• No tumor identified,
but EBV-positive
cervical node(s)
involvement
(T1)
• Tumor confined to
nasopharynx, or
extension to
oropharynx and/or
nasal cavity without
parapharyngeal
involvement
The AJCC 7th system
(T0)
• No evidence of primary
tumor
(T1)
• Tumor confined to the
nasopharynx, or tumor
extends to oropharynx
and/or nasal cavity
without parapharyngeal
extension.

T2
• Tumor with
extension to
parapharyngeal
space, and/or
adjacent soft tissue
involvement
(medial pterygoid,
lateral pterygoid,
prevertebral
muscles)
T3
• Tumor with
infiltration of bony
structures at skull
base, cervical
vertebra, pterygoid
structures, and/or
paranasal sinuses
T2
• Tumor with
parapharyngeal
extension*
T3
• Tumor involves
bony structures
of skull base
and/or paranasal
sinuses

T4
• Tumor with
intracranial
extension,
involvement of
cranial nerves,
hypopharynx, orbit,
parotid gland,
and/or extensive
soft tissue
infiltration beyond
the lateral surface
of the lateral
pterygoid muscle
T4
• Tumor with
intracranial
extension and/or
involvement of
cranial nerves,
hypopharynx,
orbit, or with
extension to the
infratemporal
fossa/masticator
space

Changes from 7th edition: N stage change
N1
• Unilateral metastasis in cervical
lymph node(s) and/or unilateral or
bilateral metastasis in
retropharyngeal lymph node(s), 6
cm or smaller in greatest dimension,
above the caudal border of cricoid
cartilage
N2
• Bilateral metastasis in cervical
lymph node(s), 6 cm or smaller in
greatest dimension, above the
caudal border of cricoid cartilage
N1
• Unilateral metastasis in cervical
lymph node(s), 6 cm or less in
supraclavicular fossa, and/or
unilateral or bilateral,
retropharyngeal lymph nodes, 6 cm
or less, in greatest dimension*
N2
• Bilateral metastasis in cervical
lymph node(s), 6 cm or less in
supraclavicular fossa*

Changes from 7th edition: N stage change
N3
• Unilateral or bilateral metastasis in
cervical lymph node(s), larger than 6
cm in greatest dimension, and/or
extension below the caudal border
of cricoid cartilage
N3a
• Greater than 6 cm in dimension
N3b
• Extension to the supraclavicular
fossa**

Stage grouping Stage 0 Tis N0 M0
Stage I T1 N0
M0
Stage II T2
T1,T2
N0
N1
Stage III T3
T1,T2
N0-N2
N2
Stage IV A
T4 N0,N1,N2
Any T N3
Stage IV B Any T Any N M1
Changes from 7th edition: TNM stage
change
The previous Sub-Stages IVA (T4N0-
2M0) and IVB (any T N3 M0) are now
merged to form IVA.
The previous IVC (any T any N M1) is
now upstaged to IVB.

Tumor related
TNM staging: most important prognostic factor.
• advanced T-category: associated with worse local control and overall
survival;
• advanced N-category: increased risk of distant metastasis and worse
survival.
• M1 stage: poor prognosis
Histopathology: nonkeratinizing and undifferentiated carcinomas more
radiosensitive and offer better prognosis than keratinizing SCC
Plasma EBV DNA & anti EBV antibodies
Prognostic Factors

Patient related
Ethnicity: no prognostic difference between ethnic Asian and non-Asian
patients with nonkeratinizing carcinoma
Age: better prognosis younger patients
Gender : not significant
Performance status, weight loss & anaemia before treatment :not
significant in pts. treated definitively
Diagnosis & treatment related
Treatment delay > 8 weeks after diagnosis or extending break during RT
adversely effect outcome
Treatment strategy & techniques: use of Chemo RT & IMRT improves
tt. outcome compared to conventional therapy
Tumor regression during RT: not significant
*Lin JC 2009:prognostic factors in NPC

Nasopharyngeal carcinoma is different from other H&N cancers in terms of:
Geographic & ethnic distribution
Association with Epstein–Barr virus (EBV)
Aggressive natural behaviour
High predilection for distant metastases
Challenges in management:
Detection is difficult: silent deep seated location
Treatment is difficult: anatomical proximity to critical structures
Role of surgery is limited to biopsy and salvage
Fortunately, this cancer is highly radiosensitive and chemosensitive;
Excellent tumor control can be achieved with RT ±CT
However, the therapeutic margin is narrow, and the most conformal and
precise radiotherapy is demanded
“Treatment of NPC is one of the greatest challenges for oncologists
and it is also one of the most gratifying”

Treatment Options
Radiotherapy:
Definitive treatment:
EBRT: Conventional, 3DCRT, IMRT
Dose escalation with altered fractionation, brachytherapy
• Chemotherapy :
• Surgery:
Concurrent
Neoadjuvant
Adjuvant
Limited role

Role of surgery
• Due to deep location of nasopharynx, and anatomic
proximity to critical structures, radical surgery is typically
not used
• Limited to
 Biopsy for histological confirmation
Neck dissections for persistently enlarged lymph nodes
Nasopharyngectomy in persistent or recurrent disease

Radiation Therapy: Definitive treatment
 Total Dose
 Time & Fractionation
 Radiation Technique
 Dose Escalation
 Addition Of Chemotherapy

Impact Of Dose
High dose is needed for NPC tumor despite its radiosensitivity
The general recommendation is : 70 Gy to the gross tumor @1.8-2 Gy /#
50-60 Gy to potential risk sites @ 1.8-2 Gy /#
Retrospective studies shown that T1-2 tumors had good local control rate of
90-100% for >70 Gy, compared to 80% for 66 to 70 Gy.
However, local control for patients with T3-4 tumours remained <55%,
even with total dose >70 Gy.
Higher doses did not significantly improve outcomes in T3-4 tumors.
These observations suggest that, besides consideration of the prescribed
dose, the problem of sufficient coverage has to be overcome for advanced
tumors.

Impact of time & fractionation
• Prolongation of treatment significantly jeopardizes local control
• Benefit of accelerated fractionation is uncertain (no benefit in local
control, increased toxicities)
• Retrospective study by Lee et al. in 1,008 patients with T1 tumours
irradiated by four different fractionation schedules demonstrated that
total dose was the most important radiation factor (p = .01).
• Dose per fraction did not affect local control; however, it was a
significant risk factor for temporal lobe necrosis.
• Therefore, a fractional dose of >2-2.12 Gy should be avoided

Trials For Altered Fractionation
Teo et al randomized 159 pts. Of NPC into 2 arms
(38% of cases were T3-4)
Arm A 2.5 Gy/#QD for 8# f/b 1.6 Gy b.id 32#
Arm B: 2.5Gy/# QD for 24 #.
Results: prematurely terminated by significant increase in
neurological complications
5-year local FFR did not improve (89% vs 85%), but there were
excessive neurological toxicities (49% vs 23%).

Trial Comparing Conventional Radiotherapy To Split Course Bifractionated
Radiation Therapy In Patients With Nasopharyngeal Carcinoma
• Daoud et al randomized 154 patients of NPC into 2 arms
• (45% T3-4 tumors)
• Arm A: 1.6 Gy/# b.id to 70.4Gy/6 weeks with split course
• Arm B: 2 Gy/# QD to 70 Gy/7 weeks
• Results: 5-yearlocoregional FFR did not improve
significantly (81% vs78%), though major excessive
toxicities were observed.

NPC-9902 Trial:
IJROBP 2006
Aim: to assess the therapeutic benefit of AF and/or concurrent-adjuvant
chemoradiotherapy (CRT).
• randomized 189 patients with locally advanced NPC (T3-T4, N0-1, M0) to four
arms:
(i) conventional fractionation (CF) alone,
(ii) AF (six fractions/week) alone,
(iii) CF with concurrent chemotherapy,
(iv) AF with concurrent chemotherapy.
Preliminary Results: median follow-up of 2.9 years
• AF did not demonstrate significant improvement in event-free survival (EFS)
when compared to CF
(AF vs. CF: HR 0.68, p = .22).
• A significant increase in acute and late toxicity in the AF arm
Lee, et al. Preliminary results of a randomized study on therapeutic gain
by concurrent chemotherapy and/or accelerated fractionation for locally
advanced NPC. IJROBP 2006;66(1):142–15

RADIATION THERAPY: Definitive treatment

Role of Radiation Therapy: Treatment of Choice
• Historically, RT alone was used, and resulted in
• 5-year OS 35-50%
• Early-stage (I-II) outcomes were good, with 5-year DFS 75-95%
and OS 70-80%
• For advanced-stage (III-IV) 5-year DFS was ~50%, and OS only
10-40%
• Early stage disease (Stage I-II) :continues to be managed with RT
alone
• Advanced stage disease (Stage III-IV) & some bulky stage II is
managed with chemotherapy and radiotherapy

RADIOTHERAPY TECHNIQUES
• Conventional technique
• Three-dimensional conformal radiation therapy.
• Intensity-modulated radiotherapy.
• Image-guided radiotherapy.

Two field technique
• Clinical field markings:
• Superior border:
• 2.5 cm above the zygomatic arch
• 5 cm above the zygomatic arch in case of intracranial
extension
• Anterior border:
• 2 cm beyond the anterior most extent of the disease
(usually placed just along the lateral canthus of the eye)
• Posterior border:
• Along the tip of the mastoid or behind the posterior most
extent of cervical lymphadenopathy
• Inferior border:
• Along the superior border of the clavicle

Two Field technique
• Radiological boundaries:
• Superior border:
• Splitting the pituitary fossa and extending along the
superior surface of the sphenoid sinus
• In case of IC extension to include at least 1 cm above the
pituitary fossa.
• Anterior border:
• At least 2 cm of the nasal cavity and maxillary antrum.
• At least 2 cm margin to the gross tumor extent
• Posterior border:
• Kept open if gross cervical Lymphadenopathy
• Else match with tips of spinous processes of the cervical
vertebrae.

Treatment volume
• The Nasopharynx.
• Posterior 2 cm of nasal cavity.
• Posterior ethmoid sinuses.
• Entire sphenoid sinus and the basiocciput
• Cavernous sinus.
• Base of skull, including the foramen ovale, carotid canal and foramen
spinosum.
• Pterygoid fossae
• Posterior 1/3rd of maxillary sinus.
• Lateral and posterior oropharyngeal wall to the level of mid-tonsillar
fossa
? Posterior 1/4th of orbit ( Fletcher – YES, Perez - NO )

Nodal volumes
• The entire neck is at high risk for microscopic spread of
disease.
• The neck nodes that should be treated are:
• Upper deep jugular
• Submandibular
• Jugulodigastric
• Midjugular
• Posterior cervical
• Retropharyngeal

Treatment planning
• Positioning:
• Supine position.
• Head should be extended
• Immobilization
• To ensure accuracy in setup patient should be
immobilized with a custom-made thermoplastic cast.
• Localization:
• All nodes are delineated with the use of radio – opaque
lead wires.
• The outer canthus the eye opposite to which simulation
film is taken is marked with a lead wire.
• Tumor localization performed with the help of CT and
clinical details.

Portal selection
• For Initial Phase:
• Two parallel opposing fields
• Three field approach
• For the boost phase:
• Fletcher’s Technique ( 4 fields – antral boost)
• Anterolateral wedge pair technique
• Ho’s technique ( with separate parapharyngeal boost)

Techniques
• Energy selection:
• Co60 : 1.25 MeV
• LINAC : 4 – 6 MV
• Higher-energies used in certain Western centers during
the boost phase to:
• Reduce dose to the mandible, temporomandibular
joints, ears and subcutaneous tissue (lateral edge
effect)
• Kutcher and associates however warn that use of these
high energy beams may be associated with underdosage
near the surface and near the paranasal sinus cavities.

Three field technique
• The superior, anterior and posterior boundaries are kept as
same.
• Inferior boundary restricted to the level of the thyroid notch
unless cervical Lymphadenopathy is present
• In latter case matching done more inferiorly.
• Dose prescription done usually at 3 cm depth.
• Several measures need to be taken to circumvent the
problem of field matching

Field Matching
• Without asymmetrical jaws:
• Using laryngeal block:
• A laryngeal block is placed at the level of the larynx.
• The block has a thickness such that it is located 1cm medial to
the lateral border of thyroid cartilage
• The block extends from the superior border of the lower field to
2 cm below the level of the cricoid cartilages.
• Using collimator tilt:
• A collimator rotation may be given for the lateral fields to
counteract the divergence of the lower anterior field – 5° for Co
60.
• May increase the dose to the supero-anterior portion of the field
where the eyes are located
• With asymmetrical jaws:
• Using an isocentric technique with half beam block for 3 fields
overdosage at the field junction can be avoided.
• Alternative is to use half beam block in the lower anterior field only
and use a small shield of 1 – 2 cm in midline to shield the spinal
cord.

Additional modifications
• In both 3 field and 2 field
techniques a higher dose can be
given to the eye due to the beam
divergence.
• Lateral fields need to angled – a
“posterior” tilt needs to be given
• Magnitude by which the field
edge shifts at the midline ( for
Co60)
• 5° – 0.5 cm
• 10° – 1.2 cm
5° 10°
1.20.5
1.1 2.5

Actual Implementation
270
°
5
°
275
°
Lateral Canthus

Doses Prescribed
• 40 – 44 Gy in 2 Gy per fraction over 20 – 22 fractions
(4 – 4½ weeks) for the entire field.
• Rest of the dose ( 20 – 26 Gy) to delivered with spine
shielding:
• Lateral fields:
• Posterior border drawn along the junction of the
posterior 1/3rd and the anterior 2/3rd of the vertebral
bodies ( Co60).
• In LINACs the posterior edge of the vertebrae may
be choosen.
• Clinically marked straight along the lobule of ear.
• Anterior fields:
• 2 cm wide midline shield is adequate.

Boosting neck nodes
• Photons only:
• Antero-posterior glancing fields ( ± wedges) – Medial
border is 2 cm from midline.
• Additional boost radiation may be delivered by posterior
fields to increase the dose to the posterior cervical nodes
after the course of RT is completed.
• Electrons:
• Direct abutting lateral fields used.
• Energy selected 9 MeV
• Prescribed at 85% isodose ( Usually 3 cm depth)
• 6 x 6 cm usually adequate
• Treated at extended SSD of 110 cm

Field marking
• The boundaries for the anterior facial fields are:
• Superiorly – below the eyeball
• Medially – 1 cm in either side of midline
• Inferiorly – upto the commissure of lips
• Laterally – Usually a distance of 6 cm – allow beam fall-off.
• In order to ensure that the superior border of the
anterior field matches the lateral fields the head
position is adjusted (hyperextended) based upon the
collimator lights.
• Beam weights are adjusted to ensure that the brain
doesn't receive excess dose.
• Anterior : Lateral = 33% : 66%

Nasopharynx Boost
• In case of gross anterior extension:
• Three field, lateral wedge pair arrangement is preferred
• Anterior border of the lateral fields are extended to cover
the anterior disease adequately
• Alternative technique is to use differential beam weights
• Electrons may be used to supplement the doses to the
anterior diseases with lateral photon fields.
• In lateralized anterior extension:
• Anterior field may be “wedged” with thin end towards
side where disease is present.
• In inferior extension:
• Boost fields are by necessity parallel opposing.

Nasopharynx Boost
• A 4 field approach can be used to boost the nasopharynx to
additional 10 – 15 Gy.
• Volume treated is roughly cuboidal and has the dimensions
of 7 cm x 6 cm.
• The anterior fields are tilted “medially” by 20° – 30° in order
to
• Increase the dose to the Posterior nasopharynx
• Spare the anterior nasal cavity and the deeper brain-stem
• Opposing lateral fields also used with lower border at the
level of angle of mandible.

Ho’s Technique
• Proponent: Prof John H C Ho
• Developed: late 1960s
• Extensive experience : 3 decades
• Special features:
• Different CTV specification
• Field arrangements and patient position are different.
• Arrangement of different shields specified based upon bony
anatomy – customized shields not necessary.
• Reproducible treatment plan.
• Lack of CT planning facilities circumvented.
• Ease of use in a busy radiotherapy department Cost saving
additional factor.
• Over 10,000 patients have been treated in Hong Kong – excellent
long term results in early disease T1, T2 and T3.

Ho’s technique: Planning
• Patient is immobilized in FLEXED head position in the
initial phase.
• Similar to the planning technique for pituitary.
• Allows easier shielding of the brainstem and the oral cavity
and reduces the field size requirements.
• Dose: 40 Gy in 20 #

• Three field arrangement:
• Opposed lateral fields
irradiate the upper cervical
lymphatics ( upto level III)
en bloc.
• An anterior field irradiates
the lower field.
• Shielding of the lateral
fields is done to adjust for
the beam overlap with the
anterior field.
• In the lower anterior field a
midline shield is placed
throughout the treatment.
Below vocal cords C6
0.5 cm above the
anterior clinoid process
Bisecting
the
maxillary
antrum

• Specialized arrangement of shielding is
done for all patients.
• Brain Stem: Shielded with 5 HVL
block placed in a manner such that
it is 0.5 cm behind the upper edge
of the clivus and 1 cm below the
lower edge.
• Eye: 5 HVL shield placed 1.5 cm
behind the lateral canthus.
• Posterior tongue also shielded
with standard block.
• Pituitary and temporal lobes:
upper half of the pituitary fossa
shielded.

• In the boost phase a 3 field arrangement
was used.
• Patient was replanned in the
EXTENDED head position with oral
stent.
• Anterior cervico-facial field was used in
all patients
• Lower border of the later fields reduced
down to level of angle of mandible.
• Allowed dose reduction to: TM joints,
ear, parotids & pinnae.
• Dose prescribed: 22.5 Gy in 9 #
• Total tumor dose was 62.5 Gy in 29#
• Biologically equivalent to 66 Gy in 33#

• In patients with parapharyngeal
disease a posterior oblique boost
was given after the 2nd phase.
• Dose prescribed was 20 Gy /10#
• This field was usually 5.5 cm x
8 cm in size.
• Ascending ramus of the
mandible was shielded in this
phase.

Ho’s vs 3D CRT and IMRT
T1 N0 M0
T4 N2 M0
Kam et al: IJROBP 2003

Is Conventional Radiotherapy good enough for NPC?

Acute: mucositis, dermatitis, xerostomia.
Late: soft tissue fibrosis, trismus, xerostomia, hearing loss, vasculopathy,
osteoradionecrosis, temporal lobe necrosis, hypothyroidism, hypopituitarism (if
included).
Otitis media: 5 - 41.8 %
Trismus: 3 - 12 %
Xerostomia: 35 - 100 %
Neck fibrosis: 3 - 36.4 %
Osteonecrosis: 0 - 2 %
Grade III - IV Complications
Temporal lobe necrosis: 2 - 33.3 %
Hearing impairment: 3 - 30.9 %
Cranial neuropathy: 0 - 4.2 %
Normal tissue complications

• How to improve the local control especially for T3 and T4
patients?
• How to reduce the post-irradiation late sequelae?
• How to reduce the ratio of distant metastasis?
Three Major Issues of the NPC

Nasopharyngeal carcinoma presents most typically as a concave
tumor, allowing for computerized three-dimensional (3D)
treatment plans to be an important technical advance for
improved radiation delivery
When compared to conventional 2D plans, 3D planning
demonstrated better tumor dose coverage while decreasing
normal tissue dose in several studies.
2D vs 3DCRT

Target Volumes
• ■ GTV/PTV: as per general principles. MRI fusion can delineate intracranial OARs, locate
tumor infiltration, and visualize nerves that need to be included.
• ■ CTV1 = GTV + 5 mm
• ■ CTV2 (per RTOG 0615) =
1) The entire nasopharynx,
2) Anterior one-half to two-thirds of the clivus (entire clivus, if involved),
3) Skull base (foramen ovale and rotundum bilaterally must be included for
all cases),
4) Pterygoid fossae,
5) Parapharyngeal space,
6) Inferior sphenoid sinus (in T3–T4 disease, the entire sphenoid sinus), and
7) Posterior third to half of the nasal cavity and maxillary sinuses (to ensure
pterygopalatine fossae coverage).
8) The cavernous sinus should be included in high-risk patients (t3, t4, bulky
disease involving the roof of the nasopharynx).
9) Posterior ethmoid sinuses
10) Include bilateral levels Ib to V and retropharyngeal/parapharyngeal nodes
for all cases.

• Special Considerations
• ■ Level Ib nodes may be spared in N0 patients, or N+ only
in retropharyngeal or level IV nodes.
• ■ If hard palate, nasal cavity, or maxillary antrum is
involved, bilateral IB nodes must be covered

The potential benefit of IMRT for NPC
• Improve the local control especially for concave shape
tumors
• Reduce the post-irradiation complications
• Reduce the rate of distant metastasis by improving the local
control
• The intensity of the radiation beams can be modulated to
deliver a high dose to the tumor with a superior target
volume coverage while significantly limiting the dose to
surrounding normal structures.

IMRT Target Delineation for
Nasopharyngeal Carcinoma

Imaging acquisition and contouring

Is IMRT really better than conventional or 3-D conformal
radiotherapy?

How to decide the doses to the different targets and
different critical organs?
• SMART: simultaneous modulated accelerated radiation therapy,
Dr. Butler and Dr. Teh, 1999
• SIB: simultaneous integrated boost, Dr. Mohan and Dr. Wu,
2000

Results
• Estimated 3 year disease free survival (DFS) was 94%.
Three year DFS for patients with EBV was 100% as
compared to 60% without EBV (p = 0.0009).
• Three year DFS for patients with undifferentiated histology
was 98% as compared to 82% with other histologies (p =
0.02).
• Acute grade 3 toxicity was seen as 21 (30.9%) having G-III
mucositis and 6 (8.8%) with G-III skin reactions.
• Late toxicity was minimal and loss of taste was seen in 3
patients (7.5%) at time of analysis.

Conclusion
• IMRT with SMART in combination with chemotherapy is
feasible and effective in terms of both the clinical response
and safety profile.
• EBV, histopathology and nodal involvement were found
important prognostic factors for locoregional recurrence.

• N=67 .
• IMRT was delivered using three different techniques:
1) manually cut partial transmission blocks,
2) computer-controlled auto-sequencing segmental multileaf collimator
(SMLC),
3) sequential tomotherapy using a dynamic multivane intensity modulating
collimator (MIMiC).
• The prescribed dose was 65–70 Gy to the gross tumor volume (GTV) and
positive neck nodes, 60 Gy to the clinical target volume (CTV), 50–60 Gy to
the clinically negative neck, and 5–7 Gy in 2 fractions for the intracavitary
brachytherapy boost.

Results: With a median follow-up of 31 months (range 7 to 72 months)
The 4-year estimates were local progression–free(97%), local-regional progression–
free(98%), and distant metastases-free rates(66%), overall survival(88%).
Acute toxicity: Grade 1 or 2 in 51 patients, Grade 3 in 15 patients, and Grade 4 in 1
patient.
Late toxicity was Grade 1 in 20 patients, Grade 2 in 15 patients, Grade 3 in 7 patients,
and Grade 4 in 1 patient.
At 3 months after IMRT, 64% of the patients had Grade 2, 28% had Grade 1, and 8%
had Grade 0 xerostomia.
At 24 months, only 3% had Grade 2, 32% had Grade 1, and 66% had Grade 0 or no
xerostomia.

• Analysis of the DVHs showed that the average maximum, mean,
and minimum dose delivered were 79.3 Gy, 74.5 Gy, and 49.4 Gy
to the GTV, and 78.9 Gy, 68.7 Gy, and 36.8 Gy to the CTV.
• An average of only 3% of the GTV and 3% of the CTV received
less than 95% of the prescribed dose.
• Conclusion: Excellent local-regional control for NPC was
achieved with IMRT. It provided excellent tumor target coverage
and allowed the delivery of a high dose to the target with
significant sparing of the salivary glands and other nearby critical
normal tissues.

• N= 208
• The prescription dose to the gross target volume of nasopharynx
(GTVnx)= 68Gy/30f, positive neck lymph nodes (GTVnd)= 60-
66Gy/30f, CTV1= 60 Gy/30f, CTV2= 54Gy/30f. The nasopharynx and
upper neck targets were irradiated using IMRT, and the lower neck and
supraclavicular fossae targets were irradiated using the half-beam
technique with conventional irradiation.

• Results: The occurrence rates induced by radiotherapy were
cervical subcutaneous fibrosis= 89.9%
hearing loss= 67.8%
skin dystrophy= 47.6%
xerostomia= 40.9%
trismus= 7.21%
temporal lobe injury= 4.33%
cranial nerve damage= 2.88%
cataract= 1.44%,
brain stem injury= 0.48%
• No spinal cord injury and mandible damage were found.
• Grade 3–4 late injuries were observed as follows: (0.48%) skin dystrophy,
(1.92%) cervical subcutaneous fibrosis, (0.96%) hearing loss, (0.96%)
cranial nerve palsy, and (0.48%) temporal lobe necrosis. No grade 3–4 late
injuries occurred in parotid, temporomandibular joints and eyes.
• Xerostomia decreased gradually over time and then showed only slight
changes after 4 years.
• Conclusion: The late injuries in most NPC patients who had long-term
survivals after IMRT are alleviated. Within the 5 years of follow-up,
xerostomia decreased gradually.

 All IMRT series reported excellent results, with local control exceeding 90% at 2-5 years
with CT
 Conversely improvement in distant failure is less impressive. Distant relapse rate varies
widely, with 2-year rates ranging from 10% to 15% and 4-year rates as high as 34%.
 Hence, more potent systemic therapy is needed for this cancer.

Dose Escalation
• ALTERED FRACTIONATION
• BRACHYTHERAPY

Brachytherapy
• Intracavitary/ interstitial implants have been used in NPC
• Indications:
as a boost treatment following EBRT
 in the treatment of recurrent disease.

History of brachytherapy
• In 1920s, Pierquin and Richard were the
first persons is to employ brachytherapy
in the treatment of nasopharyngeal
carcinomas.
• In the Christie hospital at Manchester,
Peterson used a 15 mg radium tube
inserted in a cork with a diameter of 15
to 20 mm.
• The dose prescribed was 80 rads in
seven days to a depth of 0.5 cm.
Peterson described this technique as a
useful alternative to small field X-ray
technique but not superior to the use of X-
rays
Cork
Ra226 tube
String at either end of
the cork

Brachytherapy
• The following requirements should be fulfilled prior to taking up a
patient for brachytherapy:
• Tumor thickness less than 10 mm.
• Absence of intracranial, paranasal sinus and oropharyngeal
involvement.
• Absence of involvement of underlying bone or infratemporal
fossa.
• Absence of metastatic disease.
• Expertise in nasopharyngeal intracavitary brachytherapy.
“In effect, nasopharyngeal brachytherapy is ineffective in tumors
extending beyond the nasopharynx” -Xiao-Kang Zheng

Techniques
• Techniques:
• Temporary intracavitary application
• Temporary interstitial implantation
• Permanent interstitial implantation
• Dose-rates used:
• Low dose rate (LDR).
• High dose rate (HDR).
• Situations used:
• Routine use as a boost after XRT ( Hong Kong, China and
Netherlands)
• Use with documented residual disease ( USA)
• Recurrence ( Hong Kong, USA - Syed and Chinese Series)

Limitations of brachytherapy:
Dose Delivered Is Adequate Only For Superficial Nonbulky Tumors.
Not Suitable For Treatment Of Tumors With Intracranial Extension Because Of
The Rapid Reduction Of Dose With Distance
Optimal Positioning Of The Applicators Depends Both On Clinician’s Skill And
Patient’s anatomic features
Present status of brachytherapy
Since the advent of IMRT as primary radiotherapy for nasopharyngeal carcinoma
and with its excellent local control, the use of brachytherapy as a boost treatment
following definitive EBRT has declined

Rotterdam Applicator
• Designed by Levendag.
• Designed so that the applicator could be worn by the patient
comfortably continuously throughout the fractionated course of
treatment given.
• Made up of silicone which is flexible and closely conforms to the
curvature of the nasopharynx.
• Applicator design based upon a 3 D model of the nasopharynx
(based on CT of two patients)
• Allows closer fit to the base of the skull and situated at a fixed
distance from the soft palate.
• A silicone bridge and flange used to fix the applicator against the
posterior nasal septum and the anterior one respectively.

• Tube diameter
• Outer diameter 15 F
(5.5 mm)
• Inner diameter 9 F ( 3.5
mm)
• Can accommodate the 6 F
HDR source easily.
• Two tubes ensure catheter
stability.
• The tubes are diverging at
the base
Rotterdam Applicator

Prescription points
BOS
Pa
R
NaRe
P
OC
C
Pa Pa
CR
OC
Re Re
BOS BOS
Na Na
P
No
No
No
Line 1
• Several anatomical points defined by Levendag to calculate dose to the
tumor as well as critical normal tissues.
• 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

Dose prescribed
• In case EBRT given in dose of 60 Gy:
• 3 Gy x 2 fractions per day for 6 fractions by HDR
• Total dose ~ 78 Gy
• Minimum interfraction gap of 6 hrs.
• In case of EBRT given in dose of 70 Gy:
• 3 Gy x 2 fractions for 4 fractions by HDR
• Total dose ~ 82 Gy
• Minimum interfraction gap of 6 hrs.

Advantages
• Comfortable applicator – can be kept between fractions
• Optimization possible – Na, BOS and the R points.
• Can be reused after steam sterilization.
• Reduced normal tissue dose – to the retina, palate and the nasal cavity
• In earlier work Levendag used to use two other points:
• FL point:
• corresponding to the BOS point
• Approximates the position of the foramen lacerum
• FO point:
• Situated at the foramen ovale
• Taken 2 cm lateral to the midline in then same plane as the
BOS point.

Disadvantages
• Nasal synechia have been observed in few patients.
• Corresponds to the hyperdose sleeve of 200% isodose around
the applicator.
• Approximately occurs in a radius of 6 mm around the source
axis after standard prescription
• Reduced by use of nasal pack for 7 days after ICBT
• Optimization can result in increased dose to some points
(especially the spinal point).

ADJUVANT BRACHYTHERAPY BOOST FOR PRIMARY TREATMENT
OF NASOPHARYNGEAL CARCINOMA
Table :summarizes reports on the use of brachytherapy as a boost for dose escalation.
Most studies demonstrated that local control of up to 90% to 95% could be achieved for T1-2
tumors without excessive late damages

275 patients with loco regionally advanced NPC disease (TNM stages III or M0
stage IV)
treated by induction chemotherapy followed by concurrent chemoradiotherapy to
70 Gy conventional planning
NACT :cisplatin: 100 mg/m2 and doxorubicin 50 mg/m2 or Epirubicin 75 mg/m2 3
weeks for 2 cycles followed by EBRT 70 Gy to primary & positive nodes & 46 Gy
to negative neck and concurrent weekly cisplatin 30 mg/m2 /week for 7 weeks
then randomized into 2 arms
Arm A:standard arm
Arm B:brachytherapy boost arm: received boost of 11-Gy LDR or three
fractions of 3-Gy HDR.

RESULTS:
With a median follow-up of 29 months no additional benefit
of brachytherapy boost compared with chemoradiotherapy
alone
distant-metastasis–free survival (52.6% vs. 59.8%, p =
.496)
3-year OS (63.3% vs. 62.9%, p = .742) .
locoregional-FFR (54.4% vs. 60.5%, p = .647)
Rotterdam nasopharyngeal applicator
Conclusions
The addition of a brachytherapy boost to external beam radiotherapy and
chemotherapy did not improve outcome in loco-regionally advanced nasopharyngeal
carcinoma

CHEMOTHERAPY
• Concurrent Chemo radiotherapy
• Neoadjuvant/induction Chemotherapy
• Adjuvant Chemotherapy
RT

One strategy to improve the efficacy of chemotherapy is to use an
induction-concurrent sequence.
Advantages of Induction chemotherapy better tolerated than
adjuvant chemotherapy:
1. Early use of a potent combination of cytotoxic drugs at full dose
may eradicate micrometastases.
2. Can shrink primary tumor to give a wider margin for irradiation,
can save adjacent critical neural structures during RT
INDUCTION CHEMOTHERAPY

MRI showing shrinkage of primary tumor by induction chemotherapy before proceeding to concurrent
chemoradiotherapy.
(From Lee AW, Lau KY, Hung WM, et al. Potential improvement of tumor control probability by
induction chemotherapy for advanced nasopharyngeal carcinoma. Radiother Oncol. 2008;87(2):204–
210, with permission from Elsevier.)
Lee et al showed that
3 cycles of
IC(cisplatin+5FU) could
significantly reduce the
primary GTV by an
average of 61%,
leading to significant
increase in the minimum
tumor dose
& consequent
improvement in the
estimated tumor control
probability (P= 0.002).

Currently, there are 3 ongoing randomized trials to evaluate this
strategy.
The NPC-0501 Trial aims to compare the benefit of changing the
chemotherapy sequence from concurrent- adjuvant chemotherapy (the
Intergroup-0099 regimen)
to induction-concurrent and RT fractionation from conventional to
accelerated.
The GORTEC-NPC2006 Trial aims to compare concurrent CRT at
conventional fractionation versus CRT plus induction chemotherapy
(docetaxel,cisplatin, and fluorouracil).
A third randomized trial from Singapore also tests the benefits of
induction chemotherapy in the setting of concurrent chemoradiation.
The results from these trials will provide valuable data for future
direction

TRIALS FOR ADJUVANT CHEMOTHERAPY
none achieved significant benefit in any endpoints

The first trial that achieved a significant survival benefit was Intergroup-0099
Lin et al also reported significant benefit of concurrent CTRT in both EFS and OS
Kwong et al showed non significant benefits
Table 1 :clinical trials on CTRT

Chemoradiotherapy Versus Radiotherapy in Patients With Advanced
Nasopharyngeal Cancer: Phase III Randomized Intergroup Study 0099
Muhyi Al-Sarraf, et al
Journal of Clinical Oncology, Vol 16, No 4 (April), 1998: pp 1310-1317
• Pts. were stratified by tumor stage, nodal
stage, performance status & histology
• Radiotherapy 1.8- to 2.0-Gy/d fractions for 35
to 39 fractions for a total dose of 70 Gy.
• investigational arm received chemotherapy
with cisplatin 100 mg/m 2 on days 1, 22, and
43 during radiotherapy;
• adjuvant chemotherapy with cisplatin 80
mg/m 2 on day 1 and fluorouracil 1,000 mg/m
2/d on days 1 to 4 was administered every 4
weeks for three courses.

• 3Y PFS 69% (CRT) vs. 24% (RT alone),
p<0.001
• 3Y OS 78% (CRT) vs. 47% (RT alone),
p=0.005
• The trial was closed early due to a significant
overall survival benefit in favour of CRT

5 year update
• A 5-year update confirmed progression-free survival (58% vs. 29%) and
overall survival (67% vs. 37%) in favour of CRT

The Additional Value of Chemotherapy to Radiotherapy in Locally Advanced
Nasopharyngeal Carcinoma: A Meta-Analysis of the Published Literature
Purpose: To determine the additional value of chemotherapy to radiation in the
treatment of LA-NPC
Ten randomized clinical studies. 2,450 patients.
The 10 studies included 4 neoadjuvant trials, 3 concurrent (with/without adjuvant)
trials, 2 adjuvant trials, and 1 neoadjuvant plus adjuvant trial.
Hazard ratio for death of 0.82, with absolute survival benefit of 4% after 5 years.
Subgroup analysis revealed that OS benefit was only significant for pts. receiving
concurrent chemotherapy, with a hazard ratio for death of 0.48 and absolute survival
benefit of 20% at 5 years.
Analysis of the NACT trials found a significant reduction in LRR & DM but no OS
benefit.
Conclusion The results of this study indicate that concomitant chemotherapy in
addition to radiation is probably the most effective way to improve OS in NPC.
Langendjik et al, JCO 2004

NPC in Children
• Problem of long term toxicity:
• Skull deformities
• Neurological deficits
• Pituitary dysfunction
• Hearing impairment
• TM joint ankylosis
• Visual defects
• RT is the treatment modality of choice:
• Dose 50 -60 Gy
• Boost only after skull growth is complete (15yrs)
• Lower neck usually not treated if clinically –ve.
• Outcome:
• DFS is 70 – 80% in T1 and T2 tumors
• DFS is 40 – 50% in T3 – T 4 tumors

Recurrence
• 2 types described (Wang et al)
• Persistent disease
• Relapse: Appearing 1 yr after treatment.
• Detecting recurrence:
• Tc99m SPECT
• MRI – High signal intensity on T1 weighted spin echo
images
• Options:
• Palliative treatment
• Radiation therapy
• Surgery

Surgery Radiotherapy
• Usually indicated in
situations like
isolated nodal
recurrence
• Local recurrences
may be salvaged by
extensive
craniofacial surgery
• EBRT
• Brachytherapy
• Both temporary and permanent
implants used.
• Best results from Gold grain
implantation.
• IMRT and 3 DCRT
• Investigational
• Sterotactic Radiosurgery
• Chemotherapy
• Cisplatin or taxane based
• Mainstay in:
• Distant spread
• Early recurrence
• Extensive disease

Radiotherapy
• External radiotherapy:
• High energy beams are better choosen
• Small 6 x 6 field used to treat site of local recurrence
• Doses in range of 20 – 30 Gy.
• Indications:
• Limited tumour size,
• a relatively long period since previous irradiation (minimal time
period ~ 1 year)
• Good performance status and
• Lack of evidence of skin or soft tissue damage (skin fibrosis,
atrophy or telangiectasis) from the previous irradiation course

Neurological Sequelae
• Hypothalamo-Pituitary dysfunction
• Median incidence of clinical dysfunction is 3%.
• Cumulative incidence of endocrine dysfunction higher at 67% at 2
yrs.
• Most common disturbance seen in GH secretion.
• Thyroid hormone production affected the least.
• Hearing defects:
• Almost 7% patients become deaf with standard therapy.
• Otitis media seen in 14% patients
• Prolonged tinnitus may be seen in 30% patients
• Temporal lobe injury:
• Incidence as high as 3% after 2 yrs.
• Toxicity more in altered fractionation regimens
• Cranial nerve injury:
• The incidence is as high as 6%.

Targeted Therapy
Epigenetic Therapy
• In patients with EBV-positive malignancies who have failed
conventional treatment, a clinical trial of the DNA
methyltransferace (DNMT) inhibitor Azacitidine was
conducted aiming at the demethylation of EBV promoters
and also upregulating expression of the silenced viral
antigens.
• A pioneering study of 5 patients demonstrated for the first
time that demethylation of tumor DNA in patients can be
achieved using azacitidine. A follow-up study combining the
histone deacetylase inhibitor SAHA with azacitidine is
ongoing.

Immunotherapy
• EBV is ubiquitous in undifferentiated NPC, and hence the
viral Antigens expressed by the tumor provide potential
targets for immunotherapy.
• Adoptive therapy using cytotoxic T cells (CTLs) have been
highly successful in treatment of EBV-associated, post-
transplant lymphoproliferative disease (PTLD), which
express the immunodominant EBV nuclear antigens EBNA
3A, 3B, and 3C.
• In contrast, NPC express a restricted set of less
immunogenic viral antigens EBNA1, LMP1, and LMP2.

Adoptive Therapy
• The first pilot study to treat NPC using adoptive T-cell therapy was
reported by Chua et al. where autologous EBV-transformed B-
lymphoblastoid cell line (LCL) reactivated T cells were generated in vitro
and used to treat four advanced cases of NPC. No adverse events
occurred and infusion of CTL was associated with reduction of plasma
EBV load. However, there was no evidence of tumor regression.
• Interestingly, Comoli et al. also reported the adoptive transfer of an
allogeneic EBV specific CTL in one patient with relapsed NPC resulted
in temporary stabilization of disease.
• Taken altogether, the result of these studies showed that it is feasible to
boost EBV-specific immune response in NPC patients and provide
further rationale to explore EBV as a target for immunotherapy.

Conclusion
• Nasopharyngeal malignancies make up a different
population of head and neck malignancies.
• These are eminently radio sensitive and curable.
• Treatment planning is by necessity complicated and time
consuming.
• Brachytherapy can be used for boosting the local activities.
• Chemoradiation is standard treatment in locally advanced
tumors

Carcinoma nasopharynx anatomy to management

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