MANAGEMENT OF

NASOPHARYNGEAL CANCER

Dr. Sachin Sakthivel,

Junior Resident,
Dept. of Radiotherapy &Radiation Medicine,
SSH,IMS,BHU
Medial and lateral pterygoid muscle involvement from T4 to T2
Prevertebral muscle involvement as T2
Replace the supraclavicular fossa (SCF) with the lower neck
Merge N3a and N3b into N3
T4 and N3 merged into stage IVA
CLINICAL
FEATURES
 PROGNOSTIC FACTORS

TUMOUR RELATED PATIENT RELATED

• T, N and M (most important) • Males
• Bony erosion, cranial nerve palsy (T) • Older age (>50)
• Lower nodal involvement (N) – higher risk of
distant mets
DIAGNOSIS AND TREATMENT RELATED
• Keratinizing histology (less radiosensitive)
• Treatment duration >8 weeks
• Plasma EBV DNA and anti-EBV antibodies
• IMRT> conventional RT
• GTV-P (1% increase in local failure for each 1 )
TREATMENT OPTIONS
 IS THERE A ROLE FOR SURGERY?

Not an initial treatment at the primary site

• relative lack of surgical access (deep anatomical location)
• close proximity to critical neurovascular structures

Neck dissection after RT

• residual nodal disease
• isolated neck recurrence

Nasopharyngectomy may be an option for a small, localized recurrence

 RT remains the mainstay of treatment for
patients with nasopharyngeal cancer

• Radiosensitive tumor (endemic, undifferentiated WHO III)

• Anatomic location limits a surgical approach

• Significantly improved clinical outcomes:

• Advances in high-precision RT delivery
• Integration of chemotherapy
• Improvement in tumor imaging and disease monitoring
 RADIATION THERAPY TECHNIQUES

Conventional, 3D-CRT

 IMRT, VMAT and proton therapy:

• Better long-term disease control
• Less toxicity and fewer serious complications than older techniques
• Steep dose gradients:
• adequate patient immobilization
• verify daily treatment set-up accuracy (IGRT)
 RT SIMULATION
Conventional technique:

• Supine position, arms by side

• Elevated chin
• Immobilisation
• Bony anatomy with opposing lateral fields
using simulator
• Delineate neck nodes with wires
• Mouth bite (depress tongue away)
 2D TECHNIQUE - PORTALS

Initial phase:
• Two parallel opposing field
• Three field

Boost phase:
• Ho’s technique
• Anterolateral wedge pair technique
• Fletchner’s technique (4 field with antral boost)
 TWO-FIELD APPROACH – CLINICAL FIELD
MARKINGS

Superior:
• 2.5 cm above the zygomatic arch
• 5cm above zygomatic arch in case of intracranial extension
Anterior:
• 2cm beyond anterior most disease extent (usually lateral canthus of eye)
Posterior:
• Along the mastoid tip or behind the posterior most extent of cervical lymphadenopathy
Inferior:
• Along the superior border of clavicle
 2-FIELD APPROACH –
RADIOLOGICAL BORDERS
Superior:
• splitting the pituitary fossa and along the superior border
of sphenoid sinus
• 1cm above pituitary fossa (Intracranial extension)
Anterior:
• 2cm margin to GTV
Posterior:
• Match tips of spinous processes of cervical vertebrae
• Kept open if gross cervical lymphadenopathy
Inferior:
• Just above the arytenoids
 TREATMENT VOLUME
• Nasopharynx
• Posterior 2cm of nasal cavity
• Posterior ethmoid sinuses
• Entire sphenoid sinus and basiocciput
• Cavernous sinus
• Base of skull (foramen ovale, spinosum and carotid canal)
• Pterygoid fossae
• Posterior 1/3rd of maxillary sinus
• Lateral and posterior oropharyngeal wall to the level of mid-tonsillar fossa
 NODAL VOLUMES

• Entire neck is at high risk for microscopic disease

• Upper deep jugular
• Submandibular
• Jugulodigastric
• Midjugular
• Posterior cervical
• Retropharyngeal
 HO’S TECHNIQUE

Three field arrangement:

• Opposed lateral fields irradiate upper

cervical nodes (upto level III)

• Anterior field for lower neck with midline

shield

• Brainstem, eyes, posterior tongue,

pituitary and temporal lobe shield used
 Three – field Phase II

• 2 lateral opposed fields and one anterior facial field

for Nasopharynx

• Anterior neck field – whole neck

• Same superior and anterior boundaries

• Inferior border – thyroid notch

• Posterior border: junction of ant. 2/3rd and post.

1/3rd of vertebral bodies
 FIELD MARKING

Anterior facial fields:

• Superior: below the eyeball

• Medially: 1cm in either side of midline

• Inferiorly: upto the commissure of lips

• Laterally: 6cm (to allow dose fall-off)

 LOW ANTERIOR CERVICAL FIELD

Superior: inferior border of lateral portals

Inferior: 1cm below clavicle

Lateral: medial 2/3rd of clavicle

Midline block to shield laryngeal and oesophageal

inlets

Total tumor dose 62.5Gy/29#, biologically equivalent

to 66Gy/33#
 FIELD MATCHING

Without asymmetrical jaws:

• Laryngeal block (superior border of lower field to 2cm below cricoid)

• Collimator tilt

With asymmetric jaws:

• Half beam block with isocentric technique – 3 fields

• Half beam block in lower anterior field only
 DOSE PRESCRIBED
• 40-44 Gy in 20-22# for entire field

• Rest (20-26Gy) delivered with spine shielding:

Lateral fields:
• Posterior border along the junction of posterior 1/3rd and anterior 2/3rd of
vertebral bodies (Cobalt)
• LINAC – posterior edge of vertebrae
• Clinically straight along the ear lobule

Anterior fields:
• 2cm wide midline shield
 NASOPHARYNX BOOST
Gross anterior extension:
• 3-field, lateral wedge pair preferred
• Anterior border of lateral fields are extended anteriorly
• Alternative: differential beam weights
• Electrons to supplement anterior dose with lateral photon fields

Lateralized anterior extension:

• Anterior field wedged with thin end towards side where disease is present

Inferior extension:
• Parallel opposing boost fields
 NASOPHARYNX BOOST

• 4 field approach 7*6 cm cuboidal volume

• Anterior fields tilted medially (20-30°)

• Increase dose to posterior nasopharynx
• Spare anterior nasal cavity and deeper brain stem

• Opposing lateral fields – lower border at the angle of mandible

 NECK NODE BOOST

Photons:
• Antero-posterior glancing fields
• Medial border 2cm from midline

Electrons:
• Directly abutting lateral fields
• 9 MeV prescribed at 85% isodose (usually 3cm depth)
• 6*6cm at 110cm SSD
 CONVENTIONAL TREATMENT
SEQUALAE
Overall complication rate – 31 to 66%

• Temporal lobe necrosis • Cranial nerve dysfunction

• Hearing loss • Endocrine dysfunction
• Xerostomia • Osteonecrosis
• Neck fibrosis • Soft tissue necrosis
• Transverse radiation myelitis
 RT SIMULATION
3D-CRT/IMRT:

• Supine position, arms by side

• Neutral neck
• Immobilisation
• 2-3mm thick slices from vertex to arch of aorta
• i.v. contrast
 Before beginning contouring

• Read history and examination findings

• Radiology discussion – axial anatomy

• Collect pre-treatment images

• Image registration

• Verify contouring in all 3 planes (axial, coronal and sagittal)

DELINEATION OF GTV-P
 RATIONALE FOR
CTV DELINEATION
• Sites at the highest risk adjacent to nasopharynx

High-risk sites:
• involved – 55.2% involvement of medium risk sites
• not involved - <10% invasion of medium risk sites

Conclusion:
• Local disease spreads stepwise
• Neural foramina and neural pathways - privileged
routes for infiltration
 NASOPHARYNX BOUNDARIES

Superior: base of skull

Anterior: junction with nasal choanae superiorly and medial

pterygoid plate inferiorly

Lateral: medial border of parapharyngeal space

Inferior: caudal edge of C1 vertebra

 INTRACRANIAL EXTENSION

• CTV-IC: intracranial GTV + 3-5mm (depending on

proximity to OARs)

• PTV-IC: CTV-IC + 5mm

• Dose: 60-64Gy (54-60Gy in overlap with OARs)

• High-risk consent
 NODAL CTV

CTVn1:
• >70Gy equivalent
• GTV + 5mm (no ECE) or 10mm (ECE+)

CTVn2:
• >60Gy equivalent
• CTVn1 + 5mm expansion + B/L RP, II, III, Va
• Atleast one nodal level below involved nodes

CTVn3:
• >50Gy equivalent
• IV, Vb
Lymph node metastasis (Van den Brekel et al.,) radiologically defined by

• Central necrosis (any size)

• Extracapsular spread (any size)

• Any size with overt FDG-PET uptake

• SAD ≥10 mm (11 mm for the jugulodigastric node and 5 mm for the
retropharyngeal node)

• Cluster of ≥3 lymph nodes that are borderline in size

 DOSE CONSTRAINTS – RTOG 0225
Critical Intermediate Low risk

Brain stem < 54Gy Pituitary < 60Gy Parotid < 26Gy

Spinal cord < 45Gy TMJ < 70Gy Glottic larynx < 45Gy

Optic chiasma < 54Gy Lens < 6Gy Cochlea < 50Gy

Optic nerve < 54Gy Eyeball < 35Gy Tongue < 65Gy

Temporal lobe < 60Gy, <65Gy

RADIATION DOSING AND SCHEDULE

EBRT:

• 66 to 70 Gy at 2 to 2.12 Gy per fraction to eradicate macroscopic disease

• 50 to 60 Gy to treat potential subclinical disease in at-risk sites

• once-daily fraction at five fractions per week

RADIATION DOSING AND SCHEDULE

Elective nodal volumes – B/L neck nodal basins from retropharyngeal lymph nodes
to lateral neck levels II to IV and V

• highly infiltrative nature of NPC within the nasopharyngeal mucosa

• propensity for early and bilateral involvement of regional lymph nodes

• Level IB included when level II or anterior nasal cavity involved

IMRT DOSE FRACTIONATIONS
RADIATION DOSING AND SCHEDULE

Conventional fractionation (5#/week) + CTH remains the standard of care in NPC

Accelerated fractionation:

• randomized trials suggest

• it does not improve survival
• may increase toxicity
 RADIATION DOSING AND SCHEDULE

NPC-9902 - 189 patients, T3-4, N0-1 disease

• 5-year failure-free rate:
• Accelerated RT (6#/week) + AC – 88%
• Accelerated fractionation without CTH – 56%
• Conventional fractionation (5#/week) + CCT – 65%
• Conventional fractionation (5#/week) without CCT – 63%

NPC-0501:
• Accelerated fractionation did not confer any survival benefit and was associated with
increased toxicity (acute mucositis and dehydration)
 BRACHYTHERAPY
• Boost following RT
• Recurrent disease

• The addition of a brachytherapy boost to EBRT + CTH did

not improve outcome in loco-regionally advanced NPC
LIMITATIONS AND CURRENT STATUS

• Dose delivered is adequate only for superficial non-bulky tumors

• Not suitable for intracranial extension (rapid dose fall-off)
• Optimal positioning – clinician’s skill and patient’s anatomy

• Declined after advent of IMRT

 EARLY (STAGE I) DISEASE

RT alone:
• excellent LRC
• avoids potential CTH toxicity

RTOG 0225:
• N = 68
• locoregionally advanced NPC
• subset of 9 patients with stage I disease treated with IMRT alone
• Median FU: 2.6 years
• Stage I LRF – 0%
• 2-year LPFS, PFS & OS - 92, 73 and 80 percent respectively
*Courtesy: Achille Manirakiza, Ocean Road cancer institute
*Courtesy: Achille Manirakiza, Ocean Road cancer institute
INTERMEDIATE (STAGE II) DISEASE

HIGH RISK

> 1 features
HIGH RISK FEATURES

Cervical lymph nodes ≥3 cm

Level IV or VB lymph nodes
Extranodal extension
Pretreatment plasma EBV DNA ≥4000 copies/mL
LOW RISK
None of the above
LOW RISK STAGE II
HIGH RISK STAGE II
Median FU: 60 months

Factor CRT (%) RT alone (%) p value

5-year OS rate 94.5 85.8 0.007
Progression free survival 87.9 77.8 0.017
Distant metastasis free survival 94.8 83.9 0.007
5-yr LR relapse free survival 93 91.1 0.29
Acute toxicities 72 40.4 0.001

Conclusion:
Concurrent chemotherapy and radiotherapy is associated with a considerable survival
benefit for patients with stage II NPC.

Pitfalls:
• use of non-IMRT technique
• adoption of the 1992 Chinese staging system - 13.0% study cohort being in fact N2 (stage
III) - AJCC/UICC 7th edition
HIGH RISK STAGE II
Median FU: 125 months

Factor CRT (%) RT alone (%) p value

Overall survival 83.6 65.8 0.001

Progression free survival 76.7 64 0.014

Cancer specific survival 86.2 71.9 0.002

Distant metastasis free survival 94 83.3 0.007

Conclusion:
Ten-year outcomes confirmed that CCRT could improve the OS of stage II (only T2 N1
subsets) patients without adding late toxicities compared with conventional RT
CISPLATIN – WEEKLY OR
TRIWEEKLY?

*Courtesy: Achille Manirakiza, Ocean Road cancer institute

ADVANCED, NON-METASTATIC (STAGE III &
IVa) DISEASE
Standard of care: combined modality of chemoradiotherapy and IC/AC

OS: CRT-AC > CRT > IC-CRT compared with RT alone

Conclusion:
• Addition of AC to CRT achieved the highest survival benefit and consistent improvement for
all end points
• Addition of IC to CRT achieved the highest effect on DC.
*Courtesy: Achille Manirakiza, Ocean Road cancer institute
 Lei Chen et al.

Median FU: 68.4 months

5-year FFS (75% v 71%

, P = .45)
CRT f/b AC (Cisplatin + 5-FU)
N = 251 Late toxicities (grade 3-4, 27%
v 21%, p = 0.14)
Newly diagnosed
Nonmetastatic AC failed to demonstrate
Stage III – IVB significant survival benefit
excluding T3-4N0 after CCRT in locoregionally
AJCC/UICC 6th edition advanced NPC and did not
CRT alone significantly increase late
N = 257 toxicities.

Poor compliance- only 63%

received 3 cycles
Metronomic capecitabine (650 mg/m2 BD * 1 year)

∼70% of patients received IC + CRT

Metronomic capecitabine improved

• 3-year FFS by 9.6% (85.3% vs 75.7%)
• OS by 4.7% (93.3% vs 86.6%)
• Compliance rate (74%) to AC was higher than historical studies
ADVANCED, NON-METASTATIC (STAGE III &
IVa) DISEASE
 Sun Y et al.

Median FU: 45 months

3-yr FFS: 80% vs 72%,

IC (Docetaxel, cisplatin and p=0·034)
5-FU) f/b CRT
N = 241 Grade 3 or 4 adverse events:
Newly diagnosed neutropenia 42% vs 7%,
leucopenia 41% vs 17%
Nonmetastatic
stomatitis 41% vs 35%
Stage III – IVB
excluding T3-4N0 Addition of TPF (IC) to CRT
AJCC/UICC 7th edition significantly improved FFS in
CRT alone LANPC with acceptable
N = 239 toxicity. Long-term follow-up
is required to determine long-
term efficacy and toxicities
 Sun Y et al.

Median FU: 71.5 months

5-yr FFS: 77.4% vs 66.4%, p=0.019)

OS: 85.6% vs 77.7%, p=0.042)
IC (Docetaxel,
DFS: 88% vs 79.8%, p=0.030)
cisplatin and 5-FU) LRFFS: 90.7% vs 83.8%, p=0.044)
f/b CRT
Newly diagnosed N = 241 Grade 3 or 4 late toxicities:
Nonmetastatic 8.8% vs 9.2%
Stage III – IVB
Conclusion:
excluding T3-4N0 TPF IC + CCRT in LANPC from endemic
AJCC/UICC 7th edition regions of China improved survival
CRT alone
significantly with more acute toxicities but
N = 239 does not increase late toxicities

TPF IC plus CCRT could be an option of

treatment for LANPC
Yuan Zhang et al.

5-year OS: 87.9% v 78.8%, P = .001

ICT (gemcitabine
+ cisplatin) Late toxicities - grade 3: 11.3% v 11.4%
f/b CRT
N = 242 Conclusion:
Newly diagnosed • IC + CRT significantly improved
Nonmetastatic RFS and OS compared with CRT
Stage III – IVB alone in LANPC
excluding T3-4N0 • Patients with a low
AJCC/UICC 7th edition pretreatment cell-free Epstein-
Barr virus DNA load (< 4,000
CRT alone copies/mL) might not benefit
N = 238 from induction chemotherapy
(5-year OS, 90.6% v 91.4%, P
= .77)

Median FU: 69.8 months

 SELECTION OF THERAPY

Stage III to IVA (except T3N0) disease – and good performance status:

• IC f/b CCRT

• IC:
• reduce tumor burden
• increase locoregional and systemic control
• allow for smaller high-dose radiation volumes during CCRT
 SELECTION OF THERAPY

T3N0 disease – lower risk of treatment failure and were often excluded from
randomized trials assessing the addition of ICT/AC to CCRT

T3N0 at low risk:

• RT alone

T3N0 at high risk:

• CRT > RT alone
• Addition of ICT/AC is individualized
 POST TREATMENT SURVEILLANCE

Acute toxicities: Late toxicities:

• Mucositis • Temporal lobe injury

• Dysgeusia • Cranial neuropathies
• Xerostomia • Brachial plexopathy
• Dysphagia • Hearing loss
• Dermatitis • Xerostomia
• Dysphagia
• Soft tissue fibrosis
• Endocrinopathies (thyroid and
pituitary)
 RESPONSE ASSESSMENT

• Clinical examination

• Nasoendoscopy (restricted to superficial lesions, positive biopsy at 10 - 12 weeks

post-RT indicative of persistent residual disease)

• Plasma EBV DNA (promising liquid biopsy for surveillance of distant mets, less
certain for local recurrence)

• Radiological imaging (challenge to distinguish between post-RT

osteoradionecrosis versus residual tumor)
RECURRENT AND METASTATIC
DISEASE
RECURRENT AND METASTATIC
DISEASE
Problems:

NO ONE-SIZE-FITS-
• Dose to OARS by the primary course of treatment ALL TREATMENT
• Individual intrinsic radiobiologic characteristics
• Extent and location of the recurrent tumor

Decision on trade-off between chance of salvage and risk of serious toxicity

 Treatment option Grade of recommendation

Preferred: surgical resection with clear margin High

Surgery f/b RT for positive margin High

Salvage surgery f/b RT for close margin (2-5mm) Moderate

Exclude RT after short latency < 6-12 months Moderate

Exclude RT for toxicity > grade 1 (brainstem, spinal cord and optic chiasm),
> grade 3 (optic nerve, temporal lobe, brachial plexus, soft tissue or bone) High

Addition of systemic therapy if rt3-4 N0 or rt1-4 nb High

 Treatment option Grade of recommendation

Choice of RT- proton (IMRT if proton not available) High

CTV margin (<5mm) Moderate

PTV margin (2-3mm) Moderate

Elective nodal treatment not indicated High

IMRT dose 60-66gy High

Hyperfractionation Moderate
 SUMMARY
• IMRT - mainstay of treatment

• RT targeted according to primary tumour, pathological nodes and adjacent

regions considered at risk of microscopic spread (generally both sides of neck -
levels II-V and retropharyngeal nodes)

• Total dose of 70 Gy needed for eradication of macroscopic disease

• 50-60 Gy - treatment of potential at-risk sites

 SUMMARY

Concurrent Cisplatin:
• 100mg/ every 3weeks or @ 40mg/ weekly
• Optimal cumulative dose - >200 mg/m2

Intensified systemic treatment for stage III-IVA non-keratinising NPC

• ICT with cisplatin + gemcitabine f/b CRT
• Benefit in RFS, OS and distant RFS, with more acute but not late toxicities
• Selection of patients for ICT/AC + CRT is a therapeutic area being explored
in ongoing randomised, controlled trials
 SUMMARY

• Persistent, high EBV DNA values after definitive treatment, a personalized

approach with non-cross resistant drugs or participation in a clinical trial

• Small, local recurrences are potentially curable

• Stage rT1-rT3: endoscopic nasopharyngectomy > IMRT

 SUMMARY

Lymphatic recurrences in the neck - neck dissection

Metastatic NPC - palliative ChT (good PS)

• Cisplatin + gemcitabine - first-line choice and improves OS

Newly diagnosed, metastatic NPC - locoregional RT + systemic therapy improves

LRC & OS
*Devita Principles and practice of cancer oncology
*Devita Principles and practice of cancer oncology