management of nasopharyngeal cancers

1. MANAGEMENT OF
NASOPHARYNGEAL CANCER
Dr. Sachin Sakthivel,
Junior Resident,
Dept. of Radiotherapy &Radiation Medicine,
SSH,IMS,BHU

3. Medial and lateral pterygoid muscle involvement from T4 to T2
Prevertebral muscle involvement as T2

4. Replace the supraclavicular fossa (SCF) with the lower neck
Merge N3a and N3b into N3

6. T4 and N3 merged into stage IVA

8. CLINICAL FEATURES

11. PROGNOSTIC FACTORS
TUMOUR RELATED
• T, N and M (most important)
• Bony erosion, cranial nerve palsy (T)
• Lower nodal involvement (N) – higher risk of
distant mets
• Keratinizing histology (less radiosensitive)
• Plasma EBV DNA and anti-EBV antibodies
• GTV-P (1% increase in local failure for each 1 𝑐𝑚3)
PATIENT RELATED
• Males
• Older age (>50)
DIAGNOSIS AND TREATMENT RELATED
• Treatment duration >8 weeks
• IMRT> conventional RT

12. TREATMENT OPTIONS

13. 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

15. 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

16. 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)

17. 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)

18. 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)

19. 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

20. 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

21. 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

22. NODAL VOLUMES
• Entire neck is at high risk for microscopic disease
• Upper deep jugular
• Submandibular
• Jugulodigastric
• Midjugular
• Posterior cervical
• Retropharyngeal

23. 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

24. 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

25. 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)

26. 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#

27. 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

28. 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

29. 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

30. 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

31. 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

32. CONVENTIONAL TREATMENT SEQUALAE
Overall complication rate – 31 to 66%
• Temporal lobe necrosis
• Hearing loss
• Xerostomia
• Neck fibrosis
• Cranial nerve dysfunction
• Endocrine dysfunction
• Osteonecrosis
• Soft tissue necrosis
• Transverse radiation myelitis

34. 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

35. 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)

36. DELINEATION OF GTV-P

37. 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

38. 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

39. 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

42. 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

43. 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

46. DOSE CONSTRAINTS – RTOG 0225
Critical Intermediate Low risk
Brain stem 𝐷𝑚𝑎𝑥 < 54Gy Pituitary 𝐷𝑚𝑎𝑥 < 60Gy Parotid 𝐷𝑚𝑒𝑎𝑛 < 26Gy
Spinal cord 𝐷𝑚𝑎𝑥 < 45Gy TMJ 𝐷1% < 70Gy Glottic larynx 𝐷𝑚𝑒𝑎𝑛 < 45Gy
Optic chiasma 𝐷𝑚𝑎𝑥 < 54Gy Lens 𝐷𝑚𝑎𝑥 < 6Gy Cochlea 𝐷𝑚𝑒𝑎𝑛 < 50Gy
Optic nerve 𝐷𝑚𝑎𝑥 < 54Gy Eyeball 𝐷𝑚𝑒𝑎𝑛 < 35Gy Tongue 𝐷1% < 65Gy
Temporal lobe 𝐷𝑚𝑎𝑥 < 60Gy,
𝐷1%<65Gy

51. 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

52. 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

53. IMRT DOSE FRACTIONATIONS

54. 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

55. 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)

56. BRACHYTHERAPY
• Boost following RT
• Recurrent disease
• The addition of a brachytherapy boost to EBRT + CTH did
not improve outcome in loco-regionally advanced NPC

57. 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

58. 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

61. INTERMEDIATE (STAGE II) DISEASE
HIGH RISK FEATURES
Cervical lymph nodes ≥3 cm
Level IV or VB lymph nodes
Extranodal extension
Pretreatment plasma EBV DNA ≥4000 copies/mL
HIGH RISK
> 1 features
LOW RISK
None of the above

62. LOW RISK STAGE II

63. HIGH RISK STAGE II

64. Median FU: 60 months
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
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

65. HIGH RISK STAGE II

66. Median FU: 125 months
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
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

67. CISPLATIN – WEEKLY OR TRIWEEKLY?

68. 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.

73. Newly diagnosed
Nonmetastatic
Stage III – IVB
excluding T3-4N0
AJCC/UICC 6th edition
CRT f/b AC (Cisplatin + 5-FU)
N = 251
CRT alone
N = 257
Median FU: 68.4 months
5-year FFS (75% v 71%
, P = .45)
Late toxicities (grade 3-4, 27%
v 21%, p = 0.14)
AC failed to demonstrate
significant survival benefit
after CCRT in locoregionally
advanced NPC and did not
significantly increase late
toxicities.
Poor compliance- only 63%
received 3 cycles
Lei Chen et al.

74. 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

75. ADVANCED, NON-METASTATIC (STAGE III & IVa) DISEASE

76. Newly diagnosed
Nonmetastatic
Stage III – IVB
excluding T3-4N0
AJCC/UICC 7th edition
IC (Docetaxel, cisplatin and
5-FU) f/b CRT
N = 241
CRT alone
N = 239
Median FU: 45 months
3-yr FFS: 80% vs 72%,
p=0·034)
Grade 3 or 4 adverse events:
neutropenia 42% vs 7%,
leucopenia 41% vs 17%
stomatitis 41% vs 35%
Addition of TPF (IC) to CRT
significantly improved FFS in
LANPC with acceptable
toxicity. Long-term follow-up
is required to determine
long-term efficacy and
toxicities
Sun Y et al.

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

78. Newly diagnosed
Nonmetastatic
Stage III – IVB
excluding T3-4N0
AJCC/UICC 7th edition
ICT (gemcitabine
+ cisplatin)
f/b CRT
N = 242
CRT alone
N = 238
Median FU: 69.8 months
5-year OS: 87.9% v 78.8%, P = .001
Late toxicities - grade 3: 11.3% v 11.4%
Conclusion:
• IC + CRT significantly improved
RFS and OS compared with CRT
alone in LANPC
• Patients with a low
pretreatment cell-free Epstein-
Barr virus DNA load (< 4,000
copies/mL) might not benefit
from induction chemotherapy
(5-year OS, 90.6% v 91.4%, P =
.77)
Yuan Zhang et al.

79. 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

80. 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

81. POST TREATMENT SURVEILLANCE
Acute toxicities:
• Mucositis
• Dysgeusia
• Xerostomia
• Dysphagia
• Dermatitis
Late toxicities:
• Temporal lobe injury
• Cranial neuropathies
• Brachial plexopathy
• Hearing loss
• Xerostomia
• Dysphagia
• Soft tissue fibrosis
• Endocrinopathies (thyroid and
pituitary)

82. 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)

84. RECURRENT AND METASTATIC DISEASE

85. RECURRENT AND METASTATIC DISEASE

86. Problems:
• Dose to OARS by the primary course of 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

87. 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

88. 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

90. 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

91. Concurrent Cisplatin:
• 100mg/𝑚2
every 3weeks or @ 40mg/𝑚2
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

92. • 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

93. 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
SUMMARY

94. *Devita Principles and practice of cancer oncology

95. *Devita Principles and practice of cancer oncology