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Nasopharyngeal carcinoma management principles
- 1. MANAGEMENT OF NASOPHARYNGEAL CANCER Dr.Sachin Sakthivel, Junior Resident, Dept. of Radiotherapy &Radiation Medicine, SSH,IMS,BHU
- 3. Medial and lateralpterygoid muscle involvement from T4 to T2 Prevertebral muscle involvement as T2
- 4. Replace the supraclavicularfossa (SCF) with the lower neck Merge N3a and N3b into N3
- 6. T4 and N3merged into stage IVA
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- 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
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- 13. IS THERE AROLE 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 themainstay 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 • Entireneck is at high risk for microscopic disease • Upper deep jugular • Submandibular • Jugulodigastric • Midjugular • Posterior cervical • Retropharyngeal
- 23. HO’S TECHNIQUE Three fieldarrangement: • 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 – fieldPhase 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 facialfields: • 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 CERVICALFIELD 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 asymmetricaljaws: • 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 • 40-44Gy 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 anteriorextension: • 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 • 4field 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 Overallcomplication 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: • Supineposition, 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)
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- 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: baseof 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: • >70Gyequivalent • 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 ANDSCHEDULE 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 ANDSCHEDULE 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.
- 54. RADIATION DOSING ANDSCHEDULE 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 ANDSCHEDULE 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 followingRT • Recurrent disease • The addition of a brachytherapy boost to EBRT + CTH did not improve outcome in loco-regionally advanced NPC
- 57. LIMITATIONS AND CURRENTSTATUS • 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
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- 63.
- 64. Median FU: 60months 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.
- 66. Median FU: 125months 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 – WEEKLYOR TRIWEEKLY?
- 68. ADVANCED, NON-METASTATIC (STAGEIII & 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 (650mg/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 (STAGEIII & 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 StageIII 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 T3N0disease – 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 Acutetoxicities: • 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 • Clinicalexamination • 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 METASTATICDISEASE
- 85. RECURRENT AND METASTATICDISEASE
- 86. Problems: • Dose toOARS 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 Gradeof 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 Gradeof 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 every3weeks 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, highEBV 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 inthe 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 andpractice of cancer oncology
- 95. *Devita Principles andpractice of cancer oncology