Carcinoma nasopharynx anatomy to management

carcinoma nasopharynx from anatomy to management with the latest ajcc staging

1. Carcinoma Nasopharynx Anatomy to Management By Dr. Ayush Garg

2. 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

3. 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.

4. 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

5. 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

6. 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

7. 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

8. 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 11 th , cranial nerve and the jugular lymph node chains, situated at the tip of the mastoid. To the Jugulo-digastric nodes (Lederman )

9. Different radiologic levels based on magnetic resonance imaging of 202 patients with nasopharyngeal carcinoma treated at pamela youde nethersole eastern hospital ( hong kong ). Level I-17% Level II-94% Level III-85% Level IV-19% Level V-53% Retropharyngeal -80%

10. 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.

11. 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.

12. 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

13. Etiology GENETIC ENVI RON MENT VIRAL

14. 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.

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

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

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 LATENT MEMBRANE PROTEINS (LMP) EBV-NUCLEAR ANTIGEN (EBNA) Viral Factors

18. Clinical Features

19. 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.

20. 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.

21. Superior Spread: Infiltration Of Orbital Cavity Via Inferior Orbital Fissure

22. Large tumour extending into nasal cavity,parapharyngeal & prevertebral space

23. 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.

24. Diagnostic evaluation

25. 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.

26. 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

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

28. 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 P referred 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

29. 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.

30. 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)

31. A:  Axial T1-weighted MRI demonstrating involvement of maxillary branch of trigeminal nerve by nasopharyngeal carcinoma (V 2 ) ( arrow ).   B:  Coronal contrast-enhanced MRI showing involvement of the trigeminal cave (also known as  Meckel’s cave ) by nasopharyngeal carcinoma ( arrow)

32. 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

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

34. 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

35. Metastatic Workup R outine: Chest X ray Additional: if clinically indicated or N3 disease CT Thorax: CT Abdomen: Bone Scan : PET-CT

36. 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

37. EBV specific Serological tests : Association of EBV with NPC (non keratinizing type) provides basis for serological test M ay enhance early detection of the primary disease/ relapses, supplement TNM staging & improve prognostication F or diagnosis : anti -VCA & anti EA Ab are both sensitive however IgA anti-VCA has better specificity  & may serve as screening test in high-risk patients. F or prognosis : prognostic effects of pre & post treatment Ab titre have been controversial due to inconsistent results in various studies T iters remained persistently high even in patients who achieved remission. T here 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)

38. 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

39. 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 NPC N 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

40. 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

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

42. Changes from 7th edition: T stage change The AJCC 8 th 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 7 th 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.

43. Changes from 7th edition: T stage change 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

44. Changes from 7th edition: T stage change 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

45. 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 greatest dimension, above the 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 greatest dimension, above the supraclavicular fossa*

46. 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**

47. Stage grouping Stage 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 7 th 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.

48. 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

49. 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

50. 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”

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

52. 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

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

54. 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.

55. 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

56. 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%).

57. 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.

58. 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

59. RADIATION THERAPY: Definitive treatment

60. 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

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

62. 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

63. 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.

64. 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 1/3 rd of maxillary sinus. Lateral and posterior oropharyngeal wall to the level of mid-tonsillar fossa Posterior 1/4 th of orbit ( Fletcher – YES, Perez - NO )

65. 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

66. 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.

67. 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)

68. Techniques Energy selection: Co 60 : 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.

69. 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

70. 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.

71. 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 Co 60 ) 5 ° – 0.5 cm 10 ° – 1.2 cm 5° 10° 1.2 0.5 1.1 2.5

72. Actual Implementation 270 ° 5 ° 275 ° Lateral Canthus

73. 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 1/3 rd and the anterior 2/3 rd of the vertebral bodies ( Co 60 ). 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.

74. 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

75. 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%

76. 4 field technique

77. Dose distribution

78. 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.

79. 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.

80. 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.

81. 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 #

82. Ho’s technique: Planning 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

83. Ho’s technique: Planning 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.

84. Ho’s technique: Planning 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#

85. Ho’s technique: Planning In patients with parapharyngeal disease a posterior oblique boost was given after the 2 nd 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.

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

87. Results by Ho’s Technique

88. Is Conventional Radiotherapy good enough for NPC?

89. 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

90. 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

91. 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

92. 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) = The entire nasopharynx, Anterior one-half to two-thirds of the clivus (entire clivus , if involved), Skull base (foramen ovale and rotundum bilaterally must be included for all cases), Pterygoid fossae, Parapharyngeal space, Inferior sphenoid sinus (in T3–T4 disease, the entire sphenoid sinus), and Posterior third to half of the nasal cavity and maxillary sinuses (to ensure pterygopalatine fossae coverage). The cavernous sinus should be included in high-risk patients (t3, t4, bulky disease involving the roof of the nasopharynx). Posterior ethmoid sinuses Include bilateral levels Ib to V and retropharyngeal/ parapharyngeal nodes for all cases .

93. 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

94. 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.

95. IMRT Target Delineation for Nasopharyngeal Carcinoma

96. IMRT Planning Flowchart

97. Immobilization

98. Imaging acquisition and contouring

99. List of structures contoured

100. MRI CT CT MRI

101. CT MRI FUSION

102. CTV

103. PTV 1

104. Combined PTV

105. Final Plan

106. DVH PTV Spinal Cord Parotid

107. DVH

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

109. IMRT Two opposed

110. IMRT Two opposed

111. DVH of 3-D CRT DVH of IMRT

112. 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

113. 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.

114. 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.

115. 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.

116. 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.

117. 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.

118. 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.

119. 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.

120. 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.

121. Dose Escalation ALTERED FRACTIONATION BRACHYTHERAPY

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

123. 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 Ra 226 tube String at either end of the cork

124. 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

125. 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)

126. 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

127. Technique of Insertion

128. 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.

129. 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

130. Prescription points BOS Pa R Na Re P OC C Pa Pa C R OC Re Re BOS BOS Na Na P No No No Line 1 Line 2 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

131. 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.

132. 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.

133. 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).

134. 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

135. 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/m 2  and doxorubicin 50 mg/m 2  or Epirubicin 75 mg/m 2 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.

136. 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

137. CHEMOTHERAPY Concurrent Chemo radiotherapy Neoadjuvant/induction Chemotherapy Adjuvant Chemotherapy RT

138. 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

139. 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).

140. 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. Th e 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

141. TRIALS FOR ADJUVANT CHEMOTHERAPY none achieved significant benefit in any endpoints

142. 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

143. 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 .

144. 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

145. 5 year update A 5-year update confirmed progression-free survival (58% vs. 29%) and overall survival (67% vs. 37%) in favour of CRT

146. 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

147. 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

148. Recurrence 2 types described (Wang et al) Persistent disease Relapse: Appearing 1 yr after treatment. Detecting recurrence: Tc 99m SPECT MRI – High signal intensity on T1 weighted spin echo images Options: Palliative treatment Radiation therapy Surgery

149. 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

150. 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

151. Results

152. 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%.

153. 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.

154. 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.

155. 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.

156. 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

157. THANK YOU