Cancer of nasopharynx.pptx radiation oncology aiims gkp

radiotherapy

1. Cancer of Nasopharynx Dr. Yamini Bisht Junior Resident Department of Radiotherapy AIIMS, Gorakhpur

2. ANATOMY The nasopharynx is a cuboidal chamber, slightly broader in the transverse dimension than the anterior–posterior dimension

3. BOUNDARIES OF NASOPHARYNX ANTERIOR : Continuous with the nasal cavity via the posterior choanae POSTERIOR : Superior pharyngeal constrictor muscle, pharyngobasilar fascia, and buccopharyngeal fascia ROOF : Basilar portion of the sphenoid and occipital bones FLOOR : Superior surface of the soft palate and nasopharyngeal isthmus. INFERIOR : Communicates with Oropharynx LATERAL : Pharyngotympanic tube (Eustachian tube) openings, which are bounded by a prominence known as the torus tubarius. Source: Vishram Singh

4. Source: Vishram Singh

5. Sagittal anatomic and T1-weighted, images of the nasopharynx illustrating normal anatomy. The sagittal projection demonstrates the normal adult contour of the nasopharynx. Note the sloping roof or vault, formed by the clivus and sphenoid sinus Axial T2-weighed image shows the tensor veli palatini muscle in the lateral wall, innervated by a branch of the mandibular division of the trigeminal nerve. The levator veli palatini muscle is innervated by the pharyngeal plexus. Bright parapharyngeal fat is evident lateral to the nasopharynx. normal mucosa of the torus tubarius and the mucosa lining the lateral recess ( yellow arrows). The prevertebral muscles are distinct from this mucosa.

6. FOSSA OF ROSENMULLER The pharyngotympanic tube (Eustachian tube) openings, which are bounded by a prominence known as the torus tubarius. The torus is formed by the cartilage of the pharyngotympanic tube elevating the mucous membrane of the lateral nasopharynx. Posterior to the torus is the pharyngeal recess otherwise known as the fossa of Rosenmüller. The lateral walls, including the pharyngeal recess (fossa of Rosenmüller), are the most common origin of nasopharyngeal malignancies.

7. Source: Perez and Brady

8. Axial CT at the level of nasopharynx

9. NERVE, ARTERIAL AND VENOUS SUPPLY NERVE SUPPLY ARTERIAL SUPPLY VENOUS SUPPLY AFFERENT: (anterior to the ET orifice) maxillary division of the trigeminal nerve (V2 ) Ascending pharyngeal artery, sphenopalatine artery, and the artery of the pterygoid canal. Pharyngeal plexus that drains into the internal jugular veins directly or via communication with the pterygoid plexus. Posterior to ET orifice: Glossopharyngeal Nerve MOTOR: pharyngeal branches of the glossopharyngeal nerve, vagus nerve, and sympathetic fibers from the superior cervical ganglion

10. Lymphatic Drainage Richest Lymphatic plexus in the Head and Neck region

11. 2 Major Lymph collectors 1) Lateral Pharyngeal Wall 2) Posterior Pharyngeal Wall Lateral pharyngeal node Jugulodigastric/subdigastric node (II,III,IV) 3rd, 4th and 5th nodes of the retropharyngeal group (VIIA) First node (node of Rouviere) of the retropharyngeal group (VIIA) Jugulodigastric nodes (II,III,IV) Superior-Posterior cervical Nodes (VA) Midjugular (III) Lower Jugular (IV) Posterior Cervical (V) Supraclavicular (IVB, VC)

12. BASE OF SKULL AXIAL CT OF SKULL BASE Source: Perez and Brady

13. Axial CT bone window of skull base from inferior to superior aspect showing major apertures of skull base

14. EPIDEMIOLOGY OF NASOPHARYNGEAL CARCINOMA Is an uncommon cancer in most parts of the world. The age-adjusted incidence rate (per 100,000 people per year) among men: 0.6 in the United States and Japan 26.9 in Hong Kong and Guangdong province in Southern China

15. NEW CASES: 6519 27 TH MOST COMMON DEATHS: 4780 INCIDENCE (PER 100,000): 0.54 5 YEAR PREVALENCE: 17,634

16. Source: GLOBOCAN 2022

17. A bimodal age distribution is observed in low-risk populations. The first peak incidence arises between 15 and 25 years of age, with the second peak at 50 and 59 years of age. In high-risk populations , the peak incidence occurs in the fourth and fifth decade of life . The male to female incidence ratio is 2:1 to 3:1

18. ETIOLOGY OF NASOPHARYNGEAL CARCINOMA GENETIC ENVIRONMENTAL VIRAL

19. GENETIC FACTORS Gene linked to HLA locus conferred a greatly increased risk of this disease. Several HLA haplotypes, including A2, B46, and B17, are associated with an increased risk of developing nasopharyngeal carcinoma

20. ENVIRONMENTAL FACTOR The high consumption of salted fish in Southern China has been implicated as an important environmental factor. Dimethylnitrosamine, a carcinogen found in salted fish , has been shown to induce carcinoma in the upper respiratory tract in rats. Other factors include alcohol consumption and exposure to dust, fumes, formaldehyde, and cigarette smoke

21. VIRAL FACTORS Epstein-Barr virus (EBV) has been associated with nasopharyngeal carcinoma, especially the nonkeratinizing type EBV’s tumorigenic potential is due to a set of latent genes, latent membrane proteins (LMP1, LMP2A, and LMP2B) and EBV-determined nuclear antigens (EBNA1 and EBNA2) LMP1 is the principal oncogene with evidence that the C-terminal activating regions of the protein activate a variety of signaling pathways including mitogen-activated protein (MAP) kinases, phosphoinositol-3-kinase (PI3K), nuclear factor κ-B (NF-κB), and epidermal growth factor receptor (EGFR).

22. EXTENSION

23. LOCAL EXTENSION: Anterior Common extension and infiltration of tumor into the nasal fossa. Invasion of the lateral wall of the nasal fossa can lead to involvement and destruction of the pterygoid plates. Beyond these structures, though less common, is invasion of the posterior ethmoid and maxillary sinuses. In advanced disease, infiltration of the orbital apex (typically through the inferior orbital fissure) can occur Axial post-contrast T1 weighted MRI showing a bulky nasopharyngeal carcinoma with gross extension into the right nasal cavity (arrows).

24. Superior and Posterior Extension Superiorly, tumors can directly invade the base of skull, the sphenoid sinus, and the clivus. The foramen lacerum, positioned directly above the pharyngeal recess (Rosenmuller fossa), is a vulnerable spot through which the tumor may enter the cavernous sinus and the middle cranial fossa to invade cranial nerves II to VI The foramen ovale also allows access for tumor to invade the middle cranial fossa, in addition to the petrous portion of the temporal bone, and the cavernous sinus. Posteriorly, invasion of the prevertebral (longus capitis) muscles is commonly seen. Axial post-contrast T1-weighted MRI showing a nasopharyngeal carcinoma with gross posterior retropharyngeal extension in the longus capitis muscles (asterisks), prevertebral space (long arrows), clivus (short arrows) and posterior cranial fossa (broken arrows).

25. Source: Perez and Brady

26. Inferior Extension Extension inferiorly to the oropharynx is not unlikely, with potential involvement of the tonsillar pillars, the tonsillar fossa, and the lateral and posterior oropharyngeal walls. In advanced disease, invasion of the C1 vertebra posteriorly and inferiorly can occur . Direct invasion of the soft palate is uncommon. Sagittal T1 weighted MRI showing a bulky nasopharyngeal carcinoma with inferior extension, crossing the C1/2 level, along the posterior wall into the oropharynx (arrow).

27. Lateral Extension Lateral extension occurs early with i nvolvement of the lateral parapharyngeal space along with invasion of the levator and tensor veli palatini muscles In advanced disease, invasion of the pterygoid muscles can occur. Direct extension of the tumor or l ateral retropharyngeal lymph node metastasis in the parapharyngeal space may lead to invasion or compression of cranial nerves IX to XI as they transpire the jugular foramen, cranial nerve XII as it emerges from the hypoglossal canal, and the cervical sympathetic nerves. Direct invasion or compression of the internal carotid artery can occur in advanced disease Tumor can directly i nvade the middle ear through the pharyngotympanic tube (Eustachian tube). Axial post-contrast T1 weighted MRI showing a nasopharyngeal carcinoma directly infiltrating into the left parapharyngeal space (arrow).

28. Source: Perez and Brady

29. Lymphatic Spread Up to 85% to 90% of cases present with lymphatic spread to the ipsilateral nodes Bilateral spread is present in approximately 50% of cases . Source: Perez and Brady

30. 2 Major Lymph collectors 1) Lateral Pharyngeal Wall 2) Posterior Pharyngeal Wall Lateral pharyngeal node Jugulodigastric/subdigastric node (II,III,IV) 3rd, 4th and 5th nodes of the retropharyngeal group (VIIA) First node (node of Rouviere) of the retropharyngeal group (VIIA) Jugulodigastric nodes (II,III,IV) Superior-Posterior cervical Nodes (VA) Midjugular (III) Lower Jugular (IV) Posterior Cervical (V) Supraclavicular (IVB, VC)

31. Source: Perez and Brady

32. Source: Perez and Brady

33. HEMATOGENOUS DISSEMINATION 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 > LUNGS > LIVER LUNG METS: BETTER PROGNOSIS Source: Cancer Med, Weiling Qu et al

34. CLINICAL PRESENTATION (1) Neck masses , usually appearing in the upper neck (2) Presence of tumor mass in the nasopharynx ( epistaxis, nasal obstruction and discharge), (3) Skull base erosion and palsy of cranial nerves V and VI because of tumor extension superiorly ( headache, diplopia, facial pain, and numbness ). Source: Perez and Brady

35. Cervical lymphadenopathy is present in up to 87% of patients. Typically, a mass is observable in the upper posterior neck and palpable beneath the superior portion of the sternocleidomastoid muscle close to the mastoid process. This is caused by metastasis to the parapharyngeal nodes or superior–posterior cervical nodes of the spinal accessory chain.

36. RECOMMENDED PRETREATMENT DIAGNOSTIC EVALUATIONS FOR NASOPHARYNGEAL CARCINOMA Medical history Physical examination: 1.Palpation of neck node (record size, laterality, and lowest extent of enlarged nodes) 2.Testing of cranial nerve (including assessment of vision and hearing functions) 3.Exclusion of gross signs of distant metastases 1.Fiber-optic endoscopy examination Nasopharyngoscopy and biopsies ± Panendoscopy 2.Otologic assessment Inspection of tympanic membranes (as clinically indicated) 3.Baseline audiologic testing (preferable) 4.Laboratory studies Complete blood count, Liver function tests (LFTs), Urinalysis. 5.EBV-specific serologic tests: Immunoglobulin A (IgA), Antiviral capsule antigen (VCA) titers Serum EBV DNA levels

37. Radiographic studies 1.Assessment of locoregional extent (imaging of the nasopharynx, paranasal sinuses, base of skull, nasal cavity, and neck) A.Magnetic resonance imaging (study of choice) B.Computed tomography (acceptable alternative) Chest radiograph (posterior–anterior and lateral) Additional metastatic workup if clinically indicated or N3 disease Positron-emission tomography (study of choice) Computed tomography of the chest and abdomen In patients with abnormal LFTs or clinical suspicion of lung or liver metastasis Bone scan In patients with advanced locoregional disease, symptoms suggestive of bone metastasis, or an elevated serum alkaline phosphatase

38. DIAGNOSTIC WORKUP Complete physical examination should include Thorough palpation of the neck Cranial nerve examination Percussion and auscultation of the chest Palpation of the abdomen for possible liver involvement Percussion of the spine and bones for possible bone metastasis.

39. CT VS MRI CT and MRI of the head and neck are useful in the evaluation of tumor erosion into the bony structures of the base of skull along with retropharyngeal and cervical lymphadenopathy. However, MRI is the preferred imaging technique in the staging evaluation of nasopharyngeal carcinoma. The current AJCC T classification requires a search for tumor invasion into the soft tissue (e.g., parapharyngeal space) and bony structures. MRI may be necessary for proper staging because CT has limitations in accurately defining tumor extension into these regions and MRI was used for the study that informed the updated 2017 AJCC system. MRI is superior to CT in delineating muscle and soft tissue involvement and examination of the skull base.

40. Ng et al. 54 compared MRI and CT in assessing the extent of disease. The study found a significantly higher sensitivity of MRI for skull base involvement (60% vs. 40%) , intracranial involvement (57% vs. 36%), retropharyngeal node (58% vs. 21%), and tumor infiltration of prevertebral muscles (i.e., longus colli muscles) (51% vs. 22%) compared to CT. By MRI, T-staging was modified in 27% of patients, with 22% being upstaged and 4% being downstaged.

41. When utilizing MRI, thin slices (3 mm) should be used for accurate staging. Thicker slices (e.g. ≥5 mm) risk misdiagnosis of what may be a higher T-stage disease.

42. Source: Perez and Brady

43. RADIOLOGICALLY POSITIVE LYMPH NODES According to a study by Van den Brekel et al., lymph node metastasis is commonly recommended to be radiologically defined by the presence of : Central necrosis Extracapsular spread Shortest axial diameter ≥10 mm (11 mm for the jugulodigastric node and 5 mm for the retropharyngeal node) A cluster of ≥3 lymph nodes that are borderline in size. Axial CECT

44. PET-CT FOR DISTANT METASTASIS Chang et al. demonstrated that [18F]fluorodeoxyglucose (FDG)-PET was superior to conventional workup (i.e., chest x-ray, isotope bone scan, and abdominal ultrasound) in the detection of distant metastases, where 12% of patients were upstaged to stage IVC. PET, in the study, offered a sensitivity and specificity of 100% and 90.1% , respectively. Source: Perez and Brady

45. HISTOPATHOLOGY Biopsy can typically be performed with local anesthesia in an outpatient setting. Biopsy by direct visualizatio n with general anesthesia may be necessary for diagnosis when the tumor is not visible or when the patient cannot cooperate. For suspicious cases of a nasopharyngeal primary tumor with lack of visible tumor, random biopsies of the most commonly involved sites are warranted: pharyngeal recess (fossa of Rosenmüller) on each of the lateral walls and superior–posterior wall of the nasopharynx. Non keratinizing SCC

46. FNAC Fine needle aspiration of a suspicious neck mass may establish the presence of metastatic nasopharyngeal carcinoma in the regional lymphatics. This may be performed prior to the biopsy of the nasopharynx when the primary tumor is not clinically detectable.

47. STAGING AJCC (2017)

48. Axial post-contrast T1 weighted MRI showing a nasopharyngeal carcinoma directly infiltrating into the left parapharyngeal space (arrow). Source: World Journal Of radiology

49. Axial T1 weighted MRI of the skull base showing five key bony sites to check for tumor invasion. A: Normal skull base showing T1W weighted signal of normal fatty bone marrow within the clivus (long arrow), bilateral pterygoid bases (short arrows) and petrous apices (broken arrows); B: Abnormal skull base showing loss of normal high T1 weighted signal due to tumor invasion of the clivus (long arrow), left pterygoid base (short arrow) and left petrous apex (broken arrow). Source: World Journal Of radiology

50. Coronal post-contrast T1 weighted MRI showing a nasopharyngeal carcinoma with direct infiltration through the sphenoid body (long arrows) into the sphenoid sinus (short arrows) and right cavernous sinus (broken arrows). Source: World Journal Of radiology

51. Bilateral metastasis in cervical lymph node(s), 6 cm or smaller in greatest dimension, above the caudal border of cricoid cartilage

52. 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

53. Source: AJCC 8th Edition

54. PATHOLOGICAL CLASSIFICATION Malignant nasopharyngeal tumors are: 80% to 99%: Carcinoma 5%: Lymphomas OTHER RARE cases: Adenocarcinoma, plasmacytoma, melanoma, and sarcomas Source: Perez and Brady

55. NASOPHARYNGEAL CARCINOMA KERATINIZING SQUAMOUS CELL CARCINOMA NON-KERATINIZING SQUAMOUS CELL CARCINOMA BASALOID SQUAMOUS CELL CARCINOMA DIFFERENTIATED UNDIFFERENTIATED

56. PROGNOSTIC FACTORS The extent of local invasion, regional lymphatic spread, and distant metastasis. (MOST IMPORTANT) Bone erosion Cranial nerve palsy Lower nodal level involvement Gross volume of Primary Tumor Better Prognosis in Females and younger patients Non Keratinizing And Undifferentiated carcinomas (More Radiosensitive) Plasma EBV DNA (Worse Prognosis) Over-expression of EGFR, HIF-α, VEGF

57. TREATMENT STRATEGY RADIATION THERAPY CHEMOTHERAPY SURGERY

58. RADIATION THERAPY PLANNING : Patient should be set up in a supine position with head extended for adequate separation between the primary tumor/retropharyngeal nodes and the upper neck nodes . The tip of the uvula and the base of the occiput should be on a parallel plane to the beam axis. The patient is immobilized with a thermoplastic mask covering the head to shoulder region For patients to be treated by conventional two-dimensional (2-D) technique, a mouth bite is useful to minimize the dose to the oral cavity with enlarged neck nodes to be marked with wire before imaging.

59. Source: Perez and Brady

60. DOSE TIME AND FRACTIONATION Better tumor control >70Gy in T1-T2 Tumors Fractional Dose of >2Gy to be avoided(Risk factor for Temporal lobe Necrosis) Interruption of RT >21 days: poorer Local Control 70Gy Over 7 weeks (GTV) 50-60Gy (Potential Risk sites)

61. Source: Perez and Brady

62. TUMOR TARGET VOLUMES Tumor Target Volumes The GTV should encompass the primary nasopharyngeal tumor, gross retropharyngeal lymphadenopathy, and gross nodal disease As determined by clinical, endoscopic, and radiologic examinations Lymph nodes ≥1 cm or with evidence of central necrosis are considered gross nodal disease . For patients given induction chemotherapy, it is recommended that the targets be determined by the prechemotherapy extent.

63. CTV (CLINICAL TARGET VOLUME) The clinical target volume (CTV) includes the GTV, regions of microscopic disease, and potential infiltrative spread. A gross disease CTV (CTV70) is defined as the GTV plus an additional margin of 5 mm to 1 cm surrounding all gross disease. The margin may be decreased to as small as 1 mm in critical regions near the brainstem or spinal cord.

64. The high-risk subclinical CTV (CTV59.4 ) encompasses the GTV including all potential areas of microscopic spread of disease. This volume should include at a minimum the entire nasopharynx, retropharyngeal lymph nodal regions, clivus, skull base, pterygoid fossae, parapharyngeal space, sphenoid sinus, posterior fourth to third of the nasal cavity, and posterior fourth to third of the maxillary sinuses. This CTV59.4 should also include lymph nodal groups that are at risk of potential microscopic disease spread: bilateral upper deep jugular (junctional, parapharyngeal), submandibular, subdigastric (jugulodigastric), midjugular, posterior cervical, and retropharyngeal lymph nodes. In patients with clinically N0 neck, it is not necessary to include level I nodal regions.

65. PTV (PLANNING TARGET VOLUME) The planning target volume (PTV) is defined as the CTV including a circumferential margin of typically 3 to 5 mm to all the CTVs to account for setup errors and potential patient motion. The PTV margin may be decreased to as small as 1 mm in regions near critical normal structures such as the brainstem or spinal cord.

66. PROPHYLACTIC NECK RADIATION Prophylactic neck radiation is usually recommended in N0 patients because of the high incidence of occult neck node involvement. Lee et al. found patients with a clinically negative neck who underwent elective neck irradiation had a significantly lower nodal recurrence rate than those untreated (11% vs. 40%). Additionally, even with successful salvage by subsequent treatment, patients with nodal recurrence had a significantly greater incidence of distant metastases than those without recurrence (21% vs. 6%)

67. CONVENTIONAL 2-D TREATMENT TECHNIQUES One of the most common RT approaches employed is comprised of two phases. Phase I consists of large lateral opposing faciocervical fields that encompass the primary tumor and the upper neck nodes in one volume, with a matching lower anterior cervical field for the lower cervical lymphatics. Phase II is used after 40 Gy to limit the dose to the spinal cord. This three-field technique includes lateral opposing facial fields coupled with anterior facial field for the primary tumor. Shrinking treatment fields by cone down after 50 to 60 Gy should be done, when possible, to increase protection of critical structures.

68. Conventional two-dimensional radiotherapy using Ho’s technique. A: Phase I, lateral-opposed faciocervical fields (I–II) and lower anterior cervical field (IVb). B: Phase II, sagittal view showing lateral-opposed facial fields and noncoplanar anterior facial field (III). C: Coronal view of anterior facial field (III). D: Anterior cervical field for whole neck (IV). Source: Perez and Brady

69. ADVANTAGE : The three-field technique in phase II allows the dose to be minimized to the temporomandibular joints and the bilateral temporal lobes. DISADVANTAGE : Coverage may not be sufficient for tumors with extensive posterior–lateral extension to the parapharyngeal spaces or caudal extension to the oropharynx. To remedy this deficit, an additional dose is delivered by a posterior–lateral field with avoidance of neurologic structures

70. IMRT TECHNIQUES Two different IMRT approaches are currently being utilized by different centers: (1) an extended whole-field (EWF) IMRT technique , in which the total target volume is encompassed in the IMRT plan, (2) a split-field (SF) IMRT technique, in which the target volumes superior to the vocal cords are treated with an IMRT plan and the lower neck nodes are treated with a conventional low anterior neck field. DISADVANTAGES: In SF, Perfect match between the IMRT fields and the low anterior neck field is not possible. With a EWF technique, an unnecessary dose of radiation is delivered to the normal glottic larynx. Whereas with the SF IMRT technique, the dose to the vocal cords is minimal because of shielding by a midline Cerrobend block or the multileaf collimator (MLC).

71. Isodose distributions in one NPC patient. The isodose distributions for one NPC patient (cT3N2M0) planned by 3DCRT (left) and IMRT (right) displayed on the A. axial, B. coronal, and C. sagittal planes. Color-wash areas: CTV-70: red; CTV-50: green. The red, blue, green, orange, and indigo lines were isodose curves of 70 Gy, 60 Gy, 50 Gy, 45 Gy, and 30 Gy.  

72. Source: Perez and Brady

73. Examples of MSKCC IMRT plans delivered with the dynamic multileaf collimator (MLC) system using a sliding window technique to patients with early and advanced disease, respectively. A total dose of 70 Gy at 2.12 Gy/fraction to the PTV gross disease and 59.4 Gy to the PTVhigh-risk subclinical is given over 33 once-daily fractions. For the low-neck, if split-field IMRT is used, a dose of 50.4 Gy at 1.8 Gy/fraction/day is generally prescribed. However, if the low-neck is included in the IMRT fields and is considered at low risk for nodal involvement, the PTV low-risk subclinical typically receives 54 Gy at 1.64 Gy/fraction/day.

74. Source: Perez and Brady

75. BRACHYTHERAPY FOR DOSE ESCALATION IN PATIENTS TREATED WITH CONVENTIONAL 2D technique Intracavitary insertions or interstitial implants have been used in T1 to T3 nasopharyngeal carcinomas as a boost treatment following external beam radiation therapy (EBRT) or in the treatment of recurrent disease , either alone or in combination with EBRT.

76. Brachytherapy is not suitable for treatment of tumors with intracranial extension because of the rapid reduction of dose as distance from the radioactive source increases. Since the advent of IMRT as primary radiotherapy for nasopharyngeal carcinoma, the use of brachytherapy as a boost treatment following definitive IMRT has dramatically declined. In the past, intracavitary brachytherapy was delivered using low–dose rate (LDR) techniques. However, currently remote afterloading and fractionated high–dose rate (HDR) techniques are more commonly used

77. LIMITATION : The dose delivered is adequate only for superficial nonbulky tumors. Furthermore, optimal positioning of the applicators depends both on the individual clinician’s skill and the patient’s anatomic features.

78. Endocavitary brachytherapy for nasopharyngeal carcinoma. A: The Rotterdam nasopharyngeal applicator. B: The simulator check-film showing the position of the radioactive sources and the dose distribution. Source: Perez and Brady

79. STEREOTACTIC RADIOSURGERY Stereotactic radiosurgery or fractionated radiotherapy allows for precise delivery of highly conformal RT with a rapid dose falloff and provides an alternative for dose escalation

80. Hara et al. reported a study of 82 patients with T1 to T4 tumors showing excellent 5-year L-FFR of 98% after receiving a median SRT boost of 12 Gy (range, 7 to 15 Gy) following EBRT to 66 Gy . However, despite the addition of concurrent chemotherapy in 76% of the patients, the distant failure rate was 32% and OS was 69%. With a median follow-up of 40.7 months for living patients, 12.1% of patients developed radiographic temporal lobe necrosis (only 2.4% were symptomatic with seizures) and 3.6% developed retinopathy. The risk was especially high in patients with T4 tumors

81. RESULT OF RADIOTHERAPY Dose escalation with intracavitary brachytherapy if using non-IMRT treatment techniques has been shown to improve local control. Stereotactic radiosurgery boost after external beam radiotherapy (both conventional and IMRT) has also shown improved local control. Nonkeratinizing squamous cell carcinoma (both differentiated and undifferentiated subtypes) had improved local control rates when compared to keratinizing squamous cell carcinoma in T2 to T3 lesions but not in T1 or T4 lesions. Source: Perez and Brady

82. Source: Perez and Brady

83. TOXICITY AFTER RT Temporal lobe necrosis Hearing loss Xerostomia Neck fibrosis Cranial nerve dysfunction Endocrine dysfunction Soft tissue necrosis Osteonecrosis Transverse radiation myelitis Source: Perez and Brady Toxicity Incidence (%) Temporal Lobe Necrosis 1.1-3 Brain Stem Encephalopathy 1-2.4 Cranial Neuropathy 3.3-6.8 Endocrine Dysfunction 3.5-8.6 Severe Epistaxis 0.3-1.2 Carotid Rupture 0.6 Hearing Loss 2.6-8.2 Trismus 0.6-5.1 Dysphagia 4.2 Soft Tissue Fibrosis 1.4-15.9

84. Temporal Lobe Necrosis Most troublesome complication. 65% of all irradiation-induced deaths Hallucinations, absence attacks, déjà vu; 31% Headaches, confusion, convulsions, or hemiparesis: 14% Dizziness, poor memory, or sudden changes in behavior : 39% Whereas 16% were asymptomatic Axial T2

85. Cranial Neuropathy Cranial nerves IX through XII, particularly XII, are the most frequently impaired by radiation This is related to marked radiation fibrosis, especially in patients who receive an additional boost dose to the parapharyngeal space. Common symptoms include s lurring of speech, twitching of neck muscles, and/or dysphagia. Risk of Aspiration Pneumonia: 77%

86. Oral Complications Xerostomia is an almost universal complication from treatment with conventional RT and may lead to dental caries. Dental sequelae frequently accompany xerostomia.: OSTERADIONECROSIS (4.4%) Prophylactic fluoride treatment should be employed to prevent dental decay, and decayed teeth should be extracted prior to RT to reduce this risk.

87. Aural Toxicity Hearing loss has always been a common radiation sequela Increasing use of cisplatin-based concurrent CRT has resulted in deafness rates as high as 42% Sensorineural hearing loss (SNHL) (high-frequency range): 30% patients Mean cochlea dose should be <48 Gy to minimize damage Eustachian tube damage resultis in otitis media . Lowering the dose to the external auditory canal and mastoid air cells can reduce the incidence and severity of acute external otitis and chronic serous otitis media, respectively

88. Carotid Artery Injury Carotid stenosis is a potentially fatal complication reported in patients who undergo irradiation of the head and neck region. Interval from radiotherapy was a significant independent predictor for severe carotid stenosis. Some have advocated for routine duplex ultrasound screening for high-risk patients (older than 60 years, smoking, hypertension, hypercholesterolemia, cerebrovascular symptoms). Severe cases may require carotid endarterectomy or endoplasty. Massive bleeding from ruptured pseudoaneurysms at the petrous portion of the internal carotid has been reported following IMRT with dose escalation. Urgent diagnosis and intervention with endovascular occlusion or stenting may be needed to prevent fatal consequences. Other concerns include severe telangiectasia and hypervascularization in the internal maxillary artery territory , for which emergency embolization may be considered. MR angiography showing left ICA occlusion

89. Endocrine Dysfunction The most common endocrine sequelae are amenorrhea and/or galactorrhea from hyperprolactinemia in female patients and followed by hypothyroidism and hypoadrenalism . Lam et al. : 5-year incidence of 62% , with dysfunction detected as early as 1 year following RT. The deficiency of releasing of inhibitory factors indicated that the hypothalamus is the primary location of damage. As many of these dysfunctions may be corrected pharmacologically, routine evaluation of hypothalamic, pituitary, and thyroid function should be considered in the follow-up examination of long-term survivors. Shielding may help lessen endocrine dysfunction when using 2-D technique. The need for maximum conformity to protect normal tissues during radiotherapy is paramount.

90. Second Malignancies Radiation-induced malignancy is rare, with an incidence of 0.04% and latency period >10 years. The most common histologic types are maxillary osteosarcoma and soft tissue sarcoma. Surgery presents the only chance of cure, but the prognosis is often poor. Although second primary head and neck cancer is relatively uncommon for NPC patients. Teo et al. reported an excessive incidence rate of tongue cancer at 0.13% per patient-year . The possibility of radiation carcinogenesis cannot be excluded.

91. CHEMOTHERAPY Nasopharyngeal carcinoma is generally regarded to be a highly chemosensitive disease. Although radiotherapy alone is the standard treatment for stage I NPC, concurrent chemoradiotherapy (CRT) with or without adjuvant chemotherapy is the current standard for locally advanced disease (stages III to VB)

92. Multivariate analyses found that the number of chemotherapy cycles was the only independent factor associated with improved OS, progression-free survival, and distant control. With the addition of chemotherapy, an increase in acute side effects was observed, but no significant increase in late effects was reported.

93. CONCURRENT CHEMORADIOTHERAPY CRT is the standard approach in stage III, IVA, and IVB NPC Weekly CDDP of 40mg/m 2

94. Other Chemotherapy Agents Weekly oxaliplatin (70 mg/m2) Carboplatin Cetuximab to target epidermal growth factor receptor (EGFR; EGFR overexpression is observed in >80% of NPC patients) Bevacizumab , to exploit the angiogenesis pathway (vascular endothelial growth factor; VEGF is overexpressed in about two-thirds of NPC patients)

95. Adjuvant Chemotherapy Cisplatin and 5FU Compliance with adjuvant chemotherapy can be especially difficult, as patients are recovering from the acute effects of CRT. Randomized trials comparing RT alone to RT plus adjuvant chemotherapy have all been negative to date.

96. Neoadjuvant Chemotherapy Patients treated with induction chemotherapy had significantly higher 3-year disease-free survival (82.0% vs. 74.1%, P = .028) with a strong trend for improved 3-year distant failure-free survival (86.0% vs. 82.0%, P = .056); There was no difference in overall survival Toxicity was significantly increased during concurrent chemoradiation in patients who received induction.

97. Preferred Regimens: Gemcitabine/cisplatin Docetaxel/cisplatin/5-FU (dose-adjusted) Other Recommended Regimens Cisplatin/5-FU5 Docetaxel/cisplatin

98. PERSISTENT/RECURRENT NPC Aggressive salvage treatment is usually advocated. Several approaches can be used successfully, including surgery, brachytherapy, and EBRT. Chemotherapy is generally used in conjunction with local treatment in patients with advanced disease.

99. Early Detection and Diagnosis Distinction should be made between persistent disease (tumors that do not completely regress following primary treatment) and recurrent disease (tumors that re-emerge after initial complete regression) because the prognoses and therapeutic considerations are different. Better survival and control rates for persistent disease.

100. It is important to avoid both unnecessary overtreatment and excessive delay in treatment An observation period of 10 weeks before additional treatment is recommended

101. Follow Up Early detection of locoregional failure is crucial for a better chance of salvage, and regular follow-up after completion of primary treatment is recommended. Frequently used methods include manual palpation, rigid nasopharyngeal endoscopy and nasopharyngeal biopsies, imaging techniques (e.g., CT and MRI), and serologic tests (e.g., anti-EBV titers, plasma EBV DNA levels).

102. Nasopharyngoscopy is more sensitive than CT and MRI in detecting tumor persistence/recurrence and is the preferred method for initial screening. If a patient presents with suspicious endoscopic findings or elevated anti-EBV titers, a nasopharyngeal biopsy is performed to confirm diagnosis. CT or MRI is performed upon a confirmed diagnosis to delineate the tumor extent. Although MRI has limitations in separating tumor recurrence from radiation fibrosis, it is superior to CT in demonstrating extent of soft tissue tumors, as well as identifying submucosal infiltration, marrow infiltration in the skull base, perineural invasion, and intracranial spread.

103. MIBI SPECT Technetium-99m methoxyisobutylisonitrile (MIBI) single-photon emission computed tomography (SPECT) may be a useful tool for differentiating persistent or recurrent tumor from radiation fibrosis . Was shown by Kostakoglu et al. to be superior to MRI performed at 3 to 6 months post-RT in diagnosing complete response.

104. FDG PET vs MRI FDG-PET and MRI were compared in 67 NPC patients 4 to 70 months after completion of RT and found FDG-PET superior to MRI in all aspects in detection of local recurrence, with increased sensitivity (100% vs. 62%) and specificity (93% vs. 44%). It may also contribute useful information to questionable findings on MRI. Axial fused PET/CT image and axial T1-weighted contrast-enhanced MR images. MR images reveal large nasopharyngeal mass with involvement of skull base and prevertebral space.

105. Additional Radiation for Persistent Disease Excellent results have been reported when using brachytherapy for locally persistent disease after a full course of EBRT. With 5-year L-FFR in the range of 87% to 95% for patients with initial T1 tumors.

106. Stereotactic RT is a valuable alternative for delivering additional EBRT. Yau et al . studied 755 patients with T1-4 tumors and found that 7% had positive biopsies 8 weeks after completion of primary RT. Twenty-one patients were treated with fractionated stereotactic RT to a median dose of 15 Gy and achieved a 3-year L-FFR of 82% , which was similar to the corresponding L-FFR of 86% in the complete responders and was significantly better than the corresponding L-FFR of 71% in 24 patients treated with high–dose rate brachytherapy to a median dose of 20 Gy.

107. Reirradiation for Recurrent Disease Various radiation therapy modalities are used to treat recurrent NPC, including intracavitary brachytherapy, external beam irradiation, interstitial implantation, particle beam radiotherapy, and stereotactic radiosurgery IMRT has also been used with excellent preliminary results, with control rates of up to 100% for rT1-3

108. IMRT for Recurrent Cases IMRT, 60 to 70 Gy is recommended Taking into account factors such as previous radiation amount, overlap between previously treated area and target for reirradiation, interval between RT courses, tumor bulk, and whether concurrent chemotherapy will be given.

109. Brachytherapy for Recurrent NPC Brachytherapy has been widely used for treatment of recurrent NPC and can be used effectively on its own for early-stage recurrent NPC. Using interstitial implants with radioactive gold grains , Kwong et al. reported a 5-year L-FFR of 63%; complications included headache (28%), palatal fistula (19%), and mucosal necrosis (16%). Law et al. 273 achieved excellent local salvage up to 89% using iridium mold, but the complication rate was 53%.

110. Combination of Brachytherapy and EBRT Useful, particularly when conventional 2-D technique is used. Lee et al. showed that patients reirradiated by combined modalities had an improved 5-year L-FFR of 45% compared with 32% by EBRT alone and 29% by brachytherapy alone. Also demonstrated fewer late grade 3 or higher events compared with patients receiving EBRT alone (8% vs. 73%, respectively).

111. Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy for Recurrent NPC It allows for rapid falloff of radiation dose outside tumor volume and near surrounding critical structures. Can be used either alone for smaller lesions or in combination with EBRT for larger ones. Control rates ranging from 53% to 86% have been reported. For advanced recurrence with extension beyond the nasopharynx, this method offers better dose coverage than brachytherapy . A higher salvage rate from adding stereotactic radiation as a boost after EBRT has been reported.

112. Although most series reported a low risk of complications, massive hemorrhage with potential fatal outcome has been described. Radiosurgery should thus be avoided when there is direct tumor encasement of the carotid artery or when a high cumulative dose has already been delivered.

113. Proton Beam Therapy for Recurrence Proton-beam therapy (PBT) allows for delivery of r adiation therapy dose distributions that are typically more conformal than can be achieved with IMRT. This is due to, a phenomenon known as the Bragg peak. PBT is especially useful in the setting of reirradiation , where it is critically important to minimize overlap of radiation fields from multiple treatments , particularly for the dose to surrounding sensitive organs such as the cranial nerves and brain.

114. An analysis of dose volume histograms from patients who underwent reirradiation with PBT for recurrent NPC found that: Significantly improved outcomes (overall survival of 83% for optimal coverage, 17% for suboptimal coverage) A multi-institutional study: found a favorable toxicity profile compared to historical controls of patients retreated with photon techniques. Low risk of grade 3+ dermatitis (8.7%) and dysphagia (7.1%) . However, two deaths occurred as a result of bleeding events, reflecting the increased risk of serious vascular toxicity with a second course of radiotherapy.

115. Chemotherapy for recurrent NPC Chemoradiotherapy may also improve treatment outcome for recurrent NPC in certain patients, and most recent salvage radiation series have included cisplatin-based chemotherapy for advanced-stage disease Using gemcitabine and cisplatin as induction chemotherapy followed by reirradiation with IMRT in 20 patients (95% rT3-4), Chua et al.reported a 1-year local salvage rate of 75%.

116. Surgical Management Radical neck dissection Indications : Persistent Nodal Disease with no distant metastasis. May achieve a 5-year nodal control rate of 66% and disease-free survival rate of 37%

117. Surgical Mangement of Primary Site: Salvage surgery by nasopharyngectomy Challenges: Obtaining adequate exposure and obtaining adequate surgical margins.

118. THANK YOU