Cancer of the Nasal Cavity.pptx radiation oncology

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1. Cancer of the Nasal Cavity & Paranasal Sinuses DR ANJALIKRISHNA NP PG RESIDENT RADIOTHERAPY AIIMS GORAKHPUR

2. ANATOMY OF NASAL CAVITY Extends from the Hard palate inferiorly to the Base of the skull superiorly.

3. NASAL CAVITY PROPER Each nasal cavity has a lateral wall, a medial wall, a roof and a floor.

4. Connections superior meatus posterior  ethmoidal air cells  and  sphenoid sinuses  via the  sphenoethmoidal recess   2 middle meatus frontal sinus  via frontal recess anterior ethmoidal air cells and  maxillary sinuses  via  ostiomeatal complex inferior meatus nasolacrimal duct   3

5. A coronal computed tomography scan shows middle and inferior turbinates ( asterisks ) and vertical lamella of the middle turbinate attached to the cribriform plate ( arrow ).

6. Coronal CT highlighting the anterior OMU anatomy: A = antrum; B = ethmoid bulla; U = uncinate process; MT = middle turbinate; white line = infundibulum; star (*) = maxillary sinus ostium. The anterior ostio meatal unit (OMU) is the key to the drainage of the anterior sinuses (frontal, anterior ethmoidal, and maxillary)

7. 7 Paranasal Sinuses Maxillary sinuses - Largest, 15 ml volume Ethmoidal Sinuses - Anterior, Middle & Posterior group Frontal Sinuses Sphenoidal Sinus Sinuses are lined with pseudostratified ciliated columnar epithelium The purpose of the paranasal sinuses is to lighten the bone and give resonance to the voice Snell’s Clinical Anatomy by Regions, 9 th ed.

8.   A sagittal computed tomography (CT) scan shows frontal recess of the frontal sinus, hiatus semilunaris, middle meatus ( arrow ), spheno ethmoid recess, and middle and inferior turbinates ( asterisks )

9.   An axial CT view shows sphenoethmoid recesses ( arrows )

10. SINONASAL MALIGNANCIES

11. Sinonasal malignancies are uncommon and heterogenous group of tumors Age > 40 years except esthesioneuroblastoma Cancer of the maxillary sinus is the most common of the sinonasal malignancies Incidence of nodal involvement : 10-15 % for maxillary & ethmoid sinus 5-10 % for nasal cavity 11 Introduction to Sinonasal Tumors Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

12. 12 Risk Factors Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed. Adenocarcinomas of the nasal cavity and ethmoid sinus - carpenters and sawmill workers who are exposed to wood dust Synthetic wood, binding agents, and glues as cocarcinogens. Squamous cell carcinomas of the nasal cavity - nickel workers Maxillary sinus carcinomas - radioactive thorium containing contrast material (Thorotrast) used for radiographic visualization of the maxillary sinuses Occupational exposure in the production of chromium, mustard gas, isopropyl alcohol, and radium Ill-fitting dentures, cigarette smoking and alcohol consumption

13. SITES Nasal vestibule Nasal cavity PARANASAL SINUSES Maxillary sinuses Frontal sinuses Ethmoid sinuses Sphenoid sinus 13

14. Local extension – commonest Lymphatic – 10% More in SCC & poorly diff ca Perineural spread – adenoid cystic ca Hematogenous - rare 14 Pattern of Spread Fletcher’s Textbook of Radiotherapy, 3 rd edition

15. 15 Pattern of Spread NASAL CAVITY CARCINOMA Fletcher’s Textbook of Radiotherapy, 3 rd edition Nasal Cavity – 1 – anterior cranial fossa, ethmoid cells, orbit, sphenoid sinus, Base of skull, 2 - upper nasal cavity; 3 – Maxillary sinus; 4 – Antrum, 5 – Nasopharynx Coronal Section Sagittal Section

16. Pattern of Spread of Maxillary Sinus carcinoma Anteriorly : cheek, skin Posteriorly : pterygopalatine fossa, infra temporal fossa, temporal bone middle cranial fossa Medially : nasal cavity, Nasolacrimal duct. Laterally : cheek, skin Superiorly : orbit, ethmoid sinuses Inferiorly : palate, buccal sulcus 16 Fletcher’s Textbook of Radiotherapy, 3 rd edition

17. 17 A line from medial canthus of the eye to the angle of the mandible Divides the maxillary sinus into antero-inferior ( infrastructure ) & posterosuperior ( suprastructure ) parts. Infrastructure: Good prognosis Suprastructure : Early extension (eye, skull base, pterygoids, infratemporal fossa) Ohngren’s Line Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

18. 18 Pattern of Spread Fletcher’s Textbook of Radiotherapy, 3 rd edition Frontal – 1-nasion, 2- ethmoid, 3- frontal lobe Sphenoid – 1 - NPX, 2 - middle cranial fossa, 3- post ethmoid cells & nasal cavity Ethmoid : 1- c/l ethmoid, 2- maxilla, 3- orbit, 4- nasal cavity, 5- sphenoid- BOS- NPX, 6- frontal sinus-cribriform plate-ant cranial fossa, 7-frontonasal angle

19. 19 Gray’s Anatomy, 41 st ed. Lymphatics of the Nasal Cavity The lymphatic drainage of the nasal cavity can be divided into two. The main part of the nasal cavity drains via the nasopharynx to the retropharyngeal nodes and upper deep cervical nodes (levels IIA and IIB). The lower anterior portion drains to the submandibular (level IB), parotid (preauricular) and jugulodigastric (level IIA) nodes. Walter & Miller’s Textbook of Radiotherapy, 7 th ed.

20. Lymphatic drainage is typically towards the retropharyngeal (Rouviere’s node) and upper deep cervical nodes (level II) unless the tumour is particularly anteriorly placed when the buccinator, level I and IIA nodes are at risk. The lymph system is remarkably sparse and, as such, tumors can be quite advanced without involved nodes. 20 Lymphatics of the Paranasal Sinuses Walter & Miller’s Textbook of Radiotherapy, 7 th ed.

21. Usually present as asymptomatic plaques or nodules. Are essentially skin cancers. Advanced lesions may extend beyond the vestibule and may cause pain , bleeding , or ulceration. Can spread by direct invasion or lymphatic spread; the latter is usually to the ipsilateral facial (buccinator and mandibular) and submandibular nodes . Lesions extending across the midline may spread to the contralateral nodes. The incidence of nodal metastasis at diagnosis is approximately 5%. 21 Clinical Presentation of Nasal Vestibule Carcinomas Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

22. Nasal cavity tumors present with symptoms and signs of nasal polyps, hence delaying the diagnosis. In case of advanced tumors, signs and symptoms according to the extent of involvement seen. Tumors arising in the upper nasal cavity and ethmoid cells can extend to the orbit (lamina papyracea) and to the anterior cranial fossa (cribriform plate). 22 Clinical Presentation of Nasal Cavity Carcinomas Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

23. Usually diagnosed at advanced stages. Symptoms and signs are : facial swelling, pain/paraesthesia, epistaxis, nasal discharge and obstruction, alveolar or palatal mass, unhealed tooth socket proptosis, diplopia, impaired vision, or orbital pain due to orbital invasion. Suprastructure tumors tend to show extensive local spread and have a poorer prognosis. The maxillary sinuses are believed to have a limited lymphatic supply and a correspondingly low incidence of lymphadenopathy at diagnosis. 23 Clinical Presentation of Maxillary Sinus Carcinomas Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

24. Central or facial headaches Referred pain to the nasal or retrobulbar region Subcutaneous mass at the inner canthus Nasal obstruction and discharge Diplopia, and proptosis   24 Clinical Presentation of Ethmoid Sinus Tumors Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

25. Diagnostic Workup 25 General – Complete history including occupational exposure Physical examination : Inspection and palpation of the orbits, nasal and oral cavities, and nasopharynx, assessment of cranial nerves Other – Dental evaluation with extractions/restorations as needed Baseline ophthalmologic examination Baseline speech and swallowing assessment if surgery is planned Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

26. 26 Inspection Done with anterior and posterior rhinoscopes. To note the following: Deformity – congenital or acquired Shape – Deviation of septum Colour - Inflammation Mass - Size, shape, number, bleeding, discharge, fungation , ulceration Palpation Mass - Size, shape, number , friability, mobility, consistency Clinical Examination

27. Diagnostic Workup 27 Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed. Radiographic – Fiberoptic endoscopic examination (after mucosal decongestion) with biopsies CT/MRI of the primary site and neck Chest x-ray; X-ray PNS, CT thorax if adenoid cystic or neuroendocrine carcinoma CT : 85% accuracy. Good for bone erosion in orbital walls, cribriform plate, fovea ethmoidalis Difficult to see periorbital involvement, differentiate tumor, inflammation and secretions.

28. Diagnostic Workup 28 Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed. Radiographic – MRI: 94% accuracy As a single modality gives more information than CT Good for : Fluid vs inflammation vs tumor Perineural spread, involvement of cranial nerve foramens & canals Intracranial or leptomeningeal spread Skull base erosion Better visualize lesions involving the cribriform plate, basisphenoid and floor of middle cranial fossa Orbital involvement

29. Diagnostic Workup 29 Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed. Radiographic – X-ray PNS Opacification of sinuses Soft tissue mass Bony erosion / destruction Site of origin Water’s (Occipitomental) view - maxillary antrum, portion of sphenoid, oblique portion of frontal sinus, anterior ethmoid Caldwell (Occipitofrontal) view – frontal, posterior ethmoid Lateral view – sphenoid sinus

30. Normal Lateral View Normal Calwell’s view Water’s View - Rt Maxillary sinusitis 30

31. STAGING AJCC 8 th

32. AJCC TNM Staging 32 AJCC Cancer Staging Manual, 8 th ed. Maxillary Sinus : T category T criteria Tx Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor limited to maxillary sinus mucosa with no erosion or destruction of bone

33. AJCC TNM Staging 33 AJCC Cancer Staging Manual, 8 th ed. Maxillary Sinus : T category T criteria T2 Tumor causing bone erosion or destruction including extension into the hard palate and/or middle nasal meatus, except extension to posterior wall of maxillary sinus and pterygoid plates

34. AJCC TNM Staging 34 AJCC Cancer Staging Manual, 8 th ed. Maxillary Sinus : T T criteria T3 Tumor invades any of the following: Bone of the posterior wall of maxillary sinus, Subcutaneous tissues, Floor or medial wall of orbit, Pterygoid fossa, Ethmoid sinuses

35. 35 AJCC Cancer Staging Manual, 8 th ed. Maxillary Sinus : T category T criteria T4a Moderately advanced local disease Tumor invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribriform plate, sphenoid or frontal sinuses

36. 36 AJCC Cancer Staging Manual, 8 th ed. Maxillary Sinus : T T criteria T4b Very advanced local disease Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve (V2), nasopharynx, or clivus M category M criteria M0 No distant metastasis M1 Distant Metastasis

37. 37 AJCC Cancer Staging Manual, 8 th ed. Nasal Cavity and Ethmoid Sinus : T category T criteria Tx Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor restricted to any one subsite, with or without bony invasion

38. 38 AJCC Cancer Staging Manual, 8 th ed. Nasal Cavity and Ethmoid Sinus : T category T criteria T2 Tumor invading two subsites in a single region or extending to involve an adjacent region within the nasoethmoidal complex, with or without bony invasion

39. 39 AJCC Cancer Staging Manual, 8 th ed. Nasal Cavity and Ethmoid Sinus : T category T criteria T3 Tumor extends to invade the medial wall or floor of the orbit, maxillary sinus, palate, or cribriform plate

40. 40 AJCC Cancer Staging Manual, 8 th ed. T category T criteria T4a Moderately advanced local disease Tumor invades any of the following: Anterior orbital contents, Skin of nose or cheek, Minimal extension to anterior cranial fossa, Pterygoid plates, Sphenoid or frontal sinuses Nasal Cavity and Ethmoid Sinus :

41. 41 AJCC Cancer Staging Manual, 8 th ed. T category T criteria T4b Very advanced local disease Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than (V2), nasopharynx, or clivus

42. Regional Lymph Nodes 42 AJCC Cancer Staging Manual, 8 th ed. N category Clinical N criteria (cN) Pathological N criteria (pN) Nx Regional lymph nodes cannot be assessed Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE (-) Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE (-) N2a Metastasis in a single ipsilateral lymph node, larger than 3 cm but not larger than 6 cm in greatest dimension and ENE (-) Metastasis in a single ipsilateral lymph node, larger than 3 cm but not larger than 6 cm in greatest dimension and ENE (-) OR Metastasis in a single ipsilateral or contralateral node, 3 cm or smaller in greatest dimension and ENE (+)

43. 43 AJCC Cancer Staging Manual, 8 th ed. N category Clinical N criteria (cN) Pathological N criteria (pN) N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension and ENE (-) Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension and ENE (-) N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension and ENE (-) Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension and ENE (-) N3a Metastasis in a lymph node, larger than 6 cm in greatest dimension and ENE (-) Metastasis in a lymph node, larger than 6 cm in greatest dimension and ENE (-) N3b Metastasis in any lymph node(s) with clinically overt ENE (+) Metastasis in any lymph node(s) with clinically overt ENE (+) OR Metastasis in single ipsilateral node, larger than 3 cm in greatest dimension and ENE (+) A designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L)

44. AJCC Prognostic Stage Grouping 44 AJCC Cancer Staging Manual, 8 th ed. T N M Stage Tis N0 M0 T1 N0 M0 I T2 N0 M0 II T3 N0 M0 III T1, T2, T3 N1 M0 III T4a N0, N1 M0 IVA T1, T2, T3, T4a N2 M0 IVA Any T N3 M0 IVB T4b Any N M0 IVB Any T Any N M1 IVC

45. 45 Histology Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed. Most common: squamous cell carcinoma 80 to 90 % Adenocarcinoma Adenocystic carcinoma and minor salivary gland tumour -10 to 15% Lymphoma – 5% Melanoma – 1% Others: Esthesioneuroblastoma RMS Mid line lethal granuloma– NK T cell lymphoma Extramedullary plasmacytoma Sinonasal Undifferentiated Carcinoma

46. Squamous cell carcinoma Most common type(80%) ; M>F, 50-70 years Location: Maxillary sinus (70%) and lateral nasal wall(20%) 90% have local invasion & present in advanced stages(T3/4) Lymph node metastases is more common than most other paranasal sinus malignancies(10-20%) Local recurrence rates are quite high, as high as 30% to 40% Complex 3-D anatomy makes clear margins difficult to achieve. 46

47. Nasal vestibule SCC can spread by direct invasion of the upper lip, gingivolabial sulcus, premaxilla (early events), or nasal cavity (late events) Computed tomography scans of a nasal vestibule SCC that has spread by direct invasion of the upper lip (arrow in A) and gingivolabial sulcus and premaxilla (arrow in B and C).

48. Adenocarcinoma Most often seen in ethmoid sinuses High grade: solid growth pattern with poorly defined margins. 30% present with metastasis Low grade: uniform and glandular with less incidence of perineural invasion/metastasis. 48

49. Adenoid Cystic Carcinoma About 3% to 15% of these paranasal sinus malignancies are adenoid cystic carcinoma . 3rd most common site of ACC is the nose/paranasal sinuses Perineural spread upto the base of the skull It is occurs most frequently in women 50-70 years Despite aggressive surgical resection and radiotherapy, most grow insidiously. ACC is a radiosensitive tumor; however, in most patients, radiation is not the only cure. Advantage of using postoperative radiation therapy is to clear positive margins that are left after surgery 49

50. Aggressive, high incidence of recurrence, distant metastasis & perineural spread Recurrence or metastasis can occur even decades after treatment. Poor prognosis Cytological diagnosis of ACC: The typical morphology is the presence of hyaline globules (basement-membrane like material) surrounded by tumor cells. a ,  b  Cell block preparation showed classical cribriform pattern of ACC with IHC positivity for c-Kit ( c ,  d ) (H&E, × 10,× 40

51. a ,  b  O/E a diffuse swelling over the root of nose, measuring approx. 2 × 2 cm, hard and cystic in feel, non-tender, overlying skin was pinchable;  c ,  d ,  e  CT scan of paranasal sinuses showed a large mass lesion involving the nasal cavity with bony destruction of nasal septum, thinning of nasal turbinate’s, deossification of hard palate, nasal bones &medial wall of the maxillary sinuses

52. Muco epidermoid Carcinoma Extremely rare Most patients present with low stage disease (stage I and II), although invasive growth is common with higher grade disease. 12-09-2024 52

53. An interesting case: A middle aged man with previous FESS for sinonasal polyposis underwent NECT at a private center f or recurrent nasal blockade & anosmia This CT was reported as persistent sinonasal polyposis with rarefication of bones due to long standing inflammation

54. Olfactory Neuroblastoma / Esthesioneuroblastoma R are malignant neuroectodermal neoplasm arising from the neuroepithelium. M ost commonly within the nasal cavity olfactory recess. 3% of intranasal tumors. Originate from stem cells of neural crest origin that differentiate into olfactory sensory cells. Aggressive behavior, with 50-75% local spread 20-30% distant mets . 12-09-2024 54

55. Esthesioneuroblastoma may be mistaken for any other “ small round cell tumor ,” The expansile tendency of olfactory neuroblastoma is characterized by bowing of the sinus walls. The destructive aspect is manifested as tumor replacing the turbinates , septum, and sinus walls with extension into contiguous areas. Difficulty breathing due to nasal stuffiness and fullness was the most common presenting symptom in patients with intranasal ENB. The Hyams system divides the spectrum of disease into four histopathologic grades, ranging from most differentiated (grade I), to least differentiated (grade IV), based on features such as tumor architecture, mitotic activity, nuclear polymorphism and presence of necrosis.

56. CT: Cribriform plate destruction, bony remodelling of nasal cavity MRI: Intermediate-high signal on T2, dumb-bell shaped, avid enhancement, cysts in intracranial component, T2*GRE- blooming foci

57. MRI showing a large left-sided nasal cavity mass with intracranial and orbital extension. There is a notable mass effect on the globe causing compression, proptosis and stretching of the optic nerve.   Biopsy confirmed Esthesioneuroblastoma

58. The most common route of spread for ENB is into the paranasal sinuses, followed by intracranial spread. These local routes of spread are most commonly staged by the Kadish staging system. Cervical nodal metastases have also been found up to a rate of 44%, with spread most commonly seen to level II lymph nodes. Spread to retropharyngeal lymph nodes has also been reported.  Much rarer is distant spread to the thorax and skeleton. .

59. Staging Most commonly used is the modified Kadish staging Stage Group Description A Confined to nasal cavity B Extends into the paranasal sinuses C Extends beyond the nasal cavity and paranasal sinuses including involvement of the cribriform plate, skull base, orbit, or intracranial cavity D Nodal/ Distant Metastasis 59

60. Kadish A Surgery / radiotherapy alone Adjuvant RT is indicated in close and positive margins or with residual disease No adjuvant chemotherapy Kadish B Surgery followed by adjuvant RT Kadish C Craniofacial resection  post op chemoradiation NACT -> surgery (craniofacial resection)  post op chemoradiation or chemoradiation ( unresectable cases) Kadish D Systemic chemotherapy and palliative RT to local and metastatic sites 12-09-2024 60

61. Melanoma 0.5- 1.5% of melanoma originates from the NC and PNS The nasal cavity is the most common origin of head and neck mucosal melanomas (55–79%) Anterior Septum: most common site IHC markers include S-100 protein, HMB-45, melan -A, tyrosinase , etc. Treatment is wide local excision with/without postoperative radiation therapy .Local, regional, and systemic recurrence rates of 20%, 50%, and 80%, respectively seen with lung involvement most common Classically poor prognosis with 5yr survival of about 11% 12-09-2024 61

62.   (a)  Endoscopic photograph of the lesion shows a nonmelanotic nasal septal lesion (asterisk, nasal septum; arrow, lateral nasal wall).  (b)  A preoperative coronal CT scan showing a left nasal septal lesion.  (c)  An intraoperative picture demonstrating exposure of the lesion. The type of surgery is planned according to the extent of the tumor. For small tumors involving the nasal septum, resection of the tumor along with the perichondrium and septal cartilage can be performed via lateral rhinotomy incision.

63. Rhabdomyosarcoma Most common paranasal sinus malignancy in children Rhabdomyosarcoma ( RMS ) originates from immature mesenchymal cells that are committed to skeletal muscle differentiation. It is a fast growing , highly malignant tumour . • It is more commonly found in paediatric age group , constituting 6 % of all malignancy in children below 15 years age . • It is less common in adults. • Commonly involved sites are head & neck region , genitourinary tract , retroperitoneum and to lesser extent extremities . • RMS of paranasal sinuses constitutes 10 -15 % of adult head and neck RMS . • Ethmoidal and maxillary sinuses being most common 63

64. Imaging studies of sinonasal tract rhabdomyosarcoma. a A coronal computed tomography scan shows a large destructive mass in the maxillary sinus, expanding into the orbit and nasal cavity. b A MRI (sagittal) T1 SE image shows a large destructive mass within the sinonasal tract. c An axial MRI T2 axial image shows a destructive mass breaking though the medial wall of the maxilla. d A fused PET/CT image shows high avidity in the nasal cavity and maxillary sinus tumor

65. Surgical resection is difficult and ChemoRT is the treatment of choice Commonly used chemotherapy drugs include Vincristine, Actinomycin D, Cyclophosphamide, Ifosfamide , and Etoposide A radiation dose of 50.4 GY/28#/5.5 wks is recommended. Aggressive chemo/XRT has improved survival from 51% to 81% in patients with cranial nerve deficits/skull/intracranial involvement Other sarcomas: Osteogenic Sarcoma is the most common Mandible > Maxilla

66. Lymphoma Usually Non- Hodgkins type DLBCL are the most common followed by NK-T cell lymphomas Highly Radio and chemosensitive NK-T cell Lymphoma: often EBV positive. More common in NC SMILE/GELOX chemo f/b RT 45-60 Gy DLBCL: More common in PNS R-CHOP f/b IFRT 30-36Gy/15-20# Survival: Around 50-65% at 5 years. Survival drops to 10% in case of recurrent lesions 66

67. Patient name ; Radheshyam Dx ; NHL NASAL CAVITY C1 CHOP started on 3/10/23 Image 1 ; prechemo image image 2 ; post 6 cycles of chemo

68. SMILE Day 1:  Methotrexate 2g/m 2  IV Days 2–4:  Dexamethasone 40mg IV or orally + leucovorin 15mg × 4 doses/day IV or orally + ifosfamide 1500mg/m 2  IV + etoposide 100mg/m 2  IV Days 8, 10, 12, 14, 16, 18, and 20:  L-asparaginase 6000U/m 2  IV. Repeat every 21 days for 3 cycles. GELOX 5 Day 1:  Oxaliplatin 130mg/m 2  IV + pegaspargase 2500U/m 2  IM Days 1 and 8:  Gemcitabine 1000mg/m 2  IV. Repeat every 21 days for a maximum of 6 cycles (including 3 cycles induction chemotherapy for stage stage IE/IIE patients followed by involved-field radiotherapy) R  –  r ituximab   C  –  c yclophosphamide   H  –  doxorubicin  ( h ydroxydaunomycin ) O  –  vincristine  ( O ncovin ®) P  –  p rednisolone (a  steroid ).

69. Hemangiopericytoma Originate from pericytes of Zimmerman Present as rubbery, pale/gray, well circumscribed lesions resembling nasal polyps Treatment is surgical resection with postoperative XRT for positive margins 69

70. What is your diagnosis? An elderly lady with long standing nasal blockade & recurrent epistaxis

71. Sinonasal Undifferentiated Carcinoma Rare non-squamous cell type tumor Elderly > 60 years Aggressive & high propensity for distant metastasis; perineural spread Unlike ENB, it extends beyond sinonasal cavity Diagnosed on pathological differentiation after ruling out melanoma, lymphoma, and olfactory neuroblastoma IHC can help in diagnosis: CK-8, p16 positive EBV and HPV-DNA negative. 12-09-2024 71

72. CT: Typically large enhancing mass, aggressive bony destruction, often erode cribriform plate, dumbbell shape due to intracranial component MRI: Low-intermediate T2 signal, areas of necrosis, heterogenous enhancement

73. Surgery, when feasible, may improve local control ( Reiersen et al) Resectable or marginally resectable : Primary surgery followed by adjuvant chemo-radiotherapy may be preferable May consider induction chemotherapy (Cyclophosphamide/Doxorubicin/Vincristine) followed by reassessment for surgery ( Musy et al) Unresectable: Concurrent chemoradiation Induction chemotherapy followed by concurrent chemoradiation ( Rischen et al) Optimal sequence of modalities and choice of chemotherapy regimen is still unclear

74. Treatment algorithm of Sinonasal Carcinoma

75. T1-2N0 Resection → post-op RT for close margin, PNI, adenoid cystic ca. For + margin, re-resect (if possible) → post-op RT T3-4N0 Resectable: Resection → post-op RT or chemo-RT Unresectable: Definitive RT or chemo-RT Concurrent chemo for margin positive ,ECE/PNI 75 Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

76. N+ Resection + neck dissection → post-op RT or chemo-RT. Alternatively, definitive chemo-RT Elective Nodal Irradiation In T3/T4 tumors, Histology: Squamous cell Ca or Undifferentiated carcinomas Level Ib, II and Retropharyngeal LNs are included. 76 Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

77. Perineural spread & its impact on treatment Depiction of perineural spread helps in individualisation of radiation field Perineural spread to foramen rotundum & cavernous sinus suggests low probablity of cure with radiotherapy Adenoid cystic carcinoma Rhabdomyosarcoma Mucoepidermoid carcinoma PPF + Maxillary N PPF + Vidian N +GSPN + Facial N PPF + Greater palatine nerve

78. RADIOTHERAPY as management option for sinonasal malignancies. Because these cancers are usually diagnosed at a locally advanced stage and surgery is the primary therapy, most patients receive postoperative radiation therapy. Addition of RT to surgery improves 5-years survival (44%) when compared to RT alone (23%) or surgery alone. 78 Cengiz et al. Sinonasal Tract Malignancies: Prognostic Factors and Surgery Outcomes

79. Definitive : Medically inoperable or who refuse radical surgery or early lesions Adjuvant : standard of care High risk features, close or positive margin, ECE/PNI perineural invasion ( PNI ) and extracapsular extension ( ECE) Palliative Metastatic disease Postoperative radiation therapy is started 4 to 6 weeks after surgery. Pre- and postoperative radiation may result in similar control rates. But post-operative RT preferred: Preoperative radiation increases the infection rate and the risk of post-operative wound complications. Preoperative radiation may obscure the initial extent of disease surgery can not remove the microscopic extensions of  the tumor. 79 Radiotherapy : Indications Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

80. Objective: To attain adequate tumor coverage Deliver uniform dose distribution throughout target volume Minimize doses to normal tissue Head Immobilization : with thermoplastic mask fixed to the couch Shoulders : positioned as caudally as possible 80 Radiotherapy : Planning and Simulation Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

81. Eyes open, straight ahead to keep posterior pole away from high dose region Tongue blade/cork to depress tongue out of fields Fill surgical defects with tissue equivalents to reduce dose heterogeneity For Post Operative Patients: all surgical scar, drain sites, and stoma should be wired on skin 81 Radiotherapy : Planning and Simulation Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

82. Nasal Vestibule

83. Small, well-differentiated lesions measuring  1.5 cm  small fields with a 1- to 2-cm margin are appropriate. All poorly differentiated tumors & well- differentiated primaries of >1.5 -2 cm without palpable lymphadenopathy  includes both nasal vestibules with at least 2- to 3-cm margins around the primary tumor (wider margins for infiltrative tumor) as well as bilateral facial, submandibular, and subdigastric nodes. Position : supine, neck slightly flexed to align anterior surface of maxilla parallel with the top of the couch 83 Radiotherapy Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

84. Anterior Portal Superior - bridge of the nose or higher in large tumor Inferior - depends on extent of upper lip invasion( from mid upper lip to vermillion border) Lateral portals- about 1 cm lateral to ala nasi Used when tumor size is > 1.5-2 cm Anterior right and left oppositional electron fields (usually with an approx. 15-20 degree) are used to treat facial lymphatics . 84 Borders Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

85. Lateral Portals Medial - lateral border of anterior field Anterior - oral commissure to middle of horizontal ramus of mandible Posterior - upper edge of anterior field to just above angle of mandible Inferior - split horizontal ramus of mandible and adjoins the upper neck field The combination of all three fields is known as moustache field 85 Borders

86. Upper neck field portal Used for tumor > 1.5 -2 cm in size Upper neck node are treated by parallel opposed photon field. Anterior - 1 cm fall off Posterior - just behind mastoid process Superior - matched to moustache field Inferior - just above arytenoid 86 Borders

87. Small lesions- (<1.5-2 cm) – combination of electrons and photons - 50 Gy in 25 # f/b 10-16 Gy boost in 5 to 8 # (prescribed at 90% isodose line) Larger lesions- 50 Gy in 25 # f/b 10-16 Gy boost by EBRT + elective treatment to facial (moustache area) and upper node ( 50 Gy) Palpable neck node receive a total dose of 66-70 Gy Post – op : volume is reduced off the undissected nodal regions after 50 Gy to deliver an additional 6 Gy to the surgical bed f/b 4 Gy to pre-op tumor bed = total 60 Gy 10 Gy to pre-op tumor bed in limited excision or positive margins – total 66 Gy 87 Dose Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

88. Criteria – lesions of nasal cavity and external nares lesions on the septum or the mucosa medial to ala nasi – distal 1/3 of nasal cavity Preferable for relatively smaller lesion. Using  Ir 192 wire implant or intracavitary mold. Recommended dose LDR: 60-65 Gy over 5-7 days LDR Boost: 20-25 Gy over 2 days [After EBRT 50 Gy] – median overall treatment time of 36 days HDR : 18 Gy @ 3Gy/# , 2#/d Dose prescription: 0.5 cm lateral to the tumor for lateral nasal vestibule At the center of the tumor for tumors of the septum 88 Brachytherapy Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

89. 25 Gy administered by an interstitial low-dose-rate iridium needle implant at 0.55 Gy per hour. G: Dummy wires are inserted into each hollow tube. Each tube has a ball anchor at the distal end of the needles, which is pushed snugly against the skin and sutured to the skin. Note the placement of transverse “moustache” needles. H,I: Orthogonal x-ray (anteroposterior, lateral) films taken to document the placement of the needles. CT-based planning was performed. J,K: Live sourc.es in situ. 89 Ir-192 wire implant Perez & Brady's Principles and Practice of Radiation Oncology 6 th Ed

90. 90 Mould brachy: A custom mold of the nasal vestibule is made and 2-4 plastic tubes (1.0-cm apart) inserted in the mold alongside the tumor.

91. An 87-year-old man presented with epistaxis. A biopsy of a 1-cm lesion at the anterior left nasal septum was positive for well-differentiated squamous cell carcinoma. CT of the head and neck reveals the lesion ( a ). He was treated with brachytherapy. Ten stainless-steel needles were placed in the left nasal ala, nasal tip, and left nasal septum ( b ) and were afterloaded with  192 Ir wires. A total dose of 60 Gy was delivered over 3.5 days. CT dosimetry was obtained and isodose distributions are shown on an axial plane through the tumor ( c ) and on a lateral view ( d ). The patient had no evidence of disease and no symptoms 3 years after treatment.

92. Maxillary Sinus

93. 93 Gunderson’s Clinical Radiation Oncology, 4 th ed.

94. Both halves of nasal cavity Ipsilateral maxillary sinus Ethmoid sinus and ipsilateral medial orbital wall – if the tumor extends superiorly into the ethmoid cells Target Volumes Fletcher’s Textbook of Radiotherapy, 3 rd edition

95. Supine Head – slightly hyperextended to bring the floor of the orbit parallel to the axis of the field Intraoral stent – to open mouth & depress tongue Orbital exenteration defect or palatal resection defect filled by a water filled balloon or tissue equivalent material to compensate for tissue defect Patient Setup Fletcher’s Textbook of Radiotherapy, 3 rd edition

96. Anterior field : Superior : Supraorbital ridge Inferior : Angle of mouth Medial : Contralateral medial canthus Lateral : Falling off the skin. When there is no gross involvement of the orbit, the cornea, lens & lacrimal gland are shielded. If there is disease in the orbit, cornea is spared by cutting out the cast and treating with the eyes open. 96

97. Lateral fields: Superior : Floor of anterior cranial fossa. Anterior : Lateral canthus parallel to the slope of face Posterior : covers the pterygoid plates. It is angled 5-10 degree posteriorly so that the exit beam avoids the opposite eye Optic chiasma & hypothalamus are shielded from the lateral field 97

98. Upfront radiotherapy 50 Gy in 25 # to initial target volume 16 to 20 Gy in 8-10 # to the boost volume Post op Radiotherapy Dose 60 Gy in 30 # for -ve margin 66 Gy in 33 # for +ve margin Gross residual disease- 70 Gy 98 Dose Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

99. I/L upper neck irradiation given to patient with squamous cell carcinoma or undifferentiated carcinoma, and in stage T3 to T4 Borders- lateral portal Superior- sloping up from the horizontal ramus of the mandible to the inferior border of primary portals posteriorly Anterior- just behind oral commissures Posterior- At the mastoid process Inferior – Thyroid notch B/L neck node treatment indicated with palpable nodes 99 Neck Node Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

100. Nasal Cavity and Ethmoid Sinus

101. If the ethmoid sinuses are extensively involved but there is no clinical or radiographic evidence of orbital involvement, a portion of the orbit (one-half to three-fourths) is usually irradiated to approximately 45 Gy for possible microscopic disease extension. Portals are then reduced to transect the ipsilateral eye medial to the limbus. This technique usually prevents severe lacrimal or retinal injury, but does produce a cataract 101 Ethmoid Sinus Fields

102. Advanced orbital invasion requires irradiation of the entire orbital contents and ethmoid sinus lesions. The inferior border must be shaped to cover the lowest extent of disease. If the temporal fossa is grossly invaded, the lateral border of the anterior portal is usually allowed to fall off for all or part of the treatment. The lateral portals for ethmoid is same as nasal cavity and maxillary sinus lesions. 102 Ethmoid Sinus Fields

103. Post-op RT 50 Gy/25 # / 5 weeks to initial target volume Boost – 10 Gy/ 5# (-ve margins) ; 10-16 Gy/ 5-8 # (+ve margins) Definitive RT 50 Gy/ 25 #/ 5 weeks to initial target volume Boost – 16-20 Gy/ 8- 10 # Pre-op RT 50-60 Gy/ 25-30 # Palliative RT 30 Gy/10 # , 20 Gy/ 5#, 8 Gy/ SF Doses Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

104. 104 Nasal Cavity and Ethmoid Sinus Fields Fletcher’s Textbook of Radiotherapy, 3 rd edition Unilateral ethmoid/nasal cavity involvement Field for ethmoid/nasal cavity tumor with spread to the ipsilateral maxillary antrum

105. 105 Nasal Cavity and Ethmoid Sinus Fields Fletcher’s Textbook of Radiotherapy, 3 rd edition C. Portal for ethmoid/nasal cavity tumor with invasion of the maxillary antra bilaterally D. Portal for bilateral ethmoid/nasal cavity tumor or involvement of sphenoid sinus (with left corneal eye block)

106. Why? Irregular shaped tumors Close proximity to radiosensitive normal tissues Retina, optic nerve, optic chiasma, brain, brain stem Advantages Better target coverage Dose homogeneity Dose escalation Sparing of normal critical structures Conformal RT and IMRT

107. GTV CTV 1 - primary tumor bed with 1.0- to 1.5-cm margin of normal tissue. CTV 2 - operative bed, including the bony orbit after orbital exenteration and the ethmoid, frontal, or sphenoid sinuses if explored during surgery. CTV 3 – encompass the tract of cranial nerve V2 to the foramen rotundum if perineural invasion is present. CTV HR - may also be outlined to cover, for example, gross macroscopic residual tumor or positive margins to which a higher dose may be delivered 107 IMRT Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

108. Definitive RT Target Description Dose (33-35#) GTV Gross tumor volume 66-70 Gy CTV1 (primary CTV) GTV + 1- 1.5 cm 66-70 Gy CTV2 (intermediate dose CTV) CTV1 + 1-1.5 cm 59-63 Gy CTV3 (elective CTV) Nodal volume, nerve tract , BOS margin 56-57 Gy Post-op RT (adjuvant RT) Target Description Dose (30 #) CTV – HR Suspected +ve margin ; residual 66-70 Gy CTV 1 (primary CTV) Tumor bed + 1-1.5 cm 60 Gy CTV2 (intermediate dose CTV) Surgical bed 56 Gy CTV3 (low dose CTV) Tract of V2 if perineural invasion +nt ; BOS margin ; elective nodal (if indicated) 54 Gy IMRT Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

109. EVIDENCE N = 81 40 patients with cancer of the paranasal sinuses (n = 34) or nasal cavity (n = 6) received postoperative IMRT to a dose of 60 Gy (n = 21) or 66 Gy (n = 19). Retrospectively compared with that of a previous patient group (n = 41) who were also postoperatively treated to the same doses but with three-dimensional conformal radiotherapy without intensity modulation. Median follow-up was 30 months (range, 4–74 months). Two-year local control, overall survival, and disease-free survival were 76%, 89%, and 72%, respectively. 12-09-2024 109 doi:10.1016/j.ijrobp.2009.09.067

110. 110 Compared to the three-dimensional conformal radiotherapy treatment, IMRT resulted in significantly improved disease-free survival (60% vs. 72%; ).

111. 111 The use of IMRT significantly reduced the incidence of acute as well as late side effects, especially regarding skin toxicity, mucositis, xerostomia, and dry-eye syndrome.

112. Heavy-ion therapy Use of particles more massive than protons or neutrons, such as  carbon ions. Higher biological efficiency . Role in radioresistent tumors such as adenocarcinoma, adenoid cystic carcinoma, malignant melanoma and sarcoma Due to the higher density of ionization, more DNA damage in cancer cells 112

113. TREATMENT ACCOMPANIMENTS ACUTE MORBIDITY Fatigue Dermatitis, Skin erythema Mucositis – nasal > oral Xerostomia Conjunctivitis, epiphora , blurring of vision Alopecia Raised ICT LATE MORBIDITY Late skin effects – erythema, fibrosis, telengectasia Atrophic mucositis – septal perforation Cataract, dry eye syndrome, optic neuritis, Chronic keratitis Xerostomia Facial asymmetry Osteoradionecrosis Second malignancies Neuro endocrine abnormalities(Hypopituitarism) 12-09-2024 113

114. 114 Dose Limitations Lens <10 Gy (cataracts) Retina <45 Gy (vision) May go higher if treating bid or partial volume. Optic chiasm and nerves <54 Gy at standard fractionation Brain <60 Gy (necrosis) Mandible ≤ 70Gy or 1cc PTV not more than 75Gy (osteoradionecrosis) Parotid mean dose <26 Gy Lacrimal gland <30–40 Gy Pituitary and hypothalamus mean dose <40 Gy Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

115. Treatment delivery and patient care Nasal cavity synechiae can be prevented by intermittent dilation of the nasal passages with a petroleum based jelly-coated cotton swab until mucositis has resolved. Dry mucosae can be managed symptomatically with saline nasal spray. Oro-dental hygiene Exercises to reduce trismus Prophylactic feeding tubes Ophthalmic review and Lubricating eye ointments If there is a pre-existing facial nerve palsy, the eyelid should be taped shut at night to avoid a dry eye. Pituitary function tests should be carried out annually during follow-up to evaluate late radiotherapy effects to the pituitary gland. Xerostomia can be an acute as well as late effect and can de decreased by administering Amifostine . 115

116. 116 Follow up and Recurrence Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed. Follow up Every 4 months for first three years Every 6 months for fourth and fifth year Annually for life Recurrence : Salvage surgery after primary radiation Salvage radiation after primary surgery Cumulative doses of radiation to neural tissues, namely, spinal cord, brainstem, brain, optic structures are the main limitation to re-irradiation

117. Chronic keratitis and iritis (dry-eye syndrome ) : If tumor extension to the orbital cavity mandates irradiation of the lacrimal gland to doses of more than 30 to 40 Gy . Without lacrimal irradiation, fewer than 20% of patients treated with up to 55 Gy to the cornea develop chronic corneal injury There is an approximately 5% risk (at 5 years) of cataract formation after doses of up to 10 Gy to the lenses using conventional fractionation; this risk increases to 50% at 5 years after 18 Gy . Radiation retinopathy is rare after doses of less than 45 Gy, but the incidence increases to about 50% after doses of 45 to 55 Gy . The reported incidence of optic neuropathy is <5% after 50 to 60 Gy but increases to around 30% for doses of 61 to 78 Gy 117 Sequelae Perez & Brady's Principles and Practice of Radiation Oncology, 6 th ed.

118. conclusion Sinonasal malignancies are uncommon and heterogenous group of tumors They usually present in locally advanced stages and surgery is the mainstay of treatment RT is often used in adjuvant settings and sometimes alone as definitive RT RT has advanced a long way from era of conventional RT to 3D conformal RT, IMRT . Modern techniques like Proton, IMPT and Carbon ion therapy have enabled dose escalation to tumor tissue and reduced normal organ toxicity SBRT/SRS has shown promise in delivering high dose per fraction, thus reducing the treatment time to a few days 118

119. THANK YOU