Sino-Nasal Carcinoma

1. Radiotherapy in Sinonasal Cancer: Moving From Adjuvant to Definitive Treatment Dr. Malhar Patel, DNB Consultant Radiation Oncologist CIMS Cancer Center CIMS Hospital

2. Anatomy

3. Introduction Very rare - < 3% of head and neck cancers (1 in lakh) [1] Classified as undifferentiated neuroendocrine tumor Originates from nasal cavity/paranasal sinus epithelium Disease is typically locally advanced at presentation Can involve orbit/skull/brain 10-30% present with clinically positive lymph nodes [2] Distant metastasis unusual – Bone & Lungs (Recurrent Disease) Treatment failure – Local and distant recurrence 1. Chambers KJ, Lehmann AE, Remenschneider A, et al. Incidence and survival patterns of sinonasal undifferentiated carcinoma in the United States. J Neurol Surg B Skull Base 2015;76:94–100. 2. Reiersen DA, Pahilan ME, Devaiah AK. Meta-analysis of treatment outcomes for sinonasal undifferentiated carcinoma. Otolaryngol Head Neck Surg 2012;147:7–14.

4. NCCN Staging

5. Stage Characteristics A Confined to nasal cavity B Confined to nasal cavity and paranasal sinus C Beyond nasal cavity and paranasal sinus KADISH Staging *Originally described for esthesioneuroblastoma (ENB)

6. Facts Exceedingly rare and aggressive tumor Poor prognosis – Late diagnosis (>80% Stage IV) [1] Early detection - chemotherapy, radiation, and/or surgery The literature is sparse - no consensus for optimal treatment. Surgical candidates - vast skill required – R0 – Reconstruct [2,3] 1. Lin EM, Sparano A, Spalding A, et al. Sinonasal undifferentiated carcinoma: a 13-year experience at a single institution. Skull Base 2010;20:61–7. 2. Righi PD, Francis F, Aron BS, et al. Sinonasal undifferentiated carcinoma: a 10 year experience. Am J Otolaryngol 1996;17:167–71. 3. Chen AM, Daly ME, El-sayed I, et al. Patterns of failure after combined-modality approaches incorporating radiotherapy for sinonasal undifferentiated carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2008;70:338–43.

7. Carcinoma Maxilla

8. Primary treatment - Surgical resection. Open surgery, and now endo- scopic resection Silent disease – Late diagnosis Anatomical Challenge!! In-complete resection Limiting oragan preservation Radiotherapy – Definitive ot Adjuvant

9. Surgery or Radiation??? 1. Jeng Y, Sung M, Fang C, et al. Sinonasal undifferentiated carcinoma and nasopharyngeal-type undifferentiated carcinoma: two clinically, biologically, and histopathologically distinct entities. Am J Surg Pathol 2002;26:371–6. 2. Musy PY, Reibel JF, Levine PA. Sinonasal undifferentiated carcinoma: the search for a better outcome. Laryngoscope 2002;112:1450–5. Current literature focuses on comparing the survival probabilities of patients who undergo surgery, radiation, chemotherapy, and a multi-modal approach. Single-modality - Surgery alone confers the highest survival rate [1] Musy et al report a 64% survival rate in patients who underwent surgery compared with a 25% survival rate in those who received definitive radiotherapy ± chemotherapy [2].

10. Surgery or Radiation??? Yoshida et al. 16 patients Median survival Surgery + Postoperative RT-CT: 30 months Surgery alone: 7 months Definitive RT-CT: 9 months 2 year Loco-Regional Control Surgery + Postoperatie RT-CT: 78% Surgery alone: 37% Definitive RT-CT: 18% 2 year cumulative harard function: Risk of local recurrence after 1 year less with Surgery + RT-CT

11. Al-Mamgani et at (Less T4 cases) 5 year overall survival: 74% Disease Free Survival: 64% Local failure risk is increased with bimodality treatment than trimodality treatment Surgery: Better Local Control (85% Vs 25%) Surgery or Radiation???

12. Musy et al. Residual tumour in 70% of surgical specimens after primary chemoradiation.

13. Meta-analysis Reiersen et al. 167 patients Chance of survival Surgery + radiation and/ or chemotherapy: 260% (OR = 2.6; 95% CI, 0.82-7.87) Presence of neck metastases was also a poor prognostic sign.

14. The combination of radiotherapy with surgery is superior, compared to radiation alone [1]. Complete surgical resection with post-operative radiation therapy is considered the mainstay of sinonasal cancer treatment [2]. 1.Jansen EP, Keus RB, Hilgers FJ, Haas RL, Tan IB, Bartelink H. Does the combination of radiotherapy and debulking surgery favor survival in paranasal sinus carcinoma? Int J Radiat Oncol Biol Phys. 2000;48(1):27–35. 2.Llorente JL, Lopez F, Suarez C, Hermsen MA. Sinonasal carcinoma: clinical, pathological, genetic and therapeutic advances. Nat Rev Clin Oncol. 2014; 11(8):460–72.

15. Radiation • Sx + Conventional RT Local Control 59% Overall survival 40% at 5 years [1] • Conventional radiation Loss of vision in 1/3rd patients [2,3] 1.Dulguerov P, Jacobsen MS, Allal AS, Lehmann W, Calcaterra T: Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review. Cancer 2001, 92:3012-3029. 2.Parsons JT, Mendenhall WM, Mancuso AA, Cassisi NJ, Million RR: Malignant tumors of the nasal cavity and ethmoid and sphenoid sinuses. Int J Radiat Oncol Biol Phys 1988, 14:11-22. 3.Shukovsky LJ, Fletcher GH: Retinal and optic nerve complications in a high dose irradiation technique of ethmoid sinus and nasal cavity. Radiology 1972, 104:629-634.

16. Various planning studies were already able to demonstrate that patients with sinunasal tumours highly profit from modern RT-techniques

17. 1987 – 2005 : 85 patients Post operative radiation 50% T4 lesion Median Radiation Dose: 63 Gy Median follow up: 60 months 5 year eatimate Local PFS: 62% Regional PFS: 87% Distant Metastasis FS: 82% Disease Free Survival: 55% Overall Survival: 67% IMRT Grade 3-4 late complication NONE

18. 1998-2004: 36 patients 89%: Adjuvant radiation Median Follow Up: 51 months Local Control 2 year: 62% 5 year estimates: 58% 5 year DFS: 55% OS: 45% No decreased vision recorded Minimal late toxicity

19. 32 patients Median follow up 15 months No corneal injury Dry eye symdrome: mild No grade 3 or 4 toxicity

20. Role Of Radiation Radiation Neo-Adjuvant (Musy et al) Adjuvant (Tanzler et al) Definitive (Tanzler et al) Median Dose 50 Gy 64.8 Gy 70.8 Gy Range 50-54 Gy 62.4-74.4 Gy 70-74.8 Gy

21. Evolution of Radiation Oncology Intensity Modulated Radiotherapy (IMRT) Volumetric Modulates Arc Therapy (VMAT) Image Guided Radiotherapy (IGRT) Image Fusion

22. MRI Fusion

23. PET CT Scan Fusion

24. Non-Operated GTV – MRI CTV Flanked by intact bone or cranial nerve – No margin Invades compartment – Whole compartment Invades radiologically defined space (Parapharyngeal, masticator) – Entire space or 0.5 to 1.0 cm margin Orbit – Whole or Medial part (including rectus medialis muscle) Intra cranial – Incude meningeal structures or cranial fossa PTV – 3 to 5 mm margin to CTV No elective nodal irradiation (Except T3 T4 Maxilla and Undifferentiated) Target Delineation

25. Complete Surgery GTV – Edge of resection margin CTV – Resection cavity + Variable Margin COMPARTMENTAL CTV Target Delineation

26. Planned Risk Volume (PRV) Optic chiasm, optic nerve, retina, lactimal glands, pitutary, brainstem, brain, mandible, parotid gland MRI – Posterior part of optic nerves, optic chiasm, pitutary gland Optic Pathway – 2mm isotropic expansion Brainstem – 3mm isotropic expansion

27. Dose Contraint PTV 70 Gy in 35 fractions (Definitive) 60 Gy in 30 fractions (Adjuvant) Acceptable minimum (Dmin) – 5% of precribed dose >5% underdosage – Overlaping with critical structures Dose Maximum – Must be under PTV Overdosage – 7% - ICRU guideline

28. PRV 60 Gy to D-95 95% of the Volume of the structures has to receive 60 Gy or less Very HARD to achieve Dry Eye Syndrome 30 Gy to major lacrimal gland Pitutary Gland Hormonal substitution not required below 50 Gy Dose Contraint

29. Brain Maximum dose constraint of 70Gy to a 2cm rind of brain tissue flanking the PTV. Complemented by 50 Gy dose maximum constraint for brain tissue outside the rind. Mandible 70 Gy dose maximum constraint is proposed after good dental care Parotid glands 26 Gy maximum of the mean dose is consistent with preservation of function Dose Contraint

30. Case

31. Adaptive Radiation T4 lesions

32. Recent Advances

33. Take Home Message